Znt. J . Cancer: 21, 482-489 (1978)

EFFECTIVENESS OF CLINICALLY ACTIVE ANTINEOPLASTIC DRUGS I N A SURGICAL-ADJUVANT CHEMOTHERAPY TREATMENT REGIMEN USING THE LEWIS LUNG (LL) CARCINOMA Philip C. MERKER 1 , 3, Isidore WODINSKY l, Margaret L. CANTOR and John M. VENDITTI Experimental Therapeutics Section, Arthur D . Little, Inc., Acorn Park, Cambridge, Mass. 02140; and Drug Research & Development, Division of Cancer Treatment, NIH, Bethesda, Md. 20014, USA

Surgical-adjuvant chemotherapy studies were done with BDF, mice bearing Lewis Lung (LL) carcinoma implanted intramuscularly (IM). Ten days (010) after implantation, the tumor-bearing leg was surgically amputated, and intraperitoneal (IP) drug treatment was started either 3 or 5 days after surgery using single-dose therapy or intermittent treatment given every 4 days for three doses or daily treatment for five doses. The percentage increase in life span (XILS) was used as the primary measure for evaluation. Data for 17 clinically active drugs showed that surgical-adjuvant, singleagent chemotherapy was markedly effective (%ILS>lOO) in prolonging the life span of tumorbearing animals given BCNU, MeCCNU, and cytoxan; moderate activity (%ILS, 40-100) was obtained with bleomycin and vincristine, and marginal activity (XILS, 35-40) was observed with 5-fluorouracil(5-FU), hexamethylmelamine (HMM), procarbazine, and dibromodulcitol. Surgical-adjuvant, two-drug-combination chemotherapy treatment with bleomycin plus MeCCN U or cis-platinum [cis-PT(II)] plus C C N U were more effective than single-drug chemotherapy i n prolonging the life span of tumor-bearing animals. When used in a surgical-adjuvant chemotherapy-treatment schedule, the solid tumor model was found t o be sensitive t o certain antineoplastic drugs that are of clinical benefit in the treatment of human lung cancer. Thus, the model i s potentially useful in the search for newer single agents and combinations of drugs against cancers.

as described by Karrer and Humphreys (1967), Karrer et af.(1967), Humphreys and Karrer (1970), and Mayo et al. (1972). The tumor is metastatic and thus it has been used in a variety of experiments designed to study the antimetastatic properties of chemical agents (Salsbury et al., 1974; Franchi et a/., 1971; Cattan et al., 1976), the role of systemic versus local factors controlling the formation of metastases (DeWys, 1972), and cell population kinetics of primary and metastatic disease (Simpson-Herren et al., 1974). The tumor model has also been used in combination-chemotherapy studies with surgery (Schabel, 1976) and without surgery (Kline et af., 1974), and in a combined-modality study without surgery (Johnson and Humphreys, 1969). Data for single-agent chemotherapy without surgical intervention were first published by Sugiura and Stock (1955) and more recently by Ovejera et af. (1975), Venditti (1973), and Franchi et a/. (1971). The current surgical-adjuvant chemotherapy experiments were done to determine the relative effectiveness of clinically important drugs against the LLtumor model with a view to expanding the available .experimental data base for the purpose of designing two-drug and combined-modality experiments.

Recently, Skipper (1974) was encouraged by animal experimental data and clinical therapeutic results to anticipate increased use of combined modality treatments for cancer. Currently, it is generally conceded by oncologists that one of the major thrusts in the therapy of solid tumors is the combined modality approach that requires the successful use of a systemic chemotherapy combined with the local modalities of surgery and radiotherapy (Pirigov and Trakhtenberg, 1976; Carter and Soper, 1974; Carter, 1976). The relative success of surgical-adjuvant chemotherapy in the treatment of cancer has increased the efforts to use drugs in combination with surgery. In each instance of planning, questions are posed pertaining to the choice of new single agents, the most appropriate combinations of drugs and optimal conditions of scheduling. As a first approximation, it would be helpful to have data from one or more animal tumor-model systems as discussed by Gottlieb et al. (1975). One potentially useful animal tumor model for surgical-adjuvantchemotherapy studies is the murine LL carcinoma

The LL tumor, which was originally observed by Lewis in 1951 (Sugiura and Stock, 1955) as a spontaneous carcinoma of the lung in C57BL/6 mice, was propagated and maintained in C57BL/6 mice as described by Geran et al. (1972). The tumor was propagated by subcutaneous implantation of fragments (2 to 4 mm) into the axillary region using a 12- to 14-gauge sterile trocar. For chemotherapy experiments, tumors from C57BL/6 donor mice were harvested 10 to 13 days after implantation. Under sterile conditions, tumors were removed and placed into a Petri dish; the tumors were then minced with scissors, and Earle’s balanced salt solution was added to make a 1:lO (w/v) tumor suspension. The suspension was then either passed through a tissue press or lightly homogenized (1-2 passes with a motor-driven pestle), and the resulting brei (0.1 ml) was then

METHODS AND PROCEDURES

Received: January 3, 1978. Present address : Vick Divisions Research, Department Pharmacology and Toxicology, 56 Harrison Street, New Rochelle, New York 10801.

483

SURGICAL-ADJUVANT CHEMOTHERAPY OF LUNG TUMOR

Bioassay of the lungs of tumor-bearing mice was done according to the procedure described by Karrer and Humphreys (1967). Drugs were prepared in concentrations such that the dose could be given in a volume of 0.5 ml. All drugs were given IP in doses and schedules of treatment that are specified in Tables and Figures in the " Results " section. Median survival times of treatment and control animals, tumor volumes and estimates of treatment efficacy based on survival times were calculated as described by Geran et al. (1972).

10.0

1.0

RESULTS

Growth of Lewis lung (LL)-tumor implants Data for tumor weights of IM LL implants showed that growth was rapid during the first 15 days with the tumor doubling time estimated to be about 2 days for a 10-day-old tumor (Fig. 1). Accordingfy, the tumor was in a n active phase of growth on the 10th day when surgery was routinely done in the surgical-adjuvant-chemotherapy experiments described below.

0. 1

.01

,,

I

I5

10

5

25

20

Days

FIGURE 1 - Growth of intramuscular Lewis lung tumor implanted into the hind limb of BDFl mice. Inoculum: 0.1 ml 1:IO (w/w) tumor brei.

injected I M into the right hind leg of BDF, mice. Ten days after implantation, animals were anesthetized with sodium pentobarbital (40-60 mg/ kg); the tumor-bearing leg was washed with 95 % alcohol; an incision was made above the tumor; surgical silk thread (OOO) was used to tie the femoral artery and adjacent blood vessels; and the tumorbearing leg was removed. The wound was washed with sterile normal saline and closed with Michell 11 mm wound clips.

Eflect of surgical intervention alone on the survival of BDF; mice bearing intramuscular ( I M ) implants of the Lewis lung ( L L ) tumor Data for " surgical cures " following radical amputation of the IM tumor-bearing leg, at various time intervals from 1 to 20 days post-implantation, showed that the rate of surgical " cure " was 100% when amputation was done between 1 and 6 days, 70-60% when done at 7-8 days, 10% when performed at 9-10 days, and 0% when performed more than 10 days after implantation (Table I). Eflect of transplanting the lungs from intramuscular ( I M ) Lewis lung ( L L ) tumor-bearing BDF, mice on the survival of recipient BDF, animals The percentages of surviving mice implanted with lungs obtained from IM tumor-bearing donor mice at different time periods after tumor transplantation were as follows: 1 0 0 % for 1- and 3-day lungs; 70% for 7-day lungs; 10% for 9-day lungs; and 0 % for 14-, 16-, and 18-day lungs. Tumor growth within the surgical wound Data from four surgical-adjuvant experiments showed that tumors recurred at the surgical site in about 50% of the animals within 10-11 days of surgery (Table 11) and that the times for death of

TABLE I

EFFECT OF SURGICAL REMOVAL OF TUMOR-IMPLANTED LEG ON HOST SURVIVAL ' Day of surgery following tumor implantation Experiment

LLAS LLA-6

I

3

6

1002

100 100

100

100

7

8

70

9

10

13

15

0

10

60

14

10

0

16

17

0

0

18

20

0

0

0

~~

' BDF, mice in groups of 10 for each day of surgery. Final evaluation: 90 days after tumor implantation. animals.

- a Percentage of

surviving

484

MERKER ET AL.

these animals died; the remaining 6 animals that did not develop local tumor recurrence within the surgical site survived for 60 days, at which time the experiment was ended.

TABLE I1 REGROWTH OF LEWIS LUNG TUMOR WITHIN THE SURGICAL SITE '

Experiment

No. o f Animals with regrowth No'

1 2 3 4

Total

Median survival time (days)

Animals with regrowth

Animals

26 23 21 21

26 23 26 21

519 418 419 217 15/33 (45 %)

Surgical-adjuvant chemotherapy

Surgery performed 10 days after tumor implantation, when tumors were about 9.0 x 13.0 mm in size or about 1 g in weight. Time to tumor regrowth, 10-1 I days following surgery.

animals with and without tumor regrowth were similar. Accordingly, death was probably due to the metastatic lesions arising from the primary tumor prior to surgery. Under these circumstances " curative " chemotherapeutic intervention following surgical removal of the primary tumor would have to inhibit tumor regrowth within the surgical site and the growth of metastatic lesions. This is illustrated by data from a surgical-adjuvantchemotherapy experiment done with cytoxan, at 300 mg/kg, given as a single dose, 5 days after the surgical removal of primary tumor (Table 111). Local tumor growth occurred in 4 of 10 mice, and

Data from a surgical-adjuvant-chemotherapy experiment done with bleomycin are shown to illustrate a typical experimental design (Table IV). It should be noted in this case that several schedules of drug treatment were used, e.g., a single injection given on the 5th day after surgery; an intermittent daily treatment schedule in which drug was given every 4th day for three doses starting on the 3rd day after surgery; and a daily dose schedule given for 5 days starting on the 3rd day after surgery. In addition to the groups of animals given surgicaladjuvant chemotherapy, other groups of animals received either surgery without drug or no treatment (controls). The response data from this and other surgical-adjuvant chemotherapy experiments are summarized in Tables V and VI showing schedules of treatment, dose range, optimal percentage increases in life spans, and other pertinent observations. Data for 17 drugs of clinical interest showed that seven compounds were active in a surgical-adjuvant chemotherapy treatment schedule, e.g., the percentage increases in life span (XILS) were equal to or greater than 40% (Table V). The alkylating agent, cytoxan, and the nitrosourea compounds,

TABLE I11 REGROWTH OF LEWIS LUNG TUMORS WITHIN THE SURGICAL SITE FOLLOWING CHEMOTHERAPY WITH CYTOXAN Mortality

No. of animals with

Cytoxan dose (mg/kg,3' ' D15)

tumor regrowth/ total NO. of living animals

300

4/10 (43)

'

Without tumor regrowth

414

016

6/10

414 (MST, 26 days)

Oil0

(MST, 46 days) 515

519

0

No. of 60-day survivors total No. treated

With tumor regrowth

(MST, 26 days)

(22) Da y of observation. - * MST -- Median survival time.

TABLE IV

PERCENTAGE INCREASE I N LIFE SPAN ' OF LEWIS L U N G T U MO R- BE A RI N G MICE GIVEN SURGICAL-ADJUVANT CHEMOTHERAPY WITH BLEOMYCIN (NSC 125066) Drug treatment schedule Da y 15 Do s e (mg/kg, IP)

Days 13, 17. and 21 D ose (mg/kg, IP)

Daily, days 13-17 D ose (mg/kg, IP)

96

64

32

48

32

16

12

21 0

42 21

36

51 0

58 0

53 0

50

8

No 4

Surgical removal of tumor-bearing leg (day 10) No surgery

21

IS3

45 153

31 173

13

0

Median survival time (MST): surgery, 28.2 days; no surgery, no drug (controls) 25.1 days. (Median survival times of treated (T)/control (C) animals) x 100--100. - D ay 0 = D ay of tumor implantation. - D20: Median T/I for median tumor volumes. 12 mg/ tumor volume for control animals, 5,808 mm3(N - 9); some degree of control of local tumor growthkg, 44% (N = 5); 8 mg/kg, 38% (N 7); 4 mg/kg, 38% (N 8).

>
335 (6/ 10) 0 >220 (6/10) >220 @/lo) >220 (5110) 0 >395 (7/10) 9 >326 (7/10) 0 31 31 3 108 6 121 13 195 (6/10) 59 2 (3/10) 105 0 100 (1/10) 9 55

1.5

5

0

5 (Continued on next page)

t

486

MERKER ET AL. TABLE V (continued)

Class

NSCNo.

Nitrosoureas

Drug

o

409962 BCNU

~

~

g;k~ig ~

~

Surgery (DIO)

D5

48-1 6

48

D15 D13-17

48-1 6 16-5.3

48 16

D15

0 72-32

48

(Continued)

Natural 26980 MitoC Products and Antibiotics

D13, 17,21 D1,5,9

67574 Vincristine

D15 D13-17

123127 Adriamycin

D13-17 D5 D5 D15 D13-17 D13

I25066 Bleoniycin

D15 D13,17,21 D13-17 D13, l7,21

0 3-1 3-1 0 6-2 0.75-0.25 0 3-1 3-1* 0 3-1 3-1* 0 12-4 12-4 6-1.5 0 21-7** 0 96-32 48-16 12-4 0 48-16

3 3 6 0.5 3 3 3 3 12 8 3 21 64 32 12 32

0

D13,17,21 119875 cis-Pt (11)

Heavy metal

D13, 17,21 D14,18,22 D13,17,21

Miscellaneous

32065 HU

D13, 17, 21

104800 Dibro-

D13, 17,21

modulcito1 ~~~

32-8 0 12-4 0 12-4

32 3 8

0 8 12-4 0 3000-1000 3000 0 1200-400 400 0

%

No surgery

~ Optimal e ~Optimal t dose % (mg/kg) ILS

146 (4/10) 32 75 W O ) 0 214 (6/10) 13 18 14 3 46 37 25 11 8 0 30 9 0 11 12 6 4 24 24 42 58 50

Optimal dose (mg/kg)

Optimal 2

%

ILS

16

9

48 16

6 17

32

24

2 2

18 25

4 0.25

42 28

2 2

0 0

3 3

0 0

12 12 6

0 4 3

24

0

64 16 12

21 0 15

13 32 42 6 32 32 5 8 84 22 70 4 (2/8) 6 8 62 0 5 3000 0 400 32 22

Inhibition primary tumor (Days 20-22)

26 2 0

44 0

16 22

~~

Day of tumor implantation, DO. -

% ILS (median survwal times of treated (T)/control (C) animals) x 100-I00

CCNU, MeCCNU, and BCNU, were highly active (XILS, >100) yielding cures; among the natural products, vincristine and bleomycin were moderately active (% ILS, 37-58); and the one heavy metal antineoplastic agent, cisPt (11), was moderately active (% ILS, 48). Marginally active compounds, e.g., those that yielded % ILS of 35%-40% were 5-FU, hexamethylmelamine (HMM), procarbazine,

and dibromodulcitol. Brief comments for those surgical-adjuvant-chemotherapy treatments that yielded % ILSs>40 % are given below. ‘ytoxan

Data showed that cytoxan was highly effective when given as a single dose or intermittently every 4th day or daily for 5 days following surgery.

487

SURGICAL-ADJUVANT CHEMOTHERAPY OF LUNG TUMOR TABLE VI EFFECTIVENESS OF SURGICAL-ADJUVANT TWO-DRUG COMBINATION CHEMOTHERAPY AGAINST LEWIS LUNG CARCINOMA Surgery (D10) Schedule

Drug

Dose range (mg/kitt

Optimal dose

(ma/ke)

Bleomycin MeCCNU Bleornycin

D13, 17,21 D13-17 D13, 17,21

32-8 8-2 32-8

32 8 32

MeCCNU

D13-17

8

CCNU Cis-Pt (11)

D14, 18, 22 D14, 18, 22

8-2 0 48-16 12-4

16 8

CCNU

D14, 18,22

48-16

16

+

+

Cis-Pt (11)

D14, 18, 22

12-4 0

+

+

4

No surgery

%

ILS

32 55 120 (218) 5 108

70 (218) 221 (3/8) 6

Optimal dose (mglkd

32 8 32

+

%

ILS

2 44 7

8 16 4

56 44

16

+

35

4

No. of 90-day cures ”/numberanimals treated. I‘

Combined data for the various treatment schedules showed that 34 of 50 (68%) tumor-bearing mice treated with surgery and chemotherapy were “cured” of the disease. The consistency of the curative action of surgical-adjuvant chemotherapy from experiment to experiment was noteworthy and not seen with other drugs for which replicate data are available. In addition, the drug was moderately active against the growth of the solid primary tumor, yielding a percentage tumor inhibition (%TI) of 67%. CCNU Data indicated that surgery followed by drug therapy given every 4th day for 3 doses increased the survival time of animals by l08%-121%. It is of interest to note that animals bearing the primary tumor also benefited from chemotherapy, although the increases in survival time were modest (% ILS, 50-56). MeCCNU Data showed that combined treatment with surgery and MeCCNU was effective in prolonging the life span of animals. In two experiments done with surgery followed by a single injection of drug on day 15, the average percentage increase in life span was 130% (% ILS, 50-200), and in two other experiments, in which surgery was followed by five daily treatments with drug on days 13-17, the average percentage increase in life span was 80% (% ILS, 55-105). The optimal effect was obtained when drug was used prior to surgery as a single treatment; for this regimen, the local primary tumor was inhibited (% TI, 75). BCNU Surgical-adjuvant chemotherapy with drug given as a single dose following surgery yielded results ranging from marginal (% ILS, 32) to very effective

(% ILS, 214,6/10 cures). Data from one experiment, in which drug therapy was given for 5 successive days following surgery (days 13-17), showed that surgical-adjuvant chemotherapy increased life span (% ILS, 75) and cured two of 10 animals. Data showed that a treatment regimen of therapy starting prior to surgery was considerably more effective than treatment following surgery. Bleomy cin

Surgical-adjuvant chemotherapy modestly ( % ILS, 42-58) improved animal survival. Data indicated that host survival was similar when drug treatments were given either as a single injection (D15), intermittently every 4th day (D13, 17, 21) or daily for 5 days (D13-17). In addition, data showed that the growth of the primary tumor was partially inhibited (% TI, 44) by drug alone (Table IV). Cis-Pt (11)

This drug moderately (% ILS, 58-84) prolonged the life span of surgically treated animals, and in one experiment treatment resulted in curative effects in two of eight animals. Drug therapy also moderately inhibited (% TI, 44) the growth of the primary tumor. Surgical-adjuvant therapy

two-drug

combination

chemo-

Response data are summarized in Table VI for surgical-adjuvant-combination chemotherapy experiments done with bleomycin plus MeCCNU and cis-Pt (11) plus CCNU. The combinations given in conjunction with surgery were found to be more effective than surgery and single-drug therapy. Without surgery, combination chemotherapy was found not to be more effective than single-agent chemotherapy.

488

MERKER ET AL.

Local regrowth will lead to the formation of new metastases and death of the animal; therefore, Current surgical-adjuvant-chemotherapy studies long-term cures following removal of the primary with the LL-tumor were designed to ensure that tumor will only be obtained when both metastatic 100% of the animals would die of metastatic and local residual lesions are controlled. Therefore, disease following radical amputation of the tumor- the LL surgical-adjuvant, metastatic-lung-tumor bearing leg. Data showed that surgery done after model presents a dual challenge to potentially the 9th-10th day of tumor implantation substan- useful chemotherapeutic agents. In this regard, tially met this requirement. At the time of surgery, six drugs (cytoxan, CCNU, BCNU, MeCCNU, on the 10th day of tumor implantation, the primary bleomycin, and vincristine) that have been classified tumor showed an active phase of growth and as active against human lung disease (Rubin and metastasis. Carter, 1976), were found to be active against The overall transplantation, surgical intervention, the LL disease model. The finding that MeCCNU and BCNU and and lung tissue back-transplantation data agreed with those reported by Karrer and Humphreys other potentially immuno-suppressive drugs, e x . , (1967); Karrer et a/. (1967); Humphreys and Karrer cytoxan, were effective in the surgical-adjuvant LL (1970) and indirectly support the data of Mayo model is of special interest because the effects et al. (1972); Dewys (1972); Snodgrass e t a / . (1975); were obtained in a tumor model system that develops and Salisbury et a/. (1974). Additionally, our an increased number of metastases when the immunoanalysis of survival data showed that surgically logic competence of the host animal is impaired treated LL-tumor-bearing mice, under the current (Carnaud et at., 1974). The current studies, which used a solid metastatic experimental conditions, had about 20 days of remaining life following surgical amputation of tumor in a surgical-adjuvant experimental design, the tumor-bearing leg; the effective number of were done to determine the relative effectiveness days of life were 15 to 17 days from the start of of clinically active antineoplastic drugs used as drug therapy, which was usually 3 to 5 days after single agents. The purpose of these studies was surgery. Therefore, the LL-surgical model is a to extend the single-agent chemotherapy data slightly more terminal disease than the B16 and base in such a manner that two-drug-combination C3H surgical-adjuvant solid tumor models reported chemotherapy experiments could be designed with by Schabel (1976) and the early IV artificial meta- drugs found to be active in the LL-surgical-adjuvant static LL-tumor model as used by Ovejera et al. model. The findings that bleomycin, cis-Pt (11), (1975). This may partially account for the current and vincristine were moderately active suggested findings that certain drugs (e.g., adriamycin) were using these in combination with the highly active not active in the surgical-adjuvant model ; whereas nitrosoureas, which have a different mechanism of activity was reported for the early I V model by cytotoxicity. Two combinations containing nitroOvejera et a/. (1975). A contributing factor to soureas and the moderately active drugs bleomycin this difference in responsiveness between the LL- and cis-Pt (11) were tested in the tumor model. surgical and the early IV-model systems may be Data showed that the combination of bleomycin/ related to fundamental differences in tumor cell MeCCNU and cis-Pt (II)/CCNU were more active kinetics (Simpson-Herren et a/., 1974). It is t o than single-agent chemotherapy. However, additional be noted that surgical removal of established LL studies are required to determine the influence of tumors increases the growth rate of metastatic drug scheduling on the activity of these drug lesions (DeWys, 1972); this should have been to combinations. Other potentially useful two-drug the advantage of S-phase-cycle specific drugs such combinations are cis-Pt (11) plus bleomycin and as MTX and 5-FU, but these drugs were not active. bleomycin plus vincristine. The cis-Pt (11) and bleomycin combination has been shown to be Surgical-adjuvant chemotherapy was shown to active against the solid animal tumor B16 melanoma be more effective (ILS >40%) than chemotherapy (Merker et al., 1977), and the bleomycin plus alone for 7 of 17 drugs studied: CCNU, BCNU, vincristine combination has been reported to be MeCCNU, and cytoxan were markedly effective; effective in a combined modality-treatment regimen bleomycin, vincristine, and cis-PT (11) were modestly against human lung disease (Samuels et al., 1975). effective. The marked efficacy of surgical-adjuvant Thus, the solid LL tumor, when used in a surgicaltherapy with BCNU, MeCCNU, and cytoxan adjuvant-chemotherapy treatment schedule, was against the LL tumor has been reported by Mayo found to be sensitive to antineoplastic agents that et a/. (1972), Karrer and Humphreys (1967), and are of clinical interest either as single agents or in Humphreys and Karrer (1970), while Schabel combination therapy. Accordingly, the tumor model (1 976) has recently shown that BCNU and MeCCNU can be of use in exploring the effectiveness of were markedly effective in a surgical-adjuvant newer single agents and two-drug combinations treatment protocol against the B16 and C3H against metastatic lung cancer. mammary tumor line 44 models. However, an interesting aspect of the current studies, which ACKNOWLEDGEMENTS had only been commented on by Humphreys and Supported by Contract N01-CM-53765 from the Karrer (1970), is the finding that long-term curative effects of drug therapy following surgery, as, for Division of Cancer Treatment, National Cancer example, with cytoxan, were related to the prevention Institute, National Institutes of Health, Department of local tumor regrowth within the surgical site. of Health, Education and Welfare. DISCUSSION

SURGICAL-ADJUVANT CHEMOTHERAPY OF LUNG TUMOR

489

EFFICACITE DES MEDICAMENTS ANTINEOPLAS!QUES CLINIQUEMENT ACTIFS DANS UN PROTOCOLE CHIRURGIE-CHIMIOTHERAPIE ADJUVANTE CONTRE L’EPITHELIOMA PULMONAIRE D E LEWIS L’effet de la chirurgie et d’une chimiotherapie adjuvant, a Bte Btudie chez des souris BDF, porteuses d’un epithelionia pulnionaire de Lewis implant6 par voie intramusculaire. Dix jours apres I’implantation, la patte cancereuse a ete amputee, et une chimiotherapie intraperitoneale a ete entreprise trois ou cinq jours apres, sous forme d’une dose unique ou d’un traitenient intermittent comportant trois doses (une tous les quatre jours) ou une dose quotidienne pendant cinq jours. L’evaluatioii des effets du traitement a ete fond& essentiellement sur la mesure de I’augmentation de la survie en pourcentage (ZILS). Les resultats obtenus avec 17 medicaments cliniquement actifs ont montre que f e protocole chirurgie-chimiotherapie adjuvante avec un seul agent (BCNU, MeCCNU ou cytoxan) prolongeait sensiblement (%ILS z 100) la vie des animaux cancereux; I’effet a ete modere (Z IL S, 40-100) avec la bleomycine et la vincristine, et marginal ( ZI LS, 35-40) avec le 5-fluorouracile (5-FU), I’hexamethylmelamine (HMM), la procarbazine et le dibromodulcitol. Le protocole chirurgie-chimiothkrapie adjuvante avec deux produits combines (bleomycine et MeCCNU ou cis-platine [cis-PT(II)] et CCNU) etait plus efficace que la chimiotherapie avec un seul produit. On a constate en utilisant ce protocole que le modble de tumeur solide est sensible A certains medicaments antineoplasiques d’utilitt clinique dans le traitement du cancer pulmonaire humain. Ce modele est donc pJtentiellement utile pour la recherche de nouveaux agents anticancereux utilises seuls ou en combinaisons.

REFERENCES

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Effectiveness of clinically active antineoplastic drugs in a surgical-adjuvant chemotherapy treatment regimen using the Lewis Lung (LL) carcinoma.

Znt. J . Cancer: 21, 482-489 (1978) EFFECTIVENESS OF CLINICALLY ACTIVE ANTINEOPLASTIC DRUGS I N A SURGICAL-ADJUVANT CHEMOTHERAPY TREATMENT REGIMEN US...
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