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Vinca Rosea) and Their Derivatives in Cancer Chemotherapy

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Vinca Rosea) and Their Derivatives in Cancer Chemotherapy THE ROLE OF THE ALKALOIDS OF CATHARANTHUS ROSEUS (L.) G.DON (VINCA ROSEA) AND THEIR DERIVATIVES IN CANCER CHEMOTHERAPY Gordon H. Svoboda* Indianapolis, Ind. nominator” in most combination therapies, serv- ing as the synchronizing agent. The search for useful foodstuffs, dyes, medicinal Classical methods of isolation and purification agents, and other materials from plants, animals, were of no value in obtaining the active antitumor or minerals is as old as civilization itself. It should agents from C. roseus; new techniques had to be not be surprising, therefore, to learn that all phar- devised. Use of selective/differential extraction, macological prototypes originate from one of these coupled with column chromatography and the gra- three kingdoms. dient pH technique, has resulted in the reported iso- The alkaloids, nitrogen-containing plant bases, lation of 74 alkaloids from mature plants and an ad- notwithstanding the advent of antibiotics and many ditional 21 chemical compounds from immature valuable synthetic drugs, constitute an indispensa- plants. This research and the results thereof con- ble part of our medicinal arsenal. The manufacture stitute a classic in the annals of pharmacognosy/ of alkaloids comprises an important segment of photochemistry. Collecting hundreds of thousands the fine chemicals industry. Their production is of kilograms of this plant material from the wild steeped in tradition, and processes are usually so did not seem promising or reliable. As a result, the highly specialized that it frequently takes years to plant was cultivated on farms in India and Mada- establish them on an economic basis. gascar. Because a number of variables could seri- The author has based his pharmacognosy re- ously threaten the supply of this life-saving drug, search on plants having reported folkloric usage the decision was made to attempt cultivation in the and/or recorded chemical content. After conduct- United States. This was achieved in Texas using ing appropriate literature surveys, 440 plants were modern growing and harvesting techniques. chosen for study. One of the plants collected and To date, attempts for a total synthesis of the ac- investigated was the Madagascar periwinkle, then tive antitumor alkaloids have not been successful. botanically known by three names–Vinca rosea, Synthetic modifications have produced active Catharanthus roseus, and Lochnera rosea. This agents, none of which have yet replaced the parent plant was reported to produce several desirable compounds. The drug from C. roseus is one of biological effects. Folkloric usage cited the plant as many drugs obtained from renewable resources. possessing properties that lowered blood sugar, The important drug isolated from the Madagas- thereby making it a possible source of an oral in- car periwinkle is known scientifically as leurocris- sulin substitute. It also was reported to contain tine, generically as vincristine, and is marketed by alkaloids. Related Vinca species were reported to Eli Lilly & Co., the pharmaceutical house to which contain alkaloids and to possess both neurosedative I assigned the patent, as ONCOVIN. properties and properties that lowered blood It had been an in-house concept that no anti- pressure. cancer agent would or could ever produce a profit Once obtained, extracts from Catharanthus for the marketing company. The reason was that roseus elicited none of the reported biological ac- cancer is a progressively fatal and emotional dis- tivities. (Eventually, pure compounds were isolated ease. (Diabetes can be placed in this category, yet which did possess the reported properties.) Submis- the financial track record for insulin is substantial.) sion to a cancer screening program showed a pro- Pricing for the marketing of ONCOVIN was de- found and reproducible activity against an experi- signed to recover research and development costs, mental leukemia model designed to predict clinical not an unreasonable concept. activity against human leukemia. One particular A company official was reported by William L. alkaloid, leurocristine (vincristine), was isolated. It Laurence in The New York Times as saying that was effective in treating not only acute lymphocytic “it will market the periwinkle chemicals at a price leukemia of childhood but a wide variety of human calculated to yield no profit to the company. ” neoplasms as well. It has become the “common de- Nevertheless, ONCOVIN became the highest per- cent profit item in the Lilly product line, carrying “Previously with Eli Lilly & Co. the relatively insignificant cost-of-sales of 12 per- 154 The Role of the Alkaloids of Catharanthus Roseus G. Don and Their Derivatives in Cancer Chemotherapy ● 155 cent. ONCOVIN provided an annual profit of sev- menclatural validity, the latter does, A text has been eral tens of millions of dollars. devoted to a study of this genus (39). It is impor- It has been estimated that the world contains tant to recognize that Catharanthus alkaloids are 500,000 to 750,000 higher order plants, less than different from Vinca alkaloids and ensure that in- 10 percent of which have been even cursorily in- formation is recorded under the appropriate name. vestigated. The research success potential seems The Madagascar periwinkle, C. roseus, originally enormous. However, judicious plant selection must a species endemic to Madagascar (Malagasy Repub- be coupled with appropriate biological test systems. lic), is an erect, everblooming herb or subshrub with In view of the not-for-profit pronouncements of the either pink or white flowers that now has a tropical company known to have a successful phytochem- distribution. It is cultivated as an ornamental plant ical screening program, is it any wonder that other in gardens throughout the world. domestic firms hestitate to venture into this seem- Independent interest in this plant was generated ingly risky endeavor? by reports of hypoglycemic properties of certain ex- Private enterprise in the United States usually has tracts (14). The observation by Noble, Beer, and been factorily innovative. When this occurs, in- Cutts (29) of a toxic depletion of white cells and tervention by government or others is unwarranted. bone marrow depression produced in rats by cer- However, government should expose and correct tain fractions of these extracts eventually led to the monumental profiteering. Also, when industry isolation of vincaleukoblastine (VLB) sulfate. * Svo- refuses to do the job, the government should pre- boda and Johnson, while screening selected botan- sent a choice: either do it with our cooperation, or icals for experimental antitumor activity, observed we will do it without you. We now stand at this in certain extracts and fractions a reproducible on- juncture. colytic activity primarily against P1534 leukemia, Natural plant products have served as the basis a transplanted acute lymphocytic leukemia, in of man’s medicinal arsenal since time immemorial. DBA/2 mice. This finding eventually led to the isola- The history of herbal medicine in the treatment of tion of leurosine (35),** a new dimeric alkaloid disease coincides with the history of medicine, and closely related in chemical structure to VLB. Subse- indeed with the history of civilization itself. Lit- quently, VLB itself was isolated from the extracts erature citations are recorded for more than 3,000 (21). plant species that have been used or recommended in various parts of the world for the treatment of Extraction of the cancer (15). Catharanthus Alkaloids It has been only within the last 20 years that any product from a higher order plant has been success- As with any single plant constituent, the extrac- fully used in cancer chemotherapy. Oddly enough, tion of an alkaloid is an individual problem. While the plant yielding these agents was not included in several standard techniques existed for preliminary the above-mentioned list of 3,000 plants. The isola- extraction of crude plant materials and subsequent tion of two complex alkaloids—vincaleukoblastine separation and purification of individual alkaloids, (VLB) and leurocristine (LC) from the pantropical none of these were applicable to the specific alka- plant Catharanthus roseus (L,) G. Don (Vinca rosea loids of C. roseus. Consequently, a new technique L,) (Apocynaceae)—initiated a resurgence of in- of “selective” or “differential” extraction had to be terest in this area. The success of leurocristine, devised (app. I) (36). termed a “miracle drug” (38), in treating acute This technique differed from the classical ap- childhood lymphocytic leukemia and a wide variety proach in that a measure of purification was ef- of other human neoplasms is well documented. fected during extraction by forming salts of the The following discussion will be restricted pri- stronger bases in the crude drug on addition of an marily to Catharanthus roseus compounds possess- aqueous solution of a naturally occurring weak or- ing demonstrated utility in the treatment of human ganic acid. Final purification of most of the alka- neoplasms, and in a few instances to compounds loids was accomplished by column chromatogra- considered to have some potential utility on the phy on Alcoa F-20 alumina which was partly deac- basis of antitumor effects in experimental animals. tivated with 10 percent acetic acid. This method- The true botanical name for the Madagascar peri- winkle is Catharanthus roseus (L.) G. Don (33). It has *The United States Adopted Names Committee (USAN) has approved vinblastine as the generic name
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