22

TW.NSACTKINS OF THE Ro~ar. SOCIETYOF TROPKX MEDICINEAND HYGIENE

Medicinal 2. Natural

plants in tropical products

(1991) 85, 22-25

medicine

in cancer treatment

from bench to the clinic

Operational Secretary, Cancer Research Campaign Clinical Trials Subcommittee and Deputy Brian W. Fox Director, Paterson Institute for Cancer Research, Christie Hospital, Wilmslow Road, Withington, Manchester, M20 9BX, UK Abstract

The development of anticancer agents has, in the past, relied heavily on leads derived from screening a wide variety of agents from both synthetic and natural sources. With the development of new techniques of measurement of biochemical changes in cells and the advent of molecular biological techniques, it is becoming clear that many naturally occurring agents, specifically selected for their tumour growth inhibiting activity, are highly complex and novel substances which are potentially promising as anticancer agents in the clinic. The process of getting a drug from the laboratory bench to the clinic is itself often complex due to adverse physical characteristics of the drug. The experience of the Cancer Research Campaign Clinical Trials Committee in developing several natural products, currently in various stages of development for clinical trial, is described. The drugs discussed include the vinca alkaloids, maytansine, combretastatins, bryostatin 1, pancratistatin, phyllanthoside, dolastatin 10, and taxol. Introduction

On 30 July 1980, a group of experimental and medical oncologists met at the Cancer Research Campaign (CRC) headquarters to determine from the clinical representatives whether more phase 1 and 2 trials were needed in the UK, to determine the problems involved in bringing new drugs into the clinic, and to determine how more new drugs can be brought into clinical trial more rapidly. The conclusions from this meeting led to the construction of an operation manual, outlining the basic requirements for the conduct of a phase 1 trial, and including the minimal animal toxicology data necessary for the calculation of the safe starting dose in man (VAN HOFF et al., 1984). Safe starting

recognized that, although the overall toxicity could be roughly correlated in this way, the nature of the dose-limiting toxicity appeared to vary from speciesto species. This led SCHEIN (1977) to conclude that ‘The animal systems are imperfect and those who wish to use them asif they have a direct relevance for man will be sorely disappointed’. ROZENCWEIGet al. (1981) suggested, as a result of experience with 21 anticancer agents, that a suitable safestarting dosecould be computed from 116thof the 10% lethal dose (LDlO)(mg/m ) in mice and 1/3rd of the toxic dose low (TDL) in dogs. However, by choosing 1110th of the LDlO (mg/m2>in the mouse alone, a similar number of escalation steps would be encountered, and they therefore suggested that this level would constitute a safe starting dose. After further international work, the CRC committee chose 1110thof the LDlO (mg/m*>in the mouse as the basis of the safe starting dose, with a check at this level in the rat, usually in the repeat dose schedule, to accentuate in a second species any unusual toxicity which may occur. It was then possible to establish a minimal toxicology requirement which consisted of(i) acute intraperitoneal LDlO in the mouse, with full haematological and histopathological coverage; (ii) sub-acute LDlO (intraperitoneal) in the mouse; (iii) acute intravenous LDlO in the mouse; (iv) optional gastro-intestinal study; and (v) repeated sub-acute study in the rat at the l/lOth LDlO level. In order to provide a reliable toxicological data base, acquired under reproducible good laboratory practice (GLP) conditions, this work is contracted out to specialist laboratories. GOLDSMITH et al. (1975) examined the number of steps required from the estimate of the safe starting dose, using the method of escalation based on a ‘Fibonacci’ relationship (Table), with a series of 29 anticancer drugs, and found the method to be

dose calculations

An initial attempt to compute the safe starting dose from animal data for application to patients was undertaken by FREIEREICH et al. (1966). They observed that there was a close correlation between the maximum tolerated dose (MTD) of a number of different species when the dose was expressed as mg/m’ of surface area, and given as 5 successivedaily doses.This correlation included man. The correlation was good for groups of drugs but not as good for individual drugs. The ratios (mg/m2)/(mg/kg) for mouse (3*0), rat (5*2), hamster (4-l), monkey (11.5), dog (20) and man (37) were found to be approximately true for about 18 anticancer drugs where the MTD was known in each of the species. However, it was

Table.

‘Fibonacci’

Drug dose Zn 3.3n 5n 7n 9n 12n 16n

series of dose escalations

Percentage of preceeding dose 100 67 ii 30-35 30-35 30-35

23 acceptable (i.e., less than 5 steps to reach MTD) in all but 7 of the drugs. It was considered unnacceptable to have too many (e.g., 6) steps to reach MTD. This escalation method was, however, adopted by the CRC committee, but in their experience the number of escalations necessary to reach MTD from the safe starting dose was unacceptably great for some of the agents. Over the last few years, it has become clear that in the case of some agents, a detailed pharmacokinetic analysis of the plasma of patients during the phase 1 trial, based on the work of COLLINS et al. (1986), could give a better means of escalating the doses. Recent anticancer drugs from natural sources Microtubule modifying agents

Some of the most successful antitumour agents used in the clinic and derived from natural plant HO

CH3 OOC’

= ..

’ -NI\

‘0a-b

H3C

CH3

0

Fig. 2. Maytansine.

ilicifoliu Mart., had been used in Brazil as a folk remedy for cancer. It is also known to interfere with the vincristine binding site of tubulin. Two further substances have been isolated by PETTIT et al. (1989) from a South African tree, Combrerus caffrum: combretastatin A4 and Al (Fig. 3). The powdered bark of this willow-tree has been used as a Zulu charm to harm enemies. These 2 substances exert antitumour activitv as well as interfering with the colchicine bin-ding site, thus inhibiting the assemblv of the microtubule. However the 2 ciosely related compounds differ in their interaction with the P170 glycoprotein cell membrane pump, allowing one of the compounds, Al, to behave like many other toxic natural products and to be actively excluded by the pump, whereas A4 is unaffected by the pump, and indeed there is evidence of collateral sensitivity associated with this drug

IR Her“‘COOCH, Fig. 1. Vincristitte (R=CHO) and vinblastine(R=CH,). Figs 1-8 showthe structuralformulaeof the compoundsreferredto in the text.

sources are members of the vinca group of alkaloids, namelv vincristine and vinblastine (Fix. 1). These alkaloids are derived from the Madagasc& periwinkle, Catharanthus roseus(Apocynaceae). The potential antitumour activity of these substanceswas originally recognized by NOBLE et al. (1958). The discovery was based on a series of chance observations arising from investigations of an old West Indian remedy for diabetes mellitus. These alkaloids exert their activity by interfering with the assemblv of tubulin nroteins to create the microtubular elements necessa-ryfor the efficient functioninn of cellular oreanelles. cell division, cell movemeni, cell secretionand axon elongation in nervous tissue. Using competition experiments it can be shown that there are 2 distinct binding sites on tubulin corresponding to that which binds vincristine and vinblastine (vincristine binding site) and that which is known to bind colchicine (colchicine binding site). A drug, maytansine (Fig. 2), obtained from Maytetli(s ovatus Loes. (Celastraceae),has been shown to be a powerful antitumour agent in experimental tumour systems(KUPCHAN, 1976), but it was disappointing in subsequent clinical trials. A related species,Maytenus

t)CHs

6CH3 Fig. 3. CombretastatinA4 (upper) and Al (lower).

24

(McGo~N & FOX, 1990). Such agents are of great interest for overcoming the ‘resistance’ caused by the activities of this pump which often result in failure of chemotherapy in the clinic. A considerably more potent substance has recently been isolated from the seahare (Dolubellu auriculut~) bv PETTIT et al. (1987). This marine onisthobranch has been known to contain unusual medical properties from ancient Greek times (ca 200 BC). Dolastatin 10 (Fig. 4) is one of the most powerful inhibitors of microtubule assembly known as well as a potent anticancer agent, especially against a murine melanoma. The substance is soluble and stable in aqueous

Fig. 6. Bryostatin

Fig. 4. Dolastatin

1.

and is readv for a clinical trial in Manchester and Cambridge.Pancratistatin (Fie. 7) is isolated from the bulbs of Puncrutium littot&-Jacq. (Amaryllidaceae), a plant which grows readily on marine sand dunes-in this case in Hawaii. The drug possesses interesting antiviral activity aswell as activity against tumours. It is, however, extremely insoluble and has presented the formulation pharmacist with what seems,to date, to be an almost intractable problem.

(CRC 89-02).

CH0 I-NHd

0

HO

Fig. 5. Tad

solutions and the levels of drug needed are very low, approximately 5 mgkg. Tax01 (Fig. 5) was isolated from the western yew (Tuxus brevifoliu) by WANI et al. (1971). The anticancer activity of parts of this plant had been recognized in early nineteenth century Indian medicine. It exerts its action by inducing the formation of microtubules by an as yet unknown mechanism. It is proving of considerable current clinical interest and new supplies of the drug are being sought in related Tuxus species. It has, for example, been shown to occur in the leaves of the common English yew, T. baccutu. Drugs affecting

the cell signalling

systems

One of the most interesting drugs from the natural product laboratories is a macrocyclic lactone, bryostatin 1 (Fia. 6). isolated from a brvozoon, Bunula neritin~. Ii; is effective against many-of the standard mouse tumours as well as being able to induce haemopoiesisand to modulate the immune system. It has completed formulation and preclinical toxicology

HO-OH HO Fig. 7. Pancratistatin.

Another drug derived from a natural plant product is phyllanthostatin (phyllanthoside) (Fig. 8). This is a glycoside from Phyllunthus acumiruztus Vahl. (Euphorbiaceae), a tree indigenous to Costa Rica. This drug was first isolated by KUPCHAN et al. (1977) and was studied extensively by the National Cancer Institute in the USA. During the toxicology investigations, it was tested in dogs, in which speciesit was much more sensitive than was predictable from mouse experiments. This raised the whole question of whether the extrapolation from mouse data alone would indeed always be safe in man. Subsequent clinical work now

25

0

CH=

CH-CO.

OH

Fig. 8. Phyllanthoside (NSC 328426; CW13).

suggests that it would have been safe but only just, being within one or two escalation steps of the minimum toxic dose in man. Conclusions

Many new agentsare being discovered in plants and marine organisms, whose properties in the higher mammals such as ourselves are being shown to have special interactions with the growth regulatory processesof the body. It is considered by some workers in this field that many organisms, especially of marine origin, have, as a consequence of remaining little changed for many millions of years longer than man and other land organisms, had a longer period to generatesubstancesin their biochemistry to regulate a more consistent and species-specificmorphology and reject abnormal growth behaviour such as life-threatening tumours. However esoteric this philosophy may appear, the study of the chemicals contained in these organisms is revealing a remarkable series of some of the most potent biological materials known. References Collins, J. M., Zaharko,, D. S., Dedrick, R. L. & Chabner, B. A. (1986). Potenttal roles for prechnical pharmacology in phase 1 trials. Cancer Treatment Reports, 70, 73-80.

Freiereich, E. J., Gehan, E. A., Rall, D. P., Schmidt? L. H. & Skipper, H. E. (1966). Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey and man. Cancer Chenwtherapy Reports, 50, 219-243. Goldsmith, M. A., Slav& M. & Carter, S. K. (1975). Quantitative prediction of drug toxicity in humans from toxicology in small and large animals. Cancer Research, 35, 1354-1364. Kupchan, S. M. (1976). Novel plant-derived tumor inhibitors and their mechanisms of action. Cancer Treatment Reports, 60, 1115-l 126. Kupchan, S. M., LaVoie, E. J., Braylman, A. R., Fei, B.Y., Bright, W.M. & Bryan, R. F. (1977). Phyllanthotin, a novel bisabolane aglycone from the antileukemic glycoside, phyllanthoside. ~oumal of the American Chemical Society, 99, 3199-3201. M&own, A. T. & Fox, B. W. (1990). Differential cytotoxicity of combretastatins Al and A4 in two daunorubicin-resistant P388 cell lines. Cancer Chemotherapy and I’hannacolagy, 26, 79-81. Noble, R. L., Beer, C. T. & Cutts, J. H. (1958). Role of chance observations in chemotherapy: Vinca rosea. Annals of the New York Academy of Science, 882-894. Pettit, G. R., Kamano, Y., Herald, C. L., Tuinman, A. A., Boettner, F. E., Kizu, H., Schmidt, J. M., Baczynskyi, L., Tomer, K. B. & Bontems, R. J. (1987). The isolation and structure of a remarkable marine animal antineoplastic constituent: dolastatin 10. Journal of the American Chemical Society, 109, 6883-6885. Pettit, G. R., Singh, S. B., Hamel, E., Lin, C. M., Alberts, D. S. & Garcia-Kendall, D. (1989). Isolation and structure of the strong cell growth and tubulin inhibitor, combretastatin A-4. Experientia, 45, 209-211. Rozencweig, M., Van Hoff, D. D., Staquet, M. J., Schein, P. S., Penta, J. S., Goklin, A., Muggia, F. M., Freiereich, E. J. & De Vita, V. T., Jr (1981). Animal toxicology for early clinical trials with anticancer agents. Cancer Clinical Trials, 4? 21-28. Schein, P. S. (1977). Preclmical toxicology of anticancer agents. Cancer Research, 37, 1934-1937. Van Hoff, D. D., Kuhn, J. & Clark, G. M. (1984). Design and conduct of phase 1 trials. In: Cancer Clinical Trials: Methods and Practice, Byuse, M. E., Staquet, M.J. & Sylvester, R. J. (editors). Oxford: Oxford University Press, pp. 210-220. Wani, M. C., Taylor, H. L., Wall, M. E., Coggan, P. & McPhail, A. T. (1971). Antitumour aeents VI. The isolation.and structure of taxol, a novel a&leukemic and antitumour agent from Taxus brevifolia. Journal of the American Chemical Society, 93, 2325-2327.

Medicinal plants in tropical medicine. 2. Natural products in cancer treatment from bench to the clinic.

The development of anticancer agents has, in the past, relied heavily on leads derived from screening a wide variety of agents from both synthetic and...
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