Vinblastine and vincristine

The influences of herbicides on cell division fall into two classes, ie, dismption of the mitotic sequence and inhibition of mitotic entry from interphase (G, S, G2). If ceU-cycle analyses indicate increases in abnormal mitotic figures, combined with decreases in one or more of the normal mitotic stages, the effect is upon mitosis. Mitotic effects usually involve the microtubules of the spindle apparatus in the form of spindle depolymerization, blocked tubulin synthesis, or inhibited microtubule polymerization (163). Alkaloids such as colchicine [64-86-8J,viahla.stiae [865-21-4] and vincristine [57-22-7] dismpt microtubule function (164). Colchicine prevents microtubule formation and promotes disassembly of those already present. Vinblastine and vincristine also bind to free tubulin molecules, precipitating crystalline tubulin in the cytoplasm. The capacities of these dmgs to interfere with mitotic spindles, blocking cell division, makes them useful in cancer treatment. 

The two alkaloids vinblastine and vincristine found in Catharanthus roseus have been recent targets of total synthesis because of their potency in cancer chemotherapy. The reduced tree diagram for the Fukuyama plan to vincristine is shown in Figure 4.66. There are three points of convergence, four branches leading to the target product and four tiers of reaction yields. 

Antipsychotics, bromocriptine, carbamazepine, chlorpropamide, cyclophosphamide, desmopressin, ecstasy, lamotrigine, monamine oxidase inhibitors, NSAIDs, oxcarbazepine, oxytocin, tricyclic antidepressants, selective serotonin reuptake inhibitors, vasopressin, vinblastine, and vincristine... 

Scheme 14. The structures of vindoline (46) and derivatives, vinblastine and vincristine (52 and 53), and dihydrovindoline ether (54).

Thimmaiah, K.N., Horton, J.K., Qian, X.D., Beck, W.T., Houghton, J.A. and Houghton, J. (1990) Structural determinants of phenoxazine type compounds required to modulate the accumulation of vinblastine and vincristine in multidrug-resistant cell lines. Cancer Communications, 2, 249-259. 

The role of microtubules in neutrophil function can be investigated using agents such as colchicine, colcemid, vinblastine and vincristine, which disrupt these structures. Stimulation of neutrophils with chemotactic agents causes a rapid and transient assembly of microtubules, but this assembly does not affect chemotaxis. Similarly, cytoplasts (neutrophils devoid of nu-... 

The Council encourages industry to use innovative labeling to aid practitioners in distinguishing between products with very similar names, for example, the use of tall letters such as VinBLAStine and VinCRIStine. 

The structural modification of natural products is useful in several ways. The known pharmacology of bisindole alkaloids is enriched by the diversity of chemical structures that are made available by structure modification and total synthesis. These molecules have served as biochemical probes in several areas of biology, especially in those of microtubule assembly and drug resistance. The most elusive prize, however, has remained the discovery of new compounds with clinical activity. In recent years several compounds have been evaluated in clinical trials, but vinblastine and vincristine remain the only bisindole alkaloids approved for the treatment of cancer in the United States. These compounds are joined by vindesine in Europe, and at least two new derivatives are the subject of ongoing clinical trials. Considering the breadth of chemical research in this area, the overall yield as measured by new compounds with clinical activity has been relatively low, but this observation is not unique in history of analog development in cancer research. Nevertheless, the search continues, and this chapter details the chemical endeavors to discover a new bisindole alkaloid with clinical activity. 

Experimental Antitumor Activity of Navelbine, Vinblastine, and Vincristine against P388 and L1210 Murine Leukemias... 

Navelbine administered as its tartrate salt vinblastine and vincristine administered as their sulfate salts. 

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. 

The alkaloids vinblastine and vincristine (Fig. 1) have attained a significant role in cancer chemotherapy. A relatively large number of analogs of these alkaloids have been evaluated for biological activity, but very few have advanced beyond initial clinical trials. Vindesine and vinzoli-dine (Fig. 2) are examples of compounds that have been clinically evaluated. These compounds represent structural modifications of the lower portion (vindoline) of the dimeric molecule at position 3. Thus, vinde-... 

A wide variety of other biochemical effects has been reported to be associated with treatment of cells with vinblastine, vincristine, and related compounds (S). These effects include inhibition of the biosynthesis of proteins and nucleic acids and of aspects of lipid metabolism it is not clear whether such effects contribute to the therapeutic or toxic actions of vincristine and vinblastine. Vinblastine and vincristine inhibit protein kinase C, an enzyme system that modulates cell growth and differentiation (9). The pharmacological significance of such inhibition has not been established, however, and it must be emphasized that the concentrations of the drugs required to inhibit protein kinase C are several orders of magnitude higher than those required to alter tubulin polymerization phenomena (10). 

Vincristine has been shown to enhance the accumulation of the folate antagonist methotrexate in murine leukemia cells, and the enhancement has been shown to involve inhibition of a specific efflux route for methotrexate (25) the suggestion has been made that the effect of vincristine on methotrexate efflux may be related to alterations of cell membrane electrical activity that appear to occur when cells are treated with vincristine. In this connection, it is worth mentioning that association of tubulin with membrane structures from bovine brain has been described 25a). Both vinblastine and vincristine have been reported to enhance the accumulation of the folate antagonist methotrexate in human leukemic cells (S) there is no evidence, however, to indicate that this interaction has significance in a clinical setting. 

An interesting difference in the experimental antitumor spectra of vinblastine and vincristine was noted in that vinblastine was inactive against the Ridgeway osteogenic sarcoma in mice whereas vincristine strongly inhibited the growth of this tumor. Vindesine inhibited the Ridgeway os-... 

For a number of years following the discovery and initial clinical use of vinblastine and vincristine, there was relatively little definitive information about the pharmacokinetics of these compounds. Pharmacokinetic studies were accomplished typically using radiolabeled drugs and procedures that were of limited value in distinguishing parent drugs from putative metabolites. 

Clinical pharmacokinetic investigations with both vinblastine and vincristine have revealed a triexponential elimination pattern. As for preclinical pharmacokinetic studies, early information was obtained by analysis of samples from patients receiving radiolabeled drug, but more recent investigations make use of radioimmunoassays. It should be noted that radioimmunoassays, while very sensitive in terms of detecting drugs, may also measure structurally related drug metabolites, and some caution is needed in interpretation of pharmacokinetic results obtained from such studies. 

Hepatic metabolism and excretion in the bile play major roles in the elimination of both vinblastine and vincristine in humans (52) small amounts of vincristine and vinblastine, of the order of 10% of the administered dose, are excreted unchanged in urine. Renal clearance of vinblastine has been reported to be less than 10% of total serum clearance 53). Vinblastine has been reported to inhibit a polymorphic cytochrome P-450 system in human hepatic microsomes, but the concentrations required were much higher than those observed in clinical settings (54). 

The profiles of toxicities for vinblastine and vincristine observed during treatment of patients with malignant diseases differ. Vinblastine treatment commonly is associated with leukopenia that generally begins 5-10... 

While the dose-limiting toxicity for vinblastine usually is leukopenia, that for vincristine is most commonly neurotoxicity (58). Prominent manifestations of neurotoxicity are loss of the Achilles tendon reflex, paresthesias, loss of muscle strength (e.g., in the foot and wrist), and ataxia. Constipation and abdominal pain may occur and are thought to result, at least in part, from actions on the autonomic nervous system. Leukopenia and stomatitis are possible effects of vincristine treatment, but they occur relatively infrequently. Alopecia occurs with vincristine at a frequency comparable to that observed with vinblastine, and vincristine also is a potent tissue irritant. Vincristine may produce a syndrome of inappropriate secretion of antidiuretic hormone, and some manifestations of neurotoxicity, such as seizures, have been considered to be due to electrolyte disturbances associated with the relative excess of the antidiuretic hormone (58). 

The toxicological profile for vindesine includes effects observed with both vinblastine and vincristine. Among the effects observed with vindesine are bone marrow depression, alopecia, and peripheral neurotoxicity. 

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. 

When Robert Noble carried out his studies on the periwinkle leaves, he found that they had no effect on blood sugar levels. However, they did appear to signihcantly reduce a subject s white blood cell count. Perhaps, Dr. Noble reasoned, the product could be used to treat diseases characterized by abnormally high white blood cell counts, such as leukemia. He was successful in isolating two chemicals from the periwinkle leaves, which he named vinblastine and vincristine, that markedly decreased white blood cell counts in patients with certain forms of cancer. The two chemicals were the first anticancer agents derived from natural sources to be approved for use with human patients. 

Streptoverticillium album K-25l/ the antitumoral bis-indole alkaloids vinblastine and vincristine/ verruculogen, a very potent mycotoxin produced by several Penicillium species and melatonin, a hormone found in all living creatures from algae to humans, just to mention the most important ones. 

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. 

Vinblastine and vincristine differ only in the substituent on the nitrogen atom of the indol fragment of the molecule, and are used in combination with other chemotherapeutic agents. They are mainly used for leukoses, myelomas, sarcomas, cancer of various organs, and for lymphomas. 

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