Anticancer drugs vincristine

Chemicals, which have planar molecules such as acridine, and the anticancer drugs vincristine and vinblastine can intercalate in the DNA molecule. This distorts the structure and so alters the function of the molecule, possibly leading to mutations via base insertions (see sect. 6.7.7 below). This may also interfere with the excision repair processes during meiosis. 

The observation that fractions of the rosey periwinkle, Catharanthus rosea, produced severe leukopenia, resulted in the isolation and development of two major anticancer drugs, vincristine and vinblastine. These two complex, dimeric indole-indoline alkaloids are important in the treatment of acute childhood leukemia (vincristine), Hodgkin s disease (vinblastine), and metastatic testicular tumors (vinblastine), and continue to be manufactured today by mass cultivation and processing of their natural source. 

Two vinca alkaloid anticancer drugs (vincristine and vinblastine) and two precursors (catharanthine and vindoline) were extracted fixm periwinkle leaves and separated on a Cjg column k = 2S4 nm). Good resolution and complete elution were achieved in 15 min using a 62/38/0.3 water (0.1M phosphate buffer at pH 4.14)/acetonitrile/acetic acid mobile phase [1395a]. Linear response was reported over the range from 0.25-25 pg injected. 

Anticancer drugs Paclitaxel Docetaxel Vinblastine Vincristine Tipifarnib Diflomotecan Iiinotecan Doxorubicin Daunorubicin Etoposide Tenoposide Tamoxifen (i)... 

Anticancer drugs Methotrexate Doxorubicin Daunorubicin Epirubicin Etoposide Vincristine Vinblastine Paclitaxel Iiinotecan... 

In view of the substantial current interest in drug actions at the cell membrane and the relationships between such effects and anticancer drug action, it is interesting to note that both vincristine and vinblastine produce crenellation (wrinkling) of cell membranes as a characteristic morphological effect (12). That cytotoxicity produced by treatment with vinblastine may be linked to perturbations of membrane function, suscep-... 

Most anticancer drugs damage hair follicles and produce partial or complete alopecia. Patients should be warned of this reaction, especially if paclitaxel, cyclophosphamide, doxorubicin, vincristine, methotrexate, or dactinomycin is used. Hair usually regrows normally after completion of chemotherapy. 

The result of nondisjunction, loss of one chromosome, for example, may be incompatible with survival of the cell, so aneugens are often cytotoxic. This obviously only occurs in cells, which are actively dividing, therefore such compounds find use as anticancer drugs. Two examples are vincristine and vinblastine, two vinca alkaloids, derived from a plant. 

Since 1961, nine plant-derived compounds have been approved for use as anticancer drugs in the U.S. vinblastine (Velban), vincristine (Oncovin), etoposide (VP-16,1), teniposide... 

Some anticancer drugs kill cancerous cells without acting on dna. Certain alkaloids, such as vincristine, shown in Figure 14.16, and taxol, kill dividing cells by preventing the formation of cellular microstructures needed for division. 

Another area in which natural products have had a major impact on longevity and quality of life is in the chemotherapy of cancer (see Chapter 62). In fact, most major anticancer drugs are derived from plants or microorganisms. Important examples include bleomycin, doxorubicin, daunorubicin, vincristine, vinblastine, mitomycin, streptozocin, and most recently, paclitaxel... 

Paclitaxel, camptothecin, vincristine, vinblastine, and other compounds currently under development as potential anticancer drugs (i.e., the bryostatins isolated from marine dinoflagellates) were discovered through a broad-based screening program to identify, using a whole-cell inhibition assay, natural products that are active against a battery of representative cancer cell lines. 

Vitamin E, in vitro, has been shown to enhance the cytotoxic effect of several anticancer drugs, including 5-fluorouracil (5-FU), doxorubicin, vincristine, dacarbazine, cisplatin, and tamoxifen. 

TFP (5) was the first phenothiazine demonstrated to modulate MDR in drug-resistant P338 murine leukemia cells. TFP (5) enhanced intracellular accumulation of vincristine and adriamycin (77) in resistant tumor cells by inhibiting outward transport of these anticancer drugs [167]. Studies per-... 

Figure 3.1 Combined effects of a combination of 7 anticancer drugs with different sites of action. Shown are the predicted (solid line concentration addition, broken line independent action), and the observed (circles) cytotoxic effects on DU 145 prostate cancer cells. Doxorubicin, daunorubicin, vincristin, cis-platin, etoposide, melphalan and 5-fluorouracil were combined at equitoxic concentrations. The mixture effect predictions were derived from the concentration-response curves of the individual anticancer drugs...

Catharanthus alkaloids, particularly vinblastine (Al) and vincristine (A2), are well known anticancer drugs, which are used clinically to treat Hodgkin s lymphoma and acute childhood lymphoblastic leukemia, respectively. These alkaloids interact with tubulin, a protein necessary for cell division, and are inhibitors of mitosis (the process of cell division). 

Although many other alkaloids have been isolated from C. roseus only vinblastine and vincristine have been developed for clinical use. The antiproliferative activity of the two compounds is related to their specific interaction with tubulin, thus preventing assembly of tubulin into microtubules and arresting cell division (59). However, despite this apparent identical mechanism of action and their clear chemical similarities, vinblastine and vincristine display very different clinical effects. Vinblastine, for example, is used to treat Hodgkin s disease and metastatic testicular tumors, whereas vincristine is used mainly in combination with other anticancer drugs for the treatment of acute lymphocyticleukemia in children. Toxicity profiles are also different, in that vinblastine causes bone-marrow depression, whereas peripheral neuropathy often proves to be dose-limiting in vincristine therapy. 

Vincristine is an anticancer drug that causes peripheral neuropathy, and, in clinical trials, younger patients appeared to be more susceptible to this toxicity. Vincristine clearance based on BSA was lower in infants compared to older children and adolescents (Figure 23.14), thus a dose scaled to BSA would result in higher plasma concentrations in younger patients... 

Lugassy G, Shapira A. A prospective cohort study of the effect of vincristine on audition. Anticancer Drugs 1996 7(5) 525-6. 

This reaction has been extensively studied in the case of the chlopromazine radical (R -mediated aminopyrine (S) oxidation [41], a typical reaction for xenobiotics, as well as in the case of the vindoline radical (R -mediated catharanthine (S) oxidation [42], a key reaction in the biosynthesis of the anticancer drugs, vinblastine and vincristine, which are obtained from Catharanthus roseus. 

The biosynthesis of monoterpenoid indole alkaloids has been intensively investigated since the sixties [76], The great interest in this group of alkaloids is due mainly to the cytotoxic vinblastine and vincristine, which are very useful anticancer drugs, but which are produced by the C. roseus plant in extremely low quantities. It is therefore not surprising that most of the biosynthetic and enzymology studies of monoterpenoid indole bases have been performed to elucidate the biosynthetic pathway of vinblastine and vincristine and its regulation in C. roseus plants. 

Certain adverse reactions can also be associated with individuals who are carriers of rare disease genes, patients with compromised immune systems, and patients with certain chronic diseases. Peripheral neuropathy from anticancer drugs such as vincristine can be accelerated in specific patients with Charcot-Marie tooth syndrome [38], Park et al. [39] has discussed potential mechanisms that make HIV-positive patients more susceptible to enhanced drug toxicity, and Graham et al. [40] showed that the risk of developing rhab-domyolysis from statin-fibrin combinations increased significantly in older patients with diabetes mellitus. 

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