Vinblastine/vincristine

MRP1 (ABCC1) Glucuronides and sulfate conjugates of steroid hormones and bile salts, colchicine, doxorubicin, daunorubicin, epirubicin, folate, irinotecan, methotrexate, pacitaxel, vinblastine, vincristine, and others... 

Griseofulvin, lAA, podophyllotoxin, taxol, vinblastine, vincristine Calcineurin inhibitors tacrolimus, cyclosporin A... 

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

Anticancer Cycloserine Glucocorticoids Interferon-a L-Asparaginase Leuprolide Procarbazine Tamoxifen Vinblastine Vincristine... 

Plant alkaloids Taxol (paclitaxel) Vinblastine Vincristine Inhibits mitosis Interfere with mitosis, block P tubuhn polymerisation... 

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. 

Vinblastine, vincristine, and structurally related analogs inhibit microtubule polymerization by 50% at concentrations in the range 0.1-1 xM, and the process of tubulin addition to preformed microtubules, at steady state, is comparably sensitive to inhibition by these agents (5). As shown in Table I, the differences in values for inhibition of steady-state tubulin addition by vinblastine, vincristine, vindesine, and vinepidine were relatively small, but the pattern of activity in the tubulin addition system did not parallel that observed when the compounds were evaluated for effects on the proliferation of B16 melanoma cells in vitro. Vinepidine was more than twice as potent as vinblastine as an inhibitor of steady-state tubulin addition but nearly 10-fold less potent than vinblastine as an inhibitor of cell growth (i). 

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). 

Granting that precise mechanisms responsible for the characteristic anticancer activity and mammalian toxicity of vinblastine, vincristine, and related compounds have not been rigorously established, it nevertheless is important to describe representative biological and biochemical actions of the drugs that may have mechanistic pertinence. The susceptibility to mitotic spindle dissolution of cell lines with 100-fold differences in sensitivity to vinblastine has been investigated 14). There was an excellent correlation between drug concentrations required to produce inhibition of cell colony formation and those required to dissolve mitotic spindles. It is noteworthy that effects on the mitotic spindle of vinblastine occur very rapidly and can be detected within 30 sec. 

Cells that exhibit high (several hundredfold) levels of resistance to vinblastine, vincristine, and vindesine have an extremely limited capacity to accumulate radiolabeled vinblastine for example, essentially no increase in radioactivity associated with human leukemic lymphoblastic cells resistant to vinblastine could be detected over a 60-min incubation period in the presence of concentrations of tritiated vinblastine that were cytotoxic to parent cells. The parent cells, highly sensitive to vinblastine, were observed to accumulate vinblastine to levels seven-fold higher than those observed for the resistant cells (76). 

Human KB carcinoma cells resistant to vinblastine and other drugs have been shown to exhibit increased membrane vesicular binding of tritiated vinblastine, and this binding is correlated with photoaffinity labeling of a 150,000- to 170,000-dalton protein in the vesicles. Labeling of this protein is inhibited by vinblastine, vincristine, and verapamil but not by colchicine (79). The failure of colchicine to inhibit the labeling of the membrane protein is unexpected since the cells from which the protein was isolated are resistant to colchicine as well as vinblastine. 

Estimates for the apparent volumes of distribution for vinblastine, vincristine, and vindesine are extremely high the mean value for vinblastine is approximately 2000 liters (for a 70-kg individual), and those for vincristine and vindesine are approximately 600 liters (5/). Such high estimates... 

As opposed to vinblastine, vincristine s hematologic effects are minimal. In fact, thrombocytosis is often seen following vincristine administration (10,25,26). Alopecia occurs in from 13 to 22% of patients given full doses of vincristine. Cutaneous effects are, however, more unusual and are a practical problem only when the drug is extravasated (21,22). The spectrum of vindesine side effects is similar to that seen with vincristine. 

In recent years, however, some of the greatest emphasis has been placed on the search for anticancer and antiviral agents derived from natural products. Success in that area has not heen as great as that achieved in other helds. Since 1960, only seven plant-derived drugs have heen approved by the FDA for use as anticancer agents. Four of those drugs, vinblastine, vincristine, etoposide, and teniposide, were discovered in the 1950s. The last three—Taxol , topotecan, and irinotecan—were discovered and approved much more recently. 

Aprepitant may be affected by paroxetine, CYP2C9 substrates (eg, phenytoin, tolbutamide, warfarin), CYP3A4 substrates (eg, alprazolam, cisapride, dexamethasone, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, methylprednisolone, midazolam, paclitaxel, pimozide, triazolam, vinblastine, vincristine, vinorelbine), and oral contraceptives. 

Figure 3. Schemes of taxol, vinblastine, vincristine and vincamine.

Catharanthus roseus Ajmalicine Catharan thine Vindoline Vinblastine Vincristine Vindesine Alioline... 

Aprepitant (Emend) [Centrally Acting Antiemetic] Uses Pre-vents N/V assoc w/ emetogenic CA chemo (eg, cisplatin) (use in combo w/ other antiemetics) Action Substance P/neurokinin l(NKi) receptor antagonist Dose 125 mg PO day 1, 1 h before chemo, then 80 mg PO qAM days 2 3 Caution [B, /-] Contra Use w/ pimozide, Disp Caps SE Fatigue, asthenia, hiccups Interactions T Effects W/ clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin T effects OF alprazolam, astem-izole, cisapride, dexamethasone, methylprednisolone, midazolam, pimozide, terfe-nadine, triazolam, chemo agents, eg, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine, vinorelbine i effects W/ paroxetine,... 

Chemotherapy Cyclophosphamide, erlotlnlb, ifos-famide, paclitaxel, tamoxifen, vinblastine, vincristine HIV protease inhibitors Amprenavir, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir HMG-CoA reductase inhibitors Atorvastatin, lovastatin, simvastatin... 

Vincristine is an alkaloid derivative of Vinca rosea and is closely related in structure to vinblastine. Its mechanism of action, mechanism of resistance, and clinical pharmacology are identical to those of vinblastine. Despite these similarities to vinblastine, vincristine has a strikingly different spectrum of clinical activity and safety profile. 

Catharanthus roseus (L.) G. Don Chang Chun Hua (Madagascar periwinkle) (whole plant) Vinblastine, vincristine, carosine, vinrosidine, lenrosine, lenrosivine, rovidine, perivine, perividine, vindolinine, pericalline.33 This herb is toxic. Anticancer in chronic lymphocytic leukemia and Hodgkin s disease, in acute lymphocytic leukemia. 

Pharma- ceuticals Alkaloids ajmalacine, atropine, berberine, camptothecin, ceuticals codeine, hyoscyamine, quinine, morphine, scopolamine, serpentine, vinblastine, vincristine... 

The vinca alkaloids (vinblastine, vincristine, and vindesine), which bind to tubulin, block mitosis with metaphase arrest. Vinca alkaloids are used for the following types of cancer ... 

Sulfuric acid and potassium permanganate are used to dispose of doxorubicin or daunorubicin wastes. Doxorubicin shows mutagenicity only at high concentrations. Care must be exercised by wearing protective clothing when handling urine and feces after administration of doxorubicin, etoposides, fluorouracil, methotrexate, mitoxantrone, mustine, procarbazine, melphalan, mercaptopurine, vinblastine, vincristine, and hydroxyurea.217... 

Acyclovir Erythromycin Ivermectin Itraconazole Rifampin Actinomycin D Daunorubicin Doxorubicin Docetaxel Epirubicin Etoposide Imatinib Irinotecan Paclitaxel Vinblastine Vincristine Amprenavir Indinavir Nelfinavir Ritonavir Saquinavir Cyclosporine A Tacrolimus Digoxin Quinidine Verapamil Diltiazem Aldosterone Cortisol Corticosterone Dexamethasone Hydrocortisone Cyclosporine Metkephamid Enkephalin... 

An alternative explanation to that of the molecular weight threshold of BBB transport is thought to be due to the action of an active efflux system at the BBB. It is proposed that such an active efflux system is p-glycoprotein based (see Sections 1.3.2 and 6.3.4). For example, vinblastine, vincristine, and cyclosporin are all potential substrates for p-glycoprotein. 

Increases 10X effectiveness of TUB-acting Vinblastine, Vincristine Taxol [bitter]... 

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