Vinca vincristine

Vinca, vincristine 5-Fu, 5-fluorouracil Doxo, doxorubicin Epidoxo, epidoxorubicin Mito, mitomycin PAj, peroxisomicine Aj... 

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

The alkaloid mixture from the extraction of Vinca rosea plants (as in vinblastine extraction) was chromatographed to give vincristine which was then converted to the sulfate, according to U.S. Patent 3,205,220. 

Vinca alkaloids (vincristine, vinblastine, vindesine) are derived from the periwinkle plant (Vinca rosea), they bind to tubulin and inhibit its polymerization into microtubules and spindle formation, thus producing metaphase arrest. They are cell cycle specific and interfere also with other cellular activities that involve microtubules, such as leukocyte phagocytosis, chemotaxis, and axonal transport in neurons. Vincristine is mainly neurotoxic and mildly hematotoxic, vinblastine is myelosuppressive with veiy low neurotoxicity whereas vindesine has both, moderate myelotoxicity and neurotoxicity. 

Vinca alkaloids are derived from the Madagascar periwinkle plant, Catharanthus roseus. The main alkaloids are vincristine, vinblastine and vindesine. Vinca alkaloids are cell-cycle-specific agents and block cells in mitosis. This cellular activity is due to their ability to bind specifically to tubulin and to block the ability of the protein to polymerize into microtubules. This prevents spindle formation in mitosing cells and causes arrest at metaphase. Vinca alkaloids also inhibit other cellular activities that involve microtubules, such as leukocyte phagocytosis and chemotaxis as well as axonal transport in neurons. Side effects of the vinca alkaloids such as their neurotoxicity may be due to disruption of these functions. 

Vincristine and vinblastine (vinca alkaloids) comprise another class of drugs that inhibit the polymerization of microtubules but do so by binding to the tubulin molecule at a site different from the colchicine site. Cultured cells exposed to high concentrations of vinca alkaloids develop intracytoplasmic paracrystalline aggregates of tubulin. These drugs are employed clinically in cancer chemotherapy to inhibit the growth of tumors composed of rapidly dividing cells. 

The periwinkle, or vinca plant, served as a source for the drugs vincristine and vinblastine, which are commonly referred to as the vinca alkaloids. The vinca alkaloids inhibit the assembly... 

Vinblastine is another vesicant vinca alkaloid that causes myelo-suppression and less neurotoxicity than vincristine. The pharmacokinetics of vinblastine are best described by a three-compartment model, with an a half-life of 25 minutes, a 3 half-life of 53 minutes, and a terminal half-life of 19 to 25 hours.12 Vinblastine has shown activity in the treatment of bladder, breast, and kidney cancer, as well as some lymphomas. The doses of vinblastine tend to be higher on a milligram per meter squared basis than vincristine. Nausea and vomiting are minimal with vinblastine. Other side effects include mild alopecia, rash, photosensitivity, and stomatitis. 

Vincristine -vinca alkaloid inhibits tubulin polymerization G2 phase specific -neurotoxicity—peripheral neuropathy -vesicant if extravasated -nausea and vomiting -bone marrow suppression—mild -transient transaminase elevation -constipation (often secondary to neuropathy induced ileus) —intrathecal injection is ALWAYS FATAL... 

I 14. The answer is a. (Hardman, pp 1259, 1260.) The vinca alkaloids, vincristine and vinblastine, have proved valuable because they work on a different principle from most cancer chemotherapeutic agents They (like colchicine) inhibit mitosis in metaphase by their ability to bind to tubulin. This prevents the formation of tubules and, consequently, the orderly arrangement of chromosomes, which apparently causes cell death. 

Extensive biotransformation studies have been conducted with the As-pidosperma alkaloid vindoline, but much less work has been done with monomeric Iboga and dimeric alkaloids from this plant. The long-standing interest in this group of compounds stems from the clinical importance of the dimeric alkaloids vincristine and vinblastine, both of which have been used for more than 2 decades in the treatment of cancer. Few mammalian metabolites of dimeric Catharanthus alkaloids have been characterized. Thus the potential role of alkaloid metabolism in mechanism of action or dose-limiting toxicities remains unknown. The fact that little information existed about the metabolic fate of representative Aspidosperma and Iboga alkaloids and Vinca dimers prompted detailed microbial, mammalian enzymatic, and chemical studies with such compounds as vindoline, cleavamine, catharanthine, and their derivatives. Patterns of metabolism observed with the monomeric alkaloids would be expected to occur with the dimeric compounds. 

Ciclosporin, a calcineurin inhibitor, is a potent immunosuppressant useful in the prevention of rejection in organ transplants and grafting procedures. Ciclosporin is markedly nephrotoxic. Vincristine is a vinca alkaloid cytotoxic agent fluorouracil and methotrexate are both antimetabolite cytotoxic agents and bleomycin is a cytotoxic antibiotic. 

The mitotic indices observed after treatment of both cell lines with 10-fold the IC70 concentration of each congener establish that the action of the vinca binary alkaloids with this cellular target in vivo is correlated with the ability of the molecule to inhibit microtubule assembly and not with its high-concentration-dependent activities with MTP or microtubules. Based on the current understanding that neurotoxicity and neuro-ti bule damage are concerted events, the results of our structure-activity studies support the optimistic expectation that the development of a nonneurotoxic vinblastine-vincristine congener can be achieved. 

The cause of the cell cycle specificity of the bisindole alkaloids may be associated with the ability of these compounds to interact with the protein tubulin and thereby inhibit the polymerization (and depolymerization) of microtubules (16,17). In this respect the cellular pharmacology of vinca alkaloids is similar to that of other cytotoxic natural products such as colchicine or podophyllotoxin. On closer inspection, however, Wilson determined that the specific binding site on tubulin occupied by vinblastine or vincristine is chemically distinct from the site occupied by the other natural products (18). Subsequent experiments have determined that the maytansinoids, a class of ansa-macrocycles structurally distinct from the bisindoles, may bind to tubulin at an adjacent (or overlapping) site (19). A partial correlation of the antimitotic activity of these compounds with their tubulin binding properties has been made, but discrepancies in cellular uptake probably preclude any quantitative relationship of these effects (20). 

The vinca alkaloids vinblastine and vincristine are capable of producing the MDR phenotype in a wide variety of cell types. Furthermore, cells that are made resistant to antitumor drugs such as doxorubicin, actinomy-cin D, or the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26) are often resistant to the effects of the bisindole alkaloids. The structural and mechanistic diversity of these compounds is even more striking against the backdrop of collateral resistance. 

Neurologic sequelae with vinblastine are much less common than those seen with vincristine and vindesine. Nonetheless, a causal relationship has been established for seizures, psychotic episodes, and confusional episodes. As common with other vinca agents, absence of reflexes and peripheral neuropathy are well described 23,24). 

The discovery of vinblastine and vincristine is one of the most intriguing examples of serendipity in scientihc research in recent years. In 1952, the Canadian medical researcher Robert Laing Noble (1910-90) received a package from his brother. Dr. Clark Noble, containing 25 leaves from the Madagascar periwinkle plant. Vinca rosea. Clark had received the leaves from one of his patients in Jamaica, who said that natives on the island often used the plant to control their diabetes when insulin was not available. Clark, who was retired, suggested that his brother study the plant for possible use as a drug for the treatment of diabetes. 

The contractile proteins of the spindle apparatus must draw apart the replicated chromosomes before the cell can divide. This process is prevented by the so-called spindle poisons (see also colchicine, p. 316) that arrest mitosis at metaphase by disrupting the assembly of microtubules into spindle threads. The vinca alkaloids, vincristine and vinblastine (from the periwinkle plant. Vinca rosea) exert such a cell-cycle-specific effect. Damage to the nervous system is a predicted adverse effect arising from injury to microtubule-operated axonal transport mechanisms. 

Vinblastine (4) and vincristine (5) are closely related indole-dihydroindole dimers (bisindole alkaloids), isolated from Catharanthus roseus (L.) G. Don (formerly known as Vinca rosea L.), the Madagascar periwinkle. Both of these anticancer agents, known as vinca alkaloids in the medical literature, are specific binders of tubulin, leading to tubulin depolymerization and cell cycle arrest in the metaphase stage. 

Other examples of natural drugs may be pointed out streptozotocin (from streptomyces achromogenes), bleomycin (from streptomyces verticillus), adriamy-cin and daunomycin (from streptomyces pencetius), mitomycin C (from streptomyces caesipitosus), vincristine, vinblastine and vindoline (from catharanthus roseus or vinca rosea L.). 

Vinblastine and vincristine are alkaloids isolated from plants of the periwinkle family (Vinca rosea). These compounds cause cells to stop at metaphase and inhibit assembly of microtubules, and likewise, failure of mitotic spindle formations. They inhibit synthesis of nucleic acids and proteins. 

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