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The Vinca Alkaloids : a New Class of Oncolytic Agents

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The Vinca Alkaloids : a New Class of Oncolytic Agents The Vinca Alkaloids : A New Class of Oncolytic Agents IRVING S. JOHNSON, JAMES G. ARMSTRONG, MARVIN GORMAN, AND J. PAUL BURNETT, JR. (Lilly Laboratoriesfor Research and the Lilly Laboratotiesfor Clinical Research, Indianapolis, Indiana) SUMMARY A phytochemical investigation of the plant [email protected] demonstrated that a number of alkaloidal substances can be obtained with antitumon activity. Over 30 alkaloids have been obtained, of which four—vinbiastine, vinleunosine, vincnistine, and vinrosidine—are known definitely to be active. Chemically these compounds are closely related to one another and to two monomeric alkaloids, vindoline and catharan thine. The structure of these latter two compounds has been determined, and partial structures for the biologically active alkaloids have been proposed. They represent a new class of large complex dimenic alkaloids containing both indole and dihydnoindole moieties. Experimentally, a strain-specific, transplantable, acute, lymphocytic leukemia (P-1534) carried in DBA/@mice served as a bioassay for obtaining these compounds and for predicting their clinical activity. Vinblastine, vincnistine, and vinrosidine are capable of prolonging and/on “curing―miceof the P-1534 leukemia even when therapy is delayed until a near-terminal state of generalized disease. Resistance to an additional challenge of leukemic cells has been observed in these “cured―animals. Parenteral ad ministration of vincnistine has been demonstrated to “cure―micegiven intracranial implants of the P-1534. The experimental tumor spectrum and toxicological studies are presented and discussed. Biochemical studies performed to date do not reveal any effect on cellular nespira tion, glycolysis, protein or nucleic acid synthesis. The mechanisms of action of these compounds, which may differ within the group as well as from those of other known agents, remain to be determined. Only two of these compounds, vinbiastine and vincnistine, have received extensive clinical evaluation. In spite of their close similarity, chemically, a somewhat different group of human neoplasms responds to these compounds, and there has been a singular lack of cross-resistance between these two drugs and any other oncolytic drug now in wide use. Vinblastine has proved effective in chonioepithelioma, Hodgkin's disease, and other lymphomas, and a number of beneficial results have been obtained in car cinoma of the breast and bronchus. In addition, there have been smaller numbers of a variety of other neoplasias reported as responding to this compound. Vincnistine has been striking in its ability to induce complete hematological remission of the acute leukemias of childhood, both lymphocytic and myelogenous in type. Re sponses have also been reported in a number of other malignancies. The problems and obstacles encountered in obtaining a full realization of the clinical efficacy of these new types of oncolytic compounds are discussed in addition to areas of clinical application other than those previously reported. The plant Vinca rosea Linn. (periwinkle) of the the natural state pink and white color varieties are family Apocynaceae is an ever-blooming pubescent found, and hybrids such as blush pink with red herb on sub-shrub which is widely cultivated as an eye, crimson, and white with red eye are commen ornamental in gardens throughout the world. In cially available. In a recent review (77) of current 1390 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1963 American Association for Cancer Research. JOHNSON et al.—Vinca Alkaloids . 1391 phytochemical research on this plant, Svoboda has that “indefinite―survival of animals implanted pointed out that the probable correct botanical with the P-1534 leukemia was being obtained by name for this plant is Catharanthus roseus G. Don, tneatment with crude fractions of the plant which but, owing to the frequent and prevalent use of were chemically free of both leurosine and VLB Vinca ro8ea, the latter name will be used synony (38). Further investigation of those fractions ne mously. sulted in Svoboda's obtaining still two other new This plant has enjoyed a popular reputation in active alkaloids, leurocnistine and leurosidine (74). indigenous medicine in various parts of the world. The A.M.A. Council on Drugs has approved yin Peckholt (63) in 1910 described the use in Brazil blastine' (VLB), vinleurosine (VLR), vincnistine2 of an infusion of the leaves to control hemorrhage (VCR), and vinnosidine (VRD) as generic names and scurvy, as a mouthwash for toothaches, and for these alkaloids; and they will be referred to by for the healing and cleaning of chronic wounds. In these names in the balance of this report. the British West Indies it has been used to treat The purpose of this report is to summarize our diabetic ulcer (86) and in the Philippines has been current knowledge of this new class of antineoplas reported as being an effective oral hypoglycemic tic agents, including the chemistry, pharmacology, agent (fl). The plant is also used in South Africa possible mechanisms of action, and experimental as a hypoglycemic, and, in fact, a preparation un and clinical activity. der the name of “Covinca―ismarketed for this purpose. In England the plant has been sold for ISOLATION AND CHEMISTRY diabetic treatment under the name “Vin-q-lin.― Following the initial observation that extracts The folklore reputation which this plant enjoyed of Vinca rosea Linn. produced prolongation of life as an oral hypoglycemic agent independently stim in mice with P-1534 leukemia, a detailed fractiona ulated its phytochemical investigation in two dif tion of the plant was undertaken. It was shown ferent laboratories, unknown to each other. One of (41) that the activity was found entirely in the these groups included Noble, Beer, and Cutts, then alkaloidal constituents of this material, and that at the Collip Laboratories, University of Western the alkaloids of the leaves were far more active Ontario, and the other a group in the Lilly Re than those contained in either the stems or the search Laboratories including Svoboda, Johnson, roots (73). The leaf material was therefore used for Neuss, and Gonman. Although neither group could the preparation of the compounds described hero substantiate the hypoglycemic activity, the Ca in, and a procedure of differential extractions was nadian group observed a peripheral granulocyto developed (78) which separated the alkaloids into penia and bone marrow depression in rats asso several groups, as shown in Chart 1, according to ciated with certain fractions (15, 18). Continued their varying basicities This procedure, which in investigation led to their preparation of vincaleu volves the conversion of the bases to their tartrates koblastine (VLB) sulfate, an alkoloid capable of followed by extraction into organic solvents, was producing severe leukopenia in rats (17, 60, 61). first used by Svoboda (71) to prepare alkaloids from During this period the Lilly group had demon another plant of the same family, ALitonia con strated that certain alkaloidal fractions gave a no stricta F. Muell. It was found that the antitu producible prolongation oflife of DBA/@ mice given mor activity was primarily located in fraction A implants of the acute lymphocytic neoplasm, the (Chart 1). P-1534 leukemia (41). Fraction A was partially purified by chromatog The detection of activity against the P-1534 leu raphy on alumina, deactivated by treatment with kemia was considered particularly significant, ow 10 per cent acetic acid. This yielded, in addition ing to the fact that this tumor system has detected to a number of inactive alkaloids (the results of other clinically useful antitumor agents in our lab purification of fraction A are shown in Chart @), oratory (40) and had been sensitive enough to two pure compounds possessing antitumor activity study structure-activity relationships of active (7@), vinleurosine and VLB (isolated as sulfate). compounds which correlated with the clinical ac When the noncnystalline residues obtained from tivity (@3,46, 53). An intensive phytochemical in this chromatography were tested for antitumor ac vestigation resulted in the obtaining by Svoboda tivity, certain of the post-VLB fractions appeared (7@) of leunosine, a new dimeric alkaloid closely to be more active than either vinleurosine or VLB related chemically to VLB, as well as VLB sulfate. (74). These materials were subjected to a gradient The effectiveness of both of these alkaloids against pH technic involving partition of the mixtures the P-1534 leukemia was first demonstrated in the between benzene and buffers from pH @.8to 7.5 Lilly Laboratories. 1 Velban® (Vinblastine, Lilly). Early in this investigation it became apparent 2 OncovinTM (Vincristine, Lilly). Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1963 American Association for Cancer Research. GroundPlant I SkellyB Extract DetailedDrug 1) HCI(2N) 1) 2% Tartarlc Acid 2) NH4OH.CHCI3 2) Benzene @ii@iy-SolubleI Drug @lkalolds(E)] 1) NH3 2) Benzene “AlkalineBenzeneExtract 1) 2% Tartaric Acid 1) NH4OH 2) EtCI2 Alkaline EtOH Extract Phase Phenolic Alkaloids 1) NaOH (pH 11) (C,D) 2) EtCI, CHART 1.—Extraction scheme for Vinca rosea L. leaves [Frac@on@ Ai,03 Chromatography Benzene Benz-CHCI,(1:1) CHCI, @ I I 1 I CATHARANTHINE LEUROSINE Moth Llq. Al,03 LOCHNERIDINE Combined 1 IVINDOLININE(.2HCl)@ISOLEUROSINBenzBenz(deactivated)FVIROSINE11CHCI,residues @ IA.JMALICINE@jVLB(-H,S04) chromatography I Ai,O,chromatography
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