THERAPEUTIC

New Natural Products Cancer Chemotherapy William

Four

MD,

and

Daniel

D. Von

in Hoff,

MD

natural products are reviewed. Taxol is It promotes the formation of microtubule bundles interfere with mitosis. Although phase II efficacy in the treatment of patients with ovarian carcinoma with non-small cell lung cancer and melanoma. It remains untested against several other neoplasms. The chief toxicities of taxol are myelosuppression, mucositis, anaphylactoid reactions, and peripheral neuropathy. Homoharringtonine is the most active and abundant of the cephalotaxine esters derived from the genus Cephalotaxus. This agent appears to act at the ribosome to inhibit protein synthesis and has clinical activity in patients with acute myelogenous leukemia. The dose limiting toxicities of homoharringtonine are hypotension and myelosuppression. SKF 104864 and CPT-11 are derivatives of camptothecin which are still in early clinical trials. They are cytotoxic in vitro, acting through an interaction with topoisomerase Ito induce DNA fragmentation. The spectra of activity and toxicity of SKF 104864 and CPT-1 I are still undefined. All four of these new natural products offer possibilities for clinical activity for patients with a variety of malignancies.

derived

new

J. Slichenmyer,

REVIEW

and

clinically relevant antineoplastic the bark of the western yew. which deform the cytoskeleton and testing is incomplete, taxol is effective and has some activity in patients

from

T

raditional and folk medicine have long used plant products for therapeutic purposes. Several natural products have been found to have antitumor properties. The ymca alkaloids are among the best known in this class, but more than 15 families of alkaloids with antineoplastic activity have been described.1-3 In this review we will discuss four new plant-derived antineoplastic drugs that are currently in clinical trials. TAXOL Chemistry

and Derivation

Taxol was first described in 1971 by investigators the laboratory of Monroe Wall of the Research angle Institute, Research Triangle, NC.4 They lated taxol from the stem bark of the western Taxus brevifolia, and described its structure Figure). Study of natural and semisynthetic

in

Triisoyew, (See con-

From the Division of Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, and Cancer Therapy and Research Center, San Antonio, Texas. Supported by NIH Training Grant #CA09434 and NCI Contract #CM57737. Address for reprints: Daniel D. Von Hoff, MD, Division of Oncology, Department of Medicine, University of Texas, Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7884.

770

#{149} J ClIn Pharmacol

1990;30:770-788

geners of taxol has demonstrated that an intact taxane ring and an ester side chain are required for cytotoxicity.5 The western yew is the best known source of taxol.6 This evergreen plant has a dwindling population that grows wild in the northwestern US and western Canada. Approximately three thousand trees must be sacrificed to produce one kilogram of taxol, or roughly one tree for each treatment.7 Efforts to synthesize taxol are underway,8’9 and growth of Taxus brevifolia in tissue culture or cultivation of the tree may provide increasing supplies in the future.7 Clinical trials are limited by scarcity of the drug. Mechanism

of Action

Taxol promotes the formation of microtubules from tubulin. The drug binds to tubulin dimers,1#{176}reduces the critical concentration of tubulin required for polymerization and increases the yield and rate of polymerization.11’12 Taxol allows microtubule assembly under unfavorable conditions,136 and these microtubules are abnormally resistant to depolymerization.”’17 The interactions of taxol and microtubules have been extensively reviewed elsewhere.5’18

NATURAL

IN

PRODUCTS

CHEMOTHERAPY

OCOCH, 0

C,H,CONH

0

C,

Ho-C-(cH,),C-C CH,CH,O OCOCI H,

Ill

0

0-cM,

C-O-CH,

Taxol

II

0

Homoharringtoriine

Camptothecin

CPT-11

SK&F

Figure.

Chemical

structures

of New

104864-A

Natural

Products

Cells exposed to taxol have abnormal cytoskeleton morphology. Electron microscopy demonstrates large bundles of microtubules within the cytoplasm and rough endoplasmic reticulum in a variety of cell lines.19-22 Immunofluorescence and electron microscopy study of human leukemia cell lines suggest that microtubule bundling correlates with cytotoxicity.23’24 In sensitive leukemia lines, these changes are irreversible, but in relatively resistant lines, the bundles resolve after taxol is removed from the medium.23 The cytotoxicity of taxol is probably related to microtubule-mediated interruption of mitosis. The cell cycle is blocked at the G2 or M phase after taxol exposure.25’26 The mitotic spindle is distorted by taxol-induced microtubule cross bridging and bundling,27-29 which leads to loss of spindle polarity and chromosome breakage. Analysis of the cell cycle kinetics of leukemic cells in mice supports the role of taxol as an inhibitor of mitosis.3#{176} Other mechanisms may account for taxol cytotox-

THERAPEUTIC

REVIEW

in cancer

Chemotherapy.

icity. Cell cycle populations in human leukemia suggest that taxol kills cells during interphase.23 This may be related to inhibition of DNA synthesis by taxol,31’32 to inhibition of cell migration,25 or other yet unrecognized mechanisms. Taxol has significant antineoplastic activity in preclinical studies. Numerous cell lines and human tumors implanted into nude mice are sensitive to taxol.3336 Furthermore, clinical studies have now confirmed that patients with a variety of malignancies have responded to treatment with taxol. Phase

I Clinical

Trials

of Taxol

(See

Table

I)

An early phase I trial with taxol used a 3-hour infusion every 3 weeks.37 Seventeen patients were treated with doses ranging from 15 to 230 mg/rn2. Three of five patients treated with doses greater than 185 mg/rn2 suffered anaphylactoid reactions with dyspnea and hypotension. One of these patients died

771

SLICHENMYER

AND

VON

HOFF

TABLE I Taxol Phase I Clinical Trials Recommended Dose Schedule

Once Once Once Daily Daily Daily Once Once Once Once Once

every every every X5 q X5 q X5 q every every every every every

3 weeks 3 weeks 3 weeks 4 weeks 4 weeks 3 weeks 3 weeks 3 weeks 3 weeks 3 weeks 2-3 wks

Infusion

Duration

3 hours

1 6 1 6 1 6 6 24 24 24

Dose LImiting

Phase II Dosage

hour hours hour hours hour hours hours hours hours hours

Toxicity

Reference

N/A

Hypersensitivity

N/A 212* N/A 30 X5 ci 30 X5 d 225

250

Hypersensitivity Leukopenia Hypersensitivity Leukopenia Leukopenia Myelosuppression Neuro/leukopenia

170

Leukopenia

250

Neuropathy Mucositisf

315

MSK (37) JH (38) JH (38) WCC (40) WCC (40) MDA (39) SA (41) AE (42) MSS (43) AE (44) JH (24)

MSK = Memorial Sloan-Kettering; JH = Johns Hopkins Oncology Center; WCC University of Wisconsin Clinical Cancer Center; MDA = M. D. Anderson Hospital & Tumor Institute; SA = University of Texas Health Science Center. San Antonio; AE = Albert Einstein Cancer Center; MSS = Mount Sinai School of

Medicine, NY. * Lower dose recommended for patients with prior chemotherapy. t This study treated only patients with leukemia. Leukopenia was a desired effect of treatment.

as a result of the reaction. Mild myelosuppression was observed. No clinical antitumor responses were observed in this study. Another phase I study encountered problems with hypersensitivity reactions during treatment with taxol.38 This protocol initially used a 1-hour infusion to be given every 3 weeks. The hypersensitivity reactions became less severe when the infusion was slowed to run over 6 hours and the patients were pretreated with prednisone, diphenhydramine, and cimetedine. Leukopenia was the dose limiting toxicity, and the recommended phase II doses were 170 mg/rn2 in heavily pretreated patients and 212 mg/rn2 for patients with minimal prior therapy. Clinical improvement was seen in a patient with lung adenocarcinoma and another with ovarian carcinoma. One-hour infusions were given daily for 5 days in another phase I study.39 No premedications were administered and no anaphylactoid reactions were observed. Leukopenia was the major toxicity and the recommended phase II dose was 150 mg/rn2 divided over 5 days. No responses were observed. Another study started with rapid infusions but changed to a slower rate of infusion with steroid and antihistamine pretreatment after observing anaphylactoid reactions.4#{176} With a 6-hour infusion, the maximum tolerated dose was 150 mg/rn2 divided over 5 consecutive days. No antitumor responses were observed among the 16 treated patients. A 6-hour infusion every 21 days without premedication was administered without severe hypersensi-

tivity sion mum

772

#{149} J ClIn Pharmacol

1990;30:770-788

reactions was the tolerated

recommended

sponses

in another dose limiting dose was phase

were

carcinoma

34

II dose

observed of

lung

noma of unknown tients. A similar schedule patients.42

Four

study.41 Myelosupprestoxicity and the maxi275 mg/m2, with the 225

mg/m2.

in a patient and

another

primary, was of the

with

from used first

re-

squamous adenocarci-

a total

in another 13

Partial

with

courses

of 30 pastudy were

for com-

by severe hypersensitivity reactions, and premedication with dexamethasone, diphenhydramine, and cimetedine were added for the remaining 70 courses. The recommended phase II dose was 250 mg/m2. Minor responses were seen for a patient with gastric carcinoma and another with ovarian cancer. Another patient with adenocarcinoma of unknown primary had improvement of ascites for 6 months after treatment. A phase I study administered taxol for a 24-hour infusion without premedication.43 No hypersensitivity reactions were observed, and leukopenia was dose limiting at 170 mg/rn2. Among ten patients, one with colon cancer had a transient decrease in tumor plicated

mass

and

another

patient

with

head

and

neck

carci-

had shrinkage of a neck nodule. A 24-hour infusion was used with premedication in another phase I study.44 No severe hypersensitivity reactions were noted. Peripheral neuropathy was the dose limiting toxicity and significant neutropenia was also noted. Twenty-six patients were treated, and partial responses were observed in four noma

NATURAL

PRODUCTS

of 12 with melanoma. The recommended phase II dose was 250 mg/rn2. Mucositis was the dose limiting toxicity in a phase I study for patients with refractory acute leukemia.24 A 24-hour infusion was given with premedication. The maximum tolerated dose for patients with leukemia was 390 mg/rn2 and the recommended phase II dose was 315 mg/rn2. Three of seventeen patients had complete clearance of blasts from the marrow. Clinical response correlated with in vitro microtubule bundling. The dose of taxol correlates with antitumor and toxic effects. Low doses tend to produce few and mild side effects without clinical responses. Phase I studies have determined that the doses to be administered in clinical phase II studies should be 250 mg/rn2 for patients with solid tumors42’44 and 315 mg/rn2 for patients with refractory leukemia.24 Because prior chemotherapy or radiotherapy sensitizes a patient to the myelotoxic effects of taxol, another author recommends 212 mg/rn2 or 170 mg/rn2, respectively, for patients with minimal or extensive prior treatment.38 Good results have been obtained for ovarian carcinoma with doses of 250 mg/rn2 or 200 mg/rn2, depending upon the degree of pretreatment.45 The optimal schedule for dosing is controversial. Early phase I studies employed brief daily infusions for 5 consecutive days, but this schedule has been abandoned due to toxicity despite low serum drug levels and the absence of clinical responses.39’4#{176} The most severe aspect of this toxicity was hypersensitivity reaction, so the duration of infusion was lengthened to 24 hours. The slower infusion rate and pretreatment with prophylactic agents seem to have reduced the incidence and severity of this complication, but this has not been rigorously proven. Twenty-four-hour infusions every 3 weeks have obtained good results.45’44 A shorter infusion time offers the theoretical advantage of higher peak serum levels of drug.42 Clinical

Activity

Malignancies

(See

of Taxol Against Table II)

Specific

Taxol is effective in the treatment of patients with ovarian cancer. This was first reported in phase I trials.42’38 A phase II study of forty evaluable patients with advanced, progressive, and drug-refractory ovarian cancer obtained favorable results.45 These patients were treated with a 24-hour infusion every 3 weeks with dexamethasone, diphenhydramine, and ranitidine premedication. The initial dose was 250 mg/rn2 for patients who had received only a single previous chemotherapy regimen and 200

THERAPEUTIC

REVIEW

IN

CHEMOTHERAPY

TABLE II Types of Tumors Responding to Taxol (For References, Refer to Text) Ovarian carcinoma Gastric carcinoma Colon carcinoma Adenocarcinoma, unknown primary Squamous carcinoma of head and neck Malignant melanoma Acute lymphocytic leukemia Acute myelocytic leukemia

mg/m2 for patients who had received chemotherapy plus radiotherapy or more than one chemotherapy regimen. This protocol obtained one complete response and 11 partial responses for an overall response rate of 30%. These findings contrast with a response rate of 6% for other salvage regimens in ovarian cancer.46 A phase II trial of taxol for patients with malignant melanoma obtained two complete responses and three partial responses for an overall response rate of 18%. One of the complete responses lasted for longer than 14 months and one of the partial responses lasted longer than 10 months. In addition, two patients with minor responses and two with stable disease were identified. These patients were treated every 3 weeks with 250 mg/rn2 over a period of 24 hours with premedication and neutropenia was the major toxicity. Partial responses of patients with malignant melanoma have also been reported from a phase I study.44 Patients with renal cell carcinoma were treated with taxol in a phase II study.48 A 24-hour infusion of 250 mg/rn2 with premedication was given every 3 weeks. Of eighteen patients treated, no responses were observed. Taxol at this dose and schedule appears to be ineffective in the treatment of renal cell carcinoma. Several phase I studies with taxol have obtained sporadic responses in patients with a variety of malignancies. These include acute lymphocytic and myelocytic leukemias,24 lung adenocarcinoma,38 lung squamous carcinorna,41 adenocarcinoma of unknown primary,41’42 colon cancer,42’43 metastatic gastric carcinoma,42 head and neck carcinoma,43 and sarcomas.39 Clinical

Pharmacology

The pharmacokinetics sively studied.24’4042’44’49

(See

Table

III)

of taxol have Pharmacokinetic

been

extenstudies

773

SLICHENMYER

TABLE Taxol

Pharmacology

Volume Protein

(For

Ill

References, 60 L/m2 97.5% 0.27-0.52 2.9-16.5 5%

of distribution bound

ti,2

t1,2 Urinary Peak

clearance serum

levels

Refer

to Text)

hr hr

up to 10 micromolar

using high performance liquid chromatography methods have found that peak serum levels and area under the curve are proportional to the dose, and are reached at the end of infusion.42 The drug is 97.5% protein bound44 and the volume of distribution is 60 L/m242 to 167 L/m2.41 The half-life for distribution is between 0.27 and 0.52 hours and for elimination has a range of 2.9 to 16.5 hours.24’41’42’49 Approximately 5% of the total dose is excreted in the urine.42”’49 Serum metabolites have not been found.49 Taxol in ascites reaches its peak level 15 hours postinfusion, and then remains approximately 40% higher than the serum level.42 Taxol was undetectable in the cerebrospinal fluid of one patient tested at the end of an infusion.24 Peak serum levels vary from 1.5 to 10 smol/L, depending on dose.24’42’49 Leukemic blasts develop microtubule bundles in vitro when exposed to 0.1 zmol/L taxol.24 Leukemia patients who are clinically unresponsive to taxol tend to have in vitro unresponsiveness of their blasts at low taxol concentrations. Such testing may have a role in the evaluation of patients prior to consideration for taxol therapy.24 Toxicities

of Taxol

(See Table

IV)

The toxicities of taxol have been described in several phase I studies.24’3740’42’ The most frequently encountered are hypersensitivity reactions, leukopenia, peripheral neuropathy, mucositis, and alopecia. Other important side effects have also been noted, and new ones continue to be recognized. An anaphylactoid-type hypersensitivity reaction is the most dramatic side effect of treatment with taxol. (See Table V) The usual onset is within a few minutes of initiating treatment, and can vary from fever and rash to bronchospasm, hypotension, and death.37 Life-threatening reactions require resuscitation with intubation, oxygen, fluids, and pressors.5#{176} It is now common practice to premedicate patients with steroids and antihistamines prior to receiving taxol. One such regimen uses dexamethasone 20 mg

774

#{149} J CIln Pharmacol

1990;30:770-788

AND

VON

HOFF

orally 14 and 7 hours prior to treatment and diphenhydrarnine 50 mg and ranitidine 50 mg intravenously 30 minutes before the infusion.45 Similar pretreatment reduces the incidence of severe anaphylactoid reactions from radio contrast media.51 A recent clinical trial showed that taxol can be given safely without prernedication for a 6-hour infusion.41 In this phase I study, the infusion was started at a slow rate for the first 30 minutes. If no adverse effects were noted, the rate was increased for the next 5#{189} hours. Of 30 patients treated, only one had a hypersensitivity reaction. For this patient, premedication was given and she subsequently received taxol without complications. The hypersensitivity reactions are probably related to the emulsifying vehicle in which taxol is dissolved. Cremophor EL is derived from castor oil, and is known to induce histamine release and anaphylactoid reactions n administered intravenously to dogs.52 Intradermal injection in humans causes a wheal and flare type of response.53 Cremophor is also implicated in anaphylactoid reactions with cyclosporine and teniposide.57 Leukopenia after taxol therapy is sporadic and dose-related. Some patients treated at high doses encounter only low-grade marrow suppression, while others have leukopenia as the dose limiting toxicity.38’39’42’43 One patient had four sequential treatments at the same dose, and suffered myelotoxicity grades 4, 0, 2, and 1 in succession.42 Leukopenia tends to be more severe in patients who have

TABLE Taxol

Toxicities

IV

(For References,

Refer

Dose-limiting Leukopenia

Mucositis Frequent Peripheral Alopecia

neuropathy

Myalgias Malaise

Sporadic Hypersensitivity

Thrombocytopenia Nausea Diarrhea Phlebitis Atrioventricular block Seizure Weakness Pulmonary lipid embolism Adynamic ileus

to Text)

NATURAL

PRODUCTS

IN

TABLE Role of Dose Infusion Time (hr)

Center

Schedule

and Premedication

Premedicated?

CHEMOTHERAPY

V

in Taxol-Related Hypersensitivity Grades 3-4

Hypersensitivity

Reactions (Number)

Reactions

Number of Patients Treated

Reference

1

JH

N

3

16

1 (SD)

WCC

N

2

1 (SD)

MDA

N

0

3

MSK

N N

3 1 4 0 1 0 0 0

9 20 17 30 6 10 14 7 28 26

(38) (40) (39) (37) (41) (42) (43) (38) (40) (42) (44)

6 6 24 6 6 (SD) 6

24 24 24

24

24

SA AE

N

MSS JH WCC AE AE

N V Y V V

JH

V

1

17

(24)

JH AE ECOG

V V V

0 0 4

47 18 34

(45)

MSK = Memorial Sloan-Kettering; JH = Johns Hopkins Oncology Center; WCC = University of Wisconsin Clinical Cancer Canter; MDA = M, D. Anderson Hospital & Tumor Institute; SA = University of Texas Health Science Center, San

Antonio; AE = Albert Medicine, NY; ECOG given over 5 days.

had extensive prior chemotherapy and/or radiotherapy.38 Mild thrombocytopenia has been noted, and anemia has not been a serious problem for patients. Peripheral neuropathy is a major side effect of taxol. Paresthesias and hyperpathia occur in a glove-stocking distribution.38’42 This complication is rare at taxol doses less than 200 mg/m2,58 although some patients treated at high doses of taxol have no neurologic abnormalities at all.42 The neuropathy does not appear to be an effect additive to cisplatinum neurotoxicity, and taxol therapy has been associated with resolution of symptoms of a patient with platinum neuropathy.45 Nerve conduction studies suggest that the lesion is both axonal and demyelinating in nature.58 Sural nerve biopsy from a patient with symptomatic taxol-induced neuropathy showed only subtle changes suggestive of rernyelination and no microtubule abnormalities.42 The neuropathic symptoms tend to resolve spontaneously several weeks after completion of taxol therapy.24’42’44 Uncommon neurologic abnormalities reported after taxol therapy include diplopia,38 seizure,45 proximal muscle weakness,58 fine motor weakness,38 and adynarnic ileus.44 A rat model of taxol peripheral neurotoxicity involves repeated injection of the sciatic nerve. This produces loss of Schwann cells and axonal microtubule bundles in formation.5961 These structures are

virtually

THERAPEUTIC

REVIEW

=

Einstein Eastern

Cancer Center; MSS Cooperative Oncology

(47) (48) =

Mount Sinai School of Split Dose, G roup; SD

identical to the bundles observed in Remyelination is greatly retarded or prohibited by taxol in this model. Nerve growth factor diminishes the severity of in vitro taxol neurotoxicity.65 The relevance of this model to human taxol neurotoxicity is unproven. Mucositis is a potentially severe complication of taxol therapy. In a study of patients with leukemia, mucositis was the dose limiting nonhematologic toxicity.24 Mucositis can be severe and life-threatening even at lower doses,38 but for most patients is mild to moderate.38’42’ Alopecia occurs in almost all patients treated at doses above 150 mg/rn2.24’38 The hair loss is unusually abrupt and involves all body hair, not just the scalp. The alopecia is reversible with time.38 Other toxicities include mild nausea, vomiting, and diarrhea. A-V block has been reported in two cases, one of which required placement of a pacemaker.45 A case of fatal pulmonary lipid embolism associated with taxol administration has been reported in a patient taking corticosteroids and without known fractures.66 Elevations of serum triglyceride levels after taxol have been reported37 and may be related to lipid embolism. Local phlebitis and cellulitis are associated with soft tissue infiltration of taxol.38’42 Moderate to severe myalgias and arthralgias commonly arise in the shoulders and paraspinal region on the second or third posttreatment day.24 vitro.62

775

SLICHENMYER

Despite these toxicities, patients may feel better when treated with taxol. A quantitative self assessment of symptom severity by patients67 found that symptoms are less severe during and after taxol treatment than before.42’ A statistically significant improvement in measured “outlook” (as scored by each patient) was also noted after taxol.68 Summary Taxol is a potent promoter of microtubule polymerization. Its pharrnacokinetics are well described. It is effective for the treatment of patients with ovarian carcinoma and perhaps other malignancies. The dose limiting toxicities are myelosuppression, mucositis, peripheral neuropathy, and anaphylactoid reactions. New methods of production are needed to increase the supply of taxol so additional definitive clinical trials can be performed. HOMOHARRINGTONINE Chemistry

Homoharringtonine (HHT) is a drug derived from the bark of several species of the evergreen tree genus Cephaiotaxus. These trees are indigenous to Asia, and the bark has long been used in Chinese traditional medicine for a variety of indications. Several alkaloids have been separated from the bark. The agents that have cytotoxic activity are all esters of cephalotaxine; these include harringtonine, hornoharringtonine, isoharringtonine, and deoxyharringtonine.69 Research efforts have focused on hornoharringtonine because it is the most abundant and most potent of this family of drugs.7#{176} The structure of homoharringtonine is shown in the Figure. Homoharringtonine was first isolated and characterized by Powell and colleagues.71 Spencer later identified the different alkaloids with GC mass spectrometry.72 Correlation of structure and activity was determined by nuclear magnetic resonance (NMR) with in vivo study.69 Mechanism of Action of Homoharringtonine

and

Preclinical

Activity

Homoharringtonine is thought to act at the ribosome to inhibit protein synthesis. This was first suggested by Huang in 1975 who observed that homoharringtonine causes degradation of polyribosomes in HeLa cells.73 He also noted release of globin chains from rabbit reticulocytes and inhibition of DNA synthesis. Others thought that these effects were probably secondary to inhibition of protein synthesis.74 DNA,

776

#{149} J Clin Pharmacol

1990;30:770-788

AND

VON

HOFF

RNA and protein synthesis are all inhibited by HHT in a dose-dependent manner.75 Further study showed that homoharringtonine detaches ribosomes from rough endoplasmic reticulum with formation of endoplasmic reticulum whorls.75 Fresno showed that the initiation step of protein synthesis proceeds normally but early peptide elongation (i.e., peptide bond formation) is inhibited by HHT.76 This is analogous to the action of macrolide antibiotics on bacteria. Homoharringtonine is tightly bound to microsomes, and sensitivity of cells to HHT is proportional to the amount of uptake of drug by the cell.76 Cytotoxicity is proportional to the degree of inhibition of protein synthesis.77 The degree of inhibition of DNA synthesis and protein synthesis in leukernic blasts correlates with clinical response and may provide an assay

for

prediction

of response

prior

to

selection

of

patients for treatment with HHT.78 Homoharringtonine has cell-cycle specificity. It can arrest cell growth in G1.79 Cytotoxicity is greatest during Gi and G2, and one author proposed that HHT might be clinically more useful for tumors that grow slowly and have more cells in G1.8#{176} Other investigators have found that HHT is more effective in vitro against leukemia-lymphoma cell lines that divide rapidly than against their slower growing counterparts. Furthermore, they found that the cytotoxicity of HHT depends more upon duration of exposure than upon concentration of drug.74’81 Recent data suggest that other mechanisms may be important. Homoharringtonine has been shown to inhibit glycosylation of proteins with accumulation of dolichol-linked oligosaccharides in a human bladder cancer cell line.82 Homoharringtonine may act as a prodifferentiating agent, perhaps through down-regulation of c-myc expression.83-85 One study showed that HHT is synergistic with 5-fluorouracil versus P388 cells.86 This was contradicted by another investigator who found no synergy with a variety of agents, including 5-fluorouracil.87 Cells resistant to vincristine and doxorubicin are also resistant to HHT, but cells resistant to Ara-C are sensitive to HHT.88 Resistance of neuroblastoma cells to HHT can be reversed by cyclosporin A.89 Homoharringtonine exhibits antineoplastic activity in preclinical studies. These have been well summarized by O’Dwyer.9#{176} Limited activity of HHT was shown against human tumors explanted into mouse renal cortex, especially for lung, ovarian, and cervical carcinomas. No activity was seen against colorectal carcinoma.91 Histologic study of Colon 38 tumor in mice showed extensive tumor necrosis only 24 hours after exposure to HHT.92 This contrasts with a lag time of several days until histologic

NATURAL

change is evident DNA synthesis. Early Chinese Homoharringtonine

after

Clinical

exposure

Studies

PRODUCTS

to inhibitors

IN

of

formance status and caused the death of one patient treated with a dose of 11.5 mg/rn2. Hypotension was not related to arrhythmias. The maximally tolerated dose on this schedule was 9.0 mg/m2. One partial response was noted for a patient with prostatic carcinoma. Hypotension was also the dose limiting toxicity in another phase I study.97 Forty-three patients were treated with daily 1-hour infusions for 5 days at intervals of 3-4 weeks. The dose ranged from 0.2 to 8.0 mg/m2/d. Hypotension was dose-related and resulted in cardiovascular collapse in four of 16 patients treated with doses of 5.0-6.0 mg/m2/d. Mild myelosuppression was noted in patients who had not received prior treatment. For other patients, the extent of prior chemoradiotherapy correlated with the severity of myelosuppression. Minor responses were noted in a patient with metastatic breast cancer and another with ovarian carcinoma. A patient with large cell lymphoma had a 50% reduction in a cervical lymph node but no improvement of tumor infiltrating the marrow. Three of five patients with acute leukemia had clearance of circulating blasts after treatment. Another phase I study administered HHT by intravenous bolus once daily for 5 days, repeated every

of

Antileukemic activity of cephalotaxine esters has been recognized for many years by the Chinese.93’ Their data are difficult to extrapolate to Western standards, as the patients were treated with unpurified HHT that contained some harringtonine and other cephalotaxine esters. Furthermore, the Chinese definitions of remission and relapse are differ from those of the West. Nonetheless, the Chinese data suggest that HHT is effective for remission induction in patients with acute myelogenous leukemia (AML). A Chinese study of HHT in combination chemotherapy with Ara-C, vincristine, and prednisone for patients with acute nonlymphoblastic leukemia (ANLL) reportedly caused an 82% complete response rate.95 Although this is a very high response rate, the role of HHT in the combination is unclear because this study did not include a control group. Phase I Clinical (See Table VI) An

early

Studies

phase

I study

with

in

the

Homoharringlonine

United

States

28

treated

3.5

TABLE Homoharringtonine

Daily Daily Daily Daily Once

x5 days X5 days X5 days X10 days q 21 days

Continuous Continuous Continuous Continuous Continuous * Pediatric

MSK Institute;

Infusion

=

infusion infusion infusion infusion infusion patients

THERAPEUTIC

1 hour 10 minutes Bolus 6 hours

3,0

90 minutes 5 days 5 days 5-10 days 10 days 30 days

N/A 3.25 x5 3,5 x5 7.0 X10 4.0 x10 1,0 x30

REVIEW

Hospital Vermont

& Tumor Regional

ranged

The

I Clinical

from

authors

1.0

to 5.8

mg/m2/d.

changed

their

delivery

Trials Dose Limiting Toxicity

X5 N/A N/A N/A

Cancer MDA M. D. Anderson of Medicine, NY; VRC =

dose

mg/m2/d.

Recommended Phase II Dose

Duration

The

VI

Phase

only.

Memorial Sloan-Kettering; MSS = Mount Sinai School

days.98

Hypotension was not observed in these patients, and mild leukopenia and thrombocytopenia were the chief toxicities. No responses were reported. Hypotension was observed for five times after daily bolus injections in yet another phase I study.99 The maximum tolerated dose for these patients was

30 patients with a single infusion of homoharringtonine given over a period of 90 minutes every 21 days.96 The dose limiting toxicity was hypotension, which was more severe in patients with poorer per-

Dose Schedule

CHEMOTHERAPY

Center;

Center

Reference

hypotension hypotension myelosuppression hypotension

MDA VRC UMC MSS

(98) (100)

hypotension myelosuppression myelosuppression pain myelosuppression myelosuppression

OSU MSK VRC MSK* MSS MDA

(96) (101) (99) (103) (100) (102)

UMC

=

University

of Maryland

Cancer

(97)

(99)

Center;

OSU

=

Ohio State

University.

777

SLICHENMYER

AND

schedule to continuous infusion for 5 days with lessening of the severity of the hypotension and development of mild myelosuppression. No antitumor responses were noted among 29 patients, including one with lymphoma, one with multiple myeloma, and the remainder with a variety of solid tumors. Comparison of intermittent versus continuous infusions was made in another study.10#{176}For patients given daily infusions over 6 hours for 10 days, hypotension and cardiovascular complications were seen in 14 of 22 courses, especially at doses of more than 2.0 mg/m2/d. For the patients treated with continuous infusion for 10 days, only two of four courses were interrupted due to cardiovascular complications, while leukopenia and thrombocytopenia were significant toxicities. No antitumor responses were reported. The maximally tolerated dose by continuous infusion over 10 days for patients with solid tumors was 4.0 mg/m2/d. Investigators at Memorial Sloan Kettering, New York, conducted a trial using a schedule of continuous infusion for 5 days.101 The dose ranged from 0.2 to

3.75

mg/m2/d

and

the

dose

limiting

A continuous

Schedule Single

agent

and Dose

Phase II Leukemia Homoharringtonine Warrell HHT

778

in children

found

with

a maximally

re-

toler-

for 10 days.103 Hypotendose-limiting toxicities. No induced in the 17 children

the were

has to treat

Studies with (See Tables

used

continuous

patients

with

VII and infusion

AML.104

VIII) single-agent

Seven

of 28 pa-

tients had a complete response (CR), including 4 of 10 who had been refractory despite heavy pretreatment. No CRs were seen at 5.0 mg/m2/d X 5 d, but were observed at 7.0 mg/m2/d X 7 d and at 5.0 mg/m2/d X 9 d. No CRs were obtained among ten patients with acute lymphocytic leukemia (ALL) or three with secondary (postchemotherapy) AML. Similar data were obtained from Arlin’s group who reported seven CRs among 34 evaluable patients with AML in relapse.105’106 These patients were treated with 5.0-7.0 mg/m2/d X 7-9 d, and the responses were sustained for 1-7 months. The time to complete response was 35-85 days. Two of the CRs were in patients who had failed prior therapy with daunorubicin or amsacrine. Two who failed HHT subsequently obtained a CR after treatment with daunorubicin or amsacrine.105’106 Low dose HHT by continuous infusion (2.5-3.0 mg/m2/d) for 15-21 days induced one complete remission among 31 patients with AML.107 Three patients had normalization of marrow and peripheral blood with persistent thrombocytopenia. An Eastern Cooperative Oncology Group (ECOG) study of 20 patients with refractory AML found no complete responses when treated with 3.5 mg/m2/d for one day followed by 6.0 mg/m2/d for days 2 through 8.108

VII

for Patients

with Acute

Number of Patients Evaluable

Myelocytic

Leukemia

Complete Response CR (%)

Reference

homoharringtonine

CI, variable CI, 5-7 mg/m2/d x7-9 d CI,5mg/m2X7d Cl, 7 mg/m2/d X7 d or 5 mg/m2/d x9 d CI 3.5 mg/m2/d xl d, then 6.0 mg/m2/d X7 d CI, 2.5-3.0 mg/m2/d X15-21 d * Phase

study

studied.

toxicities

Trials

infusion

sion and pain were marrow remissions

TABLE Clinical

HOFF

fractory acute leukemia ated dose of 7.0 mg/m2/d

were leukopenia and thrombocytopenia. Thirty-one patients were treated. Six had lymphoma and the remainder had a variety of solid tumors. No responses were observed. Another trial of homoharringtonine by continuous infusion treated 48 patients for 30 days each.102 Myelosuppression was severe and prolonged for some of the patients. The recommended dose on that schedule was 1.0 mg/m2/d. One patient with blast phase chronic myelogenous leukemia (CML) had clearing of peripheral and marrow blasts but died before marrow recovery. Another patient with rectal adenocarcinoma had over 50% shrinkage of a large pelvic mass but eventually progressed after an unspecified time.

Homoharringtonine

VON

I trial in children.

#{149} J Clin Pharmacol

8

Cl

1990;30:770-788

=

0 (0)

(103)*

44

7 (16)

(105,

3 28 19 31

0(0) 7 (25) 0 (0) 1(3)

(104) (104) (108) (107)

Continuous

Infusion.

106)

NATURAL

PRODUCTS

IN

TABLE Homoharrlngtonine

VIII

in Combined

etoposide

vincristine

Complete Response CR (%)

21 20 19

cytarabine amsacrine

+ + + +

Therapy

Number of [valuable Patients

Drug Combination

Homoharringtonine Homoharringtonine Homoharringtonine Homoharringtonine

CHEMOTHERAPY

+ Ara-C

(111) (110) (109) (95)*

5’(24) 3 (15) 1(5) 23

28

+ prednisone

Reference

(82)

Chinese study.

*

Homoharringtonine with

other

agents.

has HHT

been

used

at 3.5 rng/rn2/d

in combination X 9-12

days,

combined with etoposide (100 mg/m2/d X 5 d) induced only one CR among 19 patients with AML.109 Twenty patients with refractory or relapsed AML were treated with combined HHT 3.5 mg/rn2/d X 12 d and amsacrine 120 mg/m2/d X 5 d. A response rate of only 15% was obtained despite significant toxicity.11#{176} Ara-C 100 mg/m2/d X 7 d was combined with escalating doses of HHT for 7 days in 19 patients with AML.11’ Response rates were dose-dependent, obtaining no responses in three patients receiving HHT at 1.5 rng/m2/d, one CR in three patients receiving at 3.0 mg/m2/d, two CRs in six patients receiving at 4.0 rng/m2/d and two CRs among seven patients treated with 5.0 mg/m2/d. Median time to CR was 33 days. Four of five CRs were in patients with acute promyelocytic leukemia. No responses were noted among six patients with primary refractory leukemia. Homoharringtonine with Solid Tumors

for

Patients

The treatment of patients with solid tumors with HHT has been disappointing. The only published phase III study is in Chinese patients with breast carcinoma randomized to receive either CMF or CMF plus HHT 1.0 mg/rn2 IM on days one and eight of therapy. No significant improvement in response rate or median survival was noted in the HHT treated group.112 In a phase II trial of HHT for patients with squamous cell head and neck carcinoma, 17 previously treated patients were given HHT by continuous infusion at 4.0 mg/m2/d X 5 days, and no complete or partial responses were obtained.’13 Twelve patients with primary malignant glioma were treated with HHT in a phase II trial with continuous infusion of HHT at 4.0 mg/m2/d for 5 days. No complete or partial responses were found, and one patient had

THERAPEUTIC

REVIEW

stable disease for 6 months before progression.114 Fifteen patients with previously treated ovarian carcinoma received HHT by daily 4-hour infusion of HHT at 3.0-4.0 mg/rn2 for 5 days every 21 days. All patients had progression of disease while treated.115 No

response

was

seen

in a variety

of solid

tumors

in

patients in another phase II study.”6 No complete or partial responses were seen in patients with advanced and previously treated melanoma, sarcoma, head and neck carcinoma, breast and colorectal carcinomas.

These

patients

all

received

HHT

by 4-hour

infusion at 3.0-4.0 mg/rn2 daily for 5 days every 21 days. Responses in patients with solid tumors have been noticed in phase I studies. A patient with rectal adenocarcinoma had a partial response when treated with an unspecified dose of HHT administered by continuous infusion.96 In another study, marginal responses were found in a patient with breast cancer metastatic to bone and another patient with ascites secondary to ovarian carcinoma. A third patient in this study had 50% shrinkage of nodes containing large cell lyrnphorna, but there was no effect on the patient’s marrow infiltration.97 Clinical

Pharmacology

of Homoharringtonine

The pharmacokinetics of HHT have been studied indirectly. High performance liquid chromatography can reliably measure HHT at a concentration as low

as

30

ng/mL

(approximately

60

nanomolar

(nM)), but the therapeutic and toxic levels in humans are below this threshold.’17 Tritiated HHT has been given to patients and kinetic parameters derived.’18 When a dose of 3-4 mg/rn2 is infused over 6 hours, biphasic clearance is noted with tl/Za = 0.5 hours and t2 = 9.3 hours. The drug clearance rate

is 177

mL/hr/kg

and

the

volume

of distribution

estimated from the area under the curve is 2.4 L/kg. At 72 hours after dosing, 28% of tritium was excreted, and of this, 38% was unrnetabolized HHT. At least three metabolites of HHT were recognized but

779

SLICHENMYER

not identified. The half-life of the major unidentified metabolite is 67.5 hours. The pharmacokinetics of HHT in dogs have also been described.”9 In vitro HHT is metabolized by rat hepatic microsomal enzymes.’20 In a separate study patients with brain tumors were given tritiated HHT prior to craniotomy.121 The ratio of tumor to plasma radiolabel varied from 0.5 to 1.8. All tumors contained a major metabolite of HHT. Cerebrospinal fluid was assayed in one patient and found to contain 30% of the radioactivity of the serum. The inability to measure serum levels has hindered the understanding of homoharringtonine pharmacodynamics. In vitro study of six neuroblastoma cell lines showed that a concentration of HHT greater than 300 ng/mL was required to inhibit cell growth in all lines tested.122 The author doubted that HHT would be clinically useful for patients with neuroblastoma, but the clonogenic assay found complete inhibition of growth at 100 ng/mL, and HHT was effective against mice bearing implanted human neuroblastomas.123 Another in vitro study showed that the inhibitory concentration of HHT for a pancreatic carcinoma cell line was time dependent. Cells incubated with drug for 1 hour had an 1C50 of 1000 ng/mL whereas cells incubated with HHT for 5 days had an 1C50 of 5 ng/mL, a concentration which may be clinically attainable.74 These data may explain the clinical responses seen with HHT. Patients do not respond well to infusions of 5 days or less. Responses are seen with a 7-day infusion, and even longer may be better.104 No phase H trials of HHT for solid tumors have extended treatment beyond 5 days. Further clinical trials are required to test this hypothesis. Toxicity

of Homoharringtonine

(See

Table

IX)

Homoharringtonine has relatively few toxicities when given by continuous infusion. These are becoming well described. These are reversible, as described in ten phase I studies.9603’105”#{176}6 Toxicities are hypotension, leukopenia, thrombocytopenia, and nausea. The first clinical trials with HHT used brief infusions from periods of a few minutes to hours. Hypotension was the dose limiting toxicity, and in some cases this was fatal.96 In one study hypotension was not reported.98 The hypotension usually is associated with tachycardia and responds to infusions of crystalloid, occurs 4-6 hours after initiation of treatment, and tends to be more severe in patients with worse performance statuses.96’97 The hypotension is

780

#{149} J ClIn Pharmacol

1990;30:770-788

VON

AND

HOFF

TABLE

IX

Homoharringtonine (For References,

Toxicity See Text)

Dose limiting Leukopenia Hypotension Myalgias Frequent Nausea Hyperglycemia Other Thrombocytopenia Diarrhea Mucositis Dyspepsia Fever Phlebitis Fluid

retention

PVC/PAC Depression Elevated creatinine Elevated liver enzymes

not a result of arrhythmias96 or poor ventricular function.99 Homoharringtonine has been found to bind specifically to a calcium channel receptor in rat myocardium, and competes with verapamil for this receptor.124 Thus HHT may act as a calcium channel blocker to produce vasodilation and hypotension. Calcium infusion has been used to minimize the hypotension secondary to large doses of verapamil,’25 and might be considered for treatment of life-threatening hypotension after treatment with HHT. Continuous infusion of HHT causes hypotension that is less frequent and less severe than with rapid infusions of HHT.99”#{176}#{176} Hypotension was a significant morbidity when homoharringtonine was given by continuous infusion at 7.0 mg/m2/d but not at 5.0 mg/m2/d in a study of patients with acute leukemia.104 For this reason, continuous infusions of HHT have replaced bolus or rapid infusion therapy. Myelosuppression is usually the dose limiting toxicity

when

HHT

is

given

by

continuous

infusion.

Significant leukopenia is encountered at doses of 3.5 mg/m2/d given for 5 days.99’101 Neutrophil count nadirs occur 14 days after treatment,99’100’102 and thrombocytopenia is most severe 25-30 days after initiation of treatment. Bleeding is uncommon, except in two patients who died of intracranial hemorrhage while being treated with simultaneous HHT and Ara-C.’1’ A study of HHT continuous infusion at 1.0 mg/m2/d for 30 days found that the mean leukocyte nadir was 5.3 thousand and occurred on the

NATURAL

PRODUCTS

twenty-third day of treatment. These effects are self limited.126 Myalgias were the dose limiting side effect in a phase I study of children with acute leukemia.103 All patients required analgesics, usually morphine. The etiology of the pain is unknown. This adverse effect was not reported in any of the clinical studies with adults. Other side effects are less serious. Nausea is frequent but usually mild.97”#{176}1Alopecia has been reported infrequently.99 Insulin resistance with hyperglycernia is frequent, but usually does not require therapy with insulin.127 Mucositis,’#{176}#{176} diarrhea,10#{176} fever,97’99 phlebitis,’#{176}1 dysgeusia,99 premature ventricular or atrial contractions,102 fluid retention, depression or lethargy, elevated liver function tests, and elevated creatinine have all been reported.10#{176} Gastrointestinal, bone marrow, and cardiac toxicities have all been observed in animal models.128 Summary Homoharringtonine is a potent inhibitor of protein synthesis and has activity for patients with acute rnyelogenous leukemia. The pharmacokinetics are only partially described because current assays are not sufficiently sensitive to measure clinically significant concentrations. Hypotension and myelosuppression are the dose limiting toxicities. Further study is required to better define the optimal dose, schedule, and the antineoplastic spectrum of this drug. CAMPTOTHECIN

AND

RELATED

COMPOUNDS

Chemistry Camptothecin is a drug derived from the plant Cczmptotheca acuminata.129 SKF 104864 and CPT-11 are semisynthetic derivatives. The structures of camptothecin and the analogues of interest are shown in the Figure. Details of the isolation and preparation of these compounds are published elsewhere.130-134 Several other camptothecin derivatives have been tested for antineoplastic activity with some encouraging early results.134’37

IN

CHEMOTHERAPY

to specific and

of Camptothecin

Camptothecin and its active derivatives all appear to function through interaction with an intranuclear enzyme, topoisomerase I, which mediates the relaxation of supercoiled DNA.138 Topoisomerase I binds

THERAPEUTIC

REVIEW

of DNA,

reseals

the

DNA

breaks break

a single after

strand,

uncoiling.139

Camptothecins bind to the topoisomerase I-DNA complex and permit uncoiling but prevent resealing of DNA.140’141 Camptothecins are unable to bind to isolated topoisomerase I or DNA, but do bind to complexed topoisomerase I-DNA.’41 Initially, the complex is rapidly and noncovalently bound, and then a slower alkylation of the DNA or enzyme follows.142 The 20(5) configuration and 20 hydroxyl group Further

are

required for binding to the complex.’43’144 study of the E ring suggests that the lactone

structure is necessary for function as a topoisomerase I inhibitor.’40’144 Sodium camptothecin has a disrupted lactone ring but still has an inhibitory influence on topoisomerase I, probably through in vitro and in vivo reconstitution to camptothe-

cm.144’145

Study

of

these

mechanisms

by

Hsiang’s

group has shown into fragments in rnerase I and that ase I in a complex fragmentation by data that show a matid exchanges drugs.147 Camptothecin

that DNA is completely cleaved the presence of purified topoisocamptothecins “trap” topoisomercovalently bound to DNA.146 DNA camptothecins is consistent with significant number of sister chroamong cells exposed to these induces multiple DNA frag-

ments,

associated

many

not

with

topoisomerase

1.148

1 0-hydroxycamptothecin, compared with camptothecin, produces fewer DNA breaks that are unassociated with protein; thus it may be more specific than camptothecin in its interactions with topoisomerase 1.144 Cytotoxicity is related to camptothecin-induced DNA cleavage. Of a series of newly derived camptothecin analogues, every compound that had no topoisomerase inhibitory activity had no antitumor effect.13#{176}The hydroxylactone E ring is essential for cytotoxic activity.3 Inhibition of DNA synthesis reduces camptothecmn cytotoxicity, suggesting that ongoing DNA synthesis is required for camptothecmn cytotoxicity.149 Yeast deficient in DNA repair are supersensitive to the cytotoxicity of camptothecm.140 Cell lines tered topoisomerase

resistant I.150_152

to camptothecin Preliminary

that benign tissues may contain less than malignant tissues, thus making more susceptible to these drugs.’53’154 suggest

Mechanism of Action and Its Derivatives

regions

then

that

the

cytotoxicity

of the

data

have alsuggest

topoisomerase I neoplastic cells These data all camptothecins

is

related to the interaction with topoisomerase I and resultant DNA damage. Other mechanisms of antitumor activity may also be important for camptothecin and its analogues. Treatment of murine bladder cancer cell lines with 1C50 concentrations of camptothecin causes severe inhibition of DNA and RNA synthetases with resul-

781

SLICHENMYER

AND

tant abnormalities of nuclear morphology in surviving cells.155 Similar synthetase inhibition has been observed in mouse hepatoma cells treated with 10hydroxycamptothecin.’56 Purified superhelical DNA is converted to the relaxed form in the presence of camptothecin but the absence of topoisomerase 1.157 I 0-Hydroxycamptothecin treatment alters the ultrastructure of the nuclear matrix.’58 lO-Hydroxycamptothecin has also been observed to induce differentiation of HL-60 cells.159 Another unrelated analogue of camptothecin has been shown to have antimetastatic activity in mice.16#{176}Finally, camptothecin may inhibit microtubule formation by interfering with microtubule-associated proteins that are antigenically and enzymatically similar to topoisomerase 1.161 Blockade of the cell cycle at G2/M has been seen after treatment of cell lines with camptothecin derivatives, and could be explained by interference with microtubule function.162 The role of these various findings in the antineoplastic activity of camptothecin and related compounds requires further study. Preclinical and Related

Activity of Camptothecin Compounds

derivatives

lines.129 lines

CPT-11 that

are

are

is active resistant

active

against to adriamycin

against

P388

other

leukemia and

cell

cell

to vincris-

tine.163 Finally, SKF 104864 is active against P388 cell lines that are resistant to a variety of other antineoplastic agents.1M More evidence of non-cross-resistance is seen with lO-hydroxycamptothecin for KB cells that are resistant to VP-16, m-AMSA, adriamycin, vincristine, methotrexate, and mitoxantrone.165 Animal models also show antineoplastic activity of the camptothecins. CPT-11 is effective for P388 leukemia cells in mice.’6’ Other tumors implanted into mice and susceptible to CPT-11 are S180, Meth A fibrosarcoma, Lewis lung carcinoma, Ehrlich carcinoma, MH134 hepatoma, mammary C3H/HCN, and L1210.137 SKF 104864 is also effective against a variety of murine solid tumors and leukemias, including colon carcinomas 38 and 51, Lewis lung cancer, mammary adenocarcinoma 16/C, subcutaneous B16 melanoma, and human HT-29 xenografted colon cancer. Two tumor lines that were insensitive to SKF 104864 included Madison 109 lung and

colon

26 lines.IM

782

#{149} J ClIn Pharmacol

Phase

I and II Clinical

Trials

five

days

schedule

the

maximum

cumulative

dose was 120 mg/rn2 and leukopenia was the major toxicity. No responses among eight evaluable patients were found with the daily schedule. Sterile cystitis

was

of the

patients,

a significant

mg/m2 sponses

every and

Toxicity sion,

with

cause

2 weeks no partial

with nausea

no clear

of morbidity

for some

to dose. A phase II trial of camptothecin for 15 patients with malignant melanoma at a dose of 90 to 360

this and

relationship

obtained three or complete

regimen vomiting,

included alopecia,

marginal responses.’68

re-

myelosuppresdiarrhea,

and

hemorrhagic cystitis. Another phase II trial of camptothecin at 90-180 mg/m2 as a single injection every 3 weeks for 34 patients with advanced gastrointestinal adenocarcinomas obtained no responses.169 The same group continued the study with 27 patients given daily times five days administration of camptothecin every 4 weeks and obtained two partial responses.’69 Toxicities included leukopenia, mild anemia and thrombocytopenia, hemorrhagic cystitis, nausea and vomiting, alopecia, diarrhea, and stomatitis. CPT-11 was used in a phase I-Il trial for patients

with

refractory

phase

I portion

hematologic of the

malignancy.170

study, the to be 250 mg/m2

In the

maximum tolerated and leukopenia was

dose was found the dose limiting toxicity. In the phase II study, 31 patients previously treated were given either 40 mg/m2 daily times five days or 200 mg/rn2 once every

1990;30:770-788

HOFF

An early phase I study of camptothecin done in 1970 found that the maximally tolerated dose was 5.0 to 7.5 mg/kg as a single infusion given during a period of 5-10 minutes. Dose limiting myelosuppression was rioted. Camptothecin induced partial responses against three colorectal adenocarcinomas, one jejunal adenocarcinoma, and one malignant melanoma.’66 Other marginal responses in that trial were obtained for four patients with colorectal cancer, one with bronchogenic carcinoma, and one with acute myelogenous leukemia. Another phase I trial of camptothecin treated patients with either a weekly or a daily times five days schedule.167 On the weekly schedule, the maximum administered dose was 67 mg/m2 and the major toxicity was leukopenia. Of ten patients on this schedule, two responded. One had an adenocarcinoma of the lung which regressed by more than 50% for longer than 2 months. The other patient had a gastric carcinoma diagnosed by endoscopic brush cytology of an ulcer. This lesion healed completely and without recurrence after treatment. On the daily times

Camptothecin derivatives are active against neoplastic cell lines and against tumors in animal models. Camptothecin is cytotoxic for murine bladder tumor cell lines MBT-2 and 409.155 Other camptothecin

VON

3-4

weeks.

A complete

response

was

obtained

NATURAL

in one

patient

with

T-lymphoblastic

PRODUCTS

lymphoma

and

in another with Hodgkin’s lymphoma. Partial responses were seen in two patients with nonHodgkin’s lymphoma, one with acute promyelocytic leukemia and one with blast phase chronic myelogenous leukemia. All of these responses were seen in patients treated with the 5 days’ schedule. No responses were obtained with the once every 3 weeks’ schedule. A phase I trial of SK&F 104864 has been reported.17’ Patients were treated with either 2.5, 5.0, or 8.3 mg/rn2 infusion given during a period of 30 minutes every 21 days. Nineteen courses were given to 12 patients with refractory solid tumors. Hematologic toxicity was limited to pretreated patients and occurred at each dose level. This study is ongoing. lO-Hydroxycamptothecin was reported to be “effective” for Chinese patients with hepatocellular carcinoma, head and neck carcinoma, acute myelogenous and lymphocytic leukemia, gastric carcinoma, and urinary bladder carcinoma. Details of the magnitude

and

duration

of these

responses

are

This

finding

that

have

Pharmacology

for

cerebrospinal

bile,

tumor

REVIEW

the

search

for derivatives

toxicity

and

retain

their

peak level of the lactone (active) form of the drug ranges from 117 to 235 ng/mL. Peak concentration and the

AUC active

are proportional form of SK&F

to dose. The half-life of 104864 is 3 hours. Fifty

percent of an infused dose is reversibly hydrolyzed to an inactive carboxylate derivative in the first 15 minutes after infusion. The ratio of AUC of lactone and stant

of AUC for lactone plus carboxylate was conover all doses. The clearance rate for the lactone is 20 L/hr/m2, and for the total (lactone plus carboxylate) was 6 L/hr/rn2. The apparent volume

of distribution Toxicity

is 69 L/m2.

of Camptothecin

and

Related

Compounds

causes

dermatitis,

high

camptothecin

toxic

leukopenia,

thrombocyto-

anemia.’69 Other toxicities include cystitis, nausea, vomiting, diarrhea,

titis,

and and

hemstomaIn general, in patients with

alopecia.’66’69”72

levels

reactions

are

low

found

levels

in

patients

without

toxicity. However, some patients have high levels without toxicity and some have toxicity without high levels.172 Nadir reticulocyte counts occurred a median of 6 days after start of therapy. Median granulocyte nadir was day 9 and median platelet nadir day 11. Recovery

of all

cell

types

was

noted

TABLE

on

median

day

15.166

X

Pharmacokinetics of Camptothecin and SK&F 104864

speci-

mens, or postmortem samples of liver, kidney, colon, stomach, and lung. None of the organs was tested sooner than 7 days after dosing. The relationship between serum levels and myelotoxicity has been examined by Creaven.172 Gel filtration showed that over 99% of camptothecin is protein bound. A poor correspondence was seen between dose and serum levels for patients treated on the daily times five days schedule. Toxicity was not directly related to total or calculated unbound camptothecin levels, or to the use of drugs that bind albumin. The authors concluded that myelotoxicity is unpredictable and only partially related to dose.

THERAPEUTIC

prompted

predictable

antineoplastic activity. The pharmacokinetics of SK&F 104864 have been determined in an ongoing phase I clinical trial.’73 When a single dose 2.5 to 8.3 mg/rn2 SK&F 104864 is administered during a period of 30 minutes, the

orrhagic

fluid,

has

more

Camptothecin penia, and

The pharmacokinetics of camptothecin have been described elsewhere.166 For patients with normal renal function, the average recovery of drug from urine within 48 hours of dosing is 23%. An average of 16 patient samples found 98.1% of the drug to be protein bound when assayed by ultrafiltration. Disappearance half-lives after distribution of drug were longer for patients with renal insufficiency or thirdspace fluid collections. The alpha half-life (T112a) averaged 10.9 hours for patients with normal renal and fluid status versus 13.4 hours for those with renal or fluid volume abnormalities. T112 was 17.5 hours or 40.0 hours for these groups, respectively. Fluorometric assay for drug was positive for ascites (even 12 days after dosing) and gastric aspirates, but negative

CHEMOTHERAPY

not

available.126 Clinical

IN

Camptothecin (Reference 98.1% protein bound 23%

of dose

166)

is excreted in urine at 48 hours hr (increases with worsening

10.9-13.4 function) =

t1

=

17.5-40.0

hr (increases

with

function) SK&F 104864 (Reference 173) Peak concentration lactone (active) t112 = 3 hours Clearance rate for lactone fraction: Clearance rate for total: 6 1/hr/rn2. Volume of distribution: 69 L/m2.

worsening

form:

renal renal

117-235

ng/mL

20 L/hr/m2

783

SLICHENMYER

Myelotoxicity

was

5.0-7.5

every

mg/kg

dose

limiting

and

2 weeks.166

patients starting

with malignant dose of 120 mg/rn2

median

leukocyte

count

safe

at a dose

of

II study

of

In a phase

melanoma once (wbc)

treated every nadir

AND

at

2 weeks, of 2600

a a

oc-

curred between the 8th and 14th days of treatment. Two nonfatal pneumonias occurred during the neutropenic period. Four of 15 patients required transfusion of platelets and four of 15 required packed red blood cells.1M In this same phase II trial, two of 15 patients had vomiting and diarrhea so severe that treatment was discontinued. Two others had less severe gastrointestinal symptoms.1M Alopecia was noted 3 weeks after start of therapy, and regrowth of hair was found in every patient within

a few

months

after

completion

of therapy.166

Maculopapular eruption resolved spontaneously after a few days.’TM Hemorrhagic cystitis arose in patients who were dehydrated and always returned with redosing even if the patient was well hydrated with repeat treatment.1M Severe and unpredictable hemorrhagic cystitis provoked the search for camptothecin derivatives without this side effect. Mild elevations of LFTs without overt liver disease were noted in a few patients.166 The chief toxicity of SK&F 104864 in an ongoing phase I trial appears to be myelosuppression.173 Fever, mild tachycardia, and mild nausea and vomiting have also been observed. CPT-11 caused leukopenia, thrombocytopenia, diarrhea, nausea, and alopecia when given on a schedule of daily times five days or a single infusion every 3-4 weeks.17#{176} CONCLUSION SKF

104864

and

CPT-11

are

two

of several

camp-

VON

HOFF

antileukemia and antitumor Chem Soc 1971;93:2325-2327.

agent

from

taxus

brevifolia.

J Am

5. Horwitz SB, Lothstein L, Manfredi JJ, Mellado W, Parnes J, Roy SN, Schiff PB, Sorbara L, Zeheb R: Taxol: Mechanisms of action and resistance, Ann NY Acad Sci 1986;466:733-744. 6. Miller RW, Powell RG, Smith CR, Arnold kemic alkaloids from taxus wallichiana 1981

E, Clardy J: Antileuzucc. I Org Chem

;46:1469-1474.

7. Blume E: Investigators Cancer Inst 1989;81(15):1122-1123.

seek

to increase

taxol

8. Holton RA, Juo RR, Kim HB, Williams AD, enthal RE, Yogai S: A synthesis of taxusin.

supply.

J Natl

Harusawa S, LowI Am Chem Soc

1988;110:6558-6560.

9. Denis JN, Greene AE, Guenard D, Gueritte-Voegelein gatal L, Potier P: A highly efficient, practical approach taxol. JAm Chem Soc 1988;11O:5917-5919. 10. Parness J, Horwitz SB: 1981. Taxol bulin in vitro, J Cell Biol 1981;91:479-487. 11. Schiff assembly

binds

to polymerized

PB, Fant J, Horwitz SB: 1979. Promotion in vitro by taxol. Nature 277:665-667.

12. Manfredi microtubules.

JJ, Parness

J, Horwitz SB: Taxol J Cell BioI 1982;94:688-696.

13. Foisner R, Wiche C: Promotion taxol. J Ultrastruct Res 1985;93:33-41.

F, Manto natural

of MAP/MAP

tu-

of microtubule binds

to cellular

interaction

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