Of vincristine

Additive bone marrow depressive effects occur when the miotic inhibitor drugs are administered with other anti-neoplastic dragp or radiation therapy. Administration of vincristine with digoxin results in a decreased therapeutic effect of tlie digoxin and decreased plasma digoxin levels. There is a decrease in serum concentrations of phenytoin when administered widi vinblastine... 

Figure 4.66 Reduced synthesis tree for synthesis of vincristine by Fukuyama method. Step counts are shown in parantheses.

The current induction therapy for acute lymphocytic leukemia (ALL) typically consists of vincristine, asparaginase, and a steroid (prednisone or dexamethasone). An anthracycline is added for higher-risk patients. 

Chloride channels themselves may directly export drugs, particularly since certain chloride channels appear to act in the same manner as P-glycoprotein (multiple drug resistance protein) [227], which is involved in the export of vincristine [228,229], daunomycin [228,229], gramicidin D [230], and cyclosporin... 

Ronghe, M., Burke, G.A., Lowis, S.R, and Estlin, E.J. 2001. Remission induction therapy for childhood acute lymphoblastic leukaemia clinical and cellular pharmacology of vincristine, corticosteroids, L-asparaginase and anthracyclines. Cancer Treatment Reviews 27(6), 327-337. 

Sahenk, Z., Brady, S. T. and Mendell, J. R. Studies on the pathogenesis of vincristine-induced neuropathy. Muscle Nerve 10 80-84,1987. 

Loe, D.W., Deeley, R.G. and Cole, S.P. (1998) Characterization of vincristine transport by the M(r) 190,000 multidrug resistance protein (MRP) evidence for cotransport with reduced glutathione. Cancer Research, 58, 5130-5136. 

Ozgen, U., Savasan, S., Stout, M., Buck, S., and Ravindranath, Y., 2000, Further elucidation of mechanism of resistance to vincristine in myeloid ceUs role ofhypochlorous add in degradation of vincristine by myeloperoxidase, Leukemia 14 47-51. 

Webb MS, Harasym TO, Masin D, Bally MB, Mayer LD. Sphingomyelin-cholesterol liposomes significantly enhance the pharmacokinetic and therapeutic properties of vincristine in murine and human tumour models. Br J Cancer 1995 72 896. 

Tokudome Y, Oku N, Doi K, Namba Y, Okada S. Antitumor activity of vincristine encapsulated in glucuronide-modified long-circulating liposomes in mice bearing Meth A sarcoma. Biochim Biophys Acta 1996 1279 70. 

Boman NL, Mayer LD, Cullis PR. Optimization of the retention properties of vincristine in liposomal systems. Biochim Biophys Acta 1993 1152 253. 

Zhu G, Oto E, Vaage J, et al. The effect of vincristine-polyanion complexes in STEALTH liposomes on pharmacokinetics, toxicity and anti tumor activity. Cancer Chemother Pharmacol 1996 39 138. 

Allen TM, Newman MS, Woodle MC, et al. Pharmacokinetics and anti-tumor activity of vincristine encapsulated in sterically stabilized liposomes. Int J... 

The absolute configuration of the stereo centers of vinblastine (1) was determined from the X-ray crystal structure of vincristine (2) methiodide (79,80) in view of the known relationship between 1 and 2. The absolute stereochemistry at C-I8 in vinblastine (1) and related derivatives can also be deduced by means of ORD and CD spectroscopy (81,82). The determination was made possible by the synthesis and structure elucidation of several compounds possessing the unnatural configuration at C-18 (82,84). Because this stereo center controls the relative geometry of the... 

Vincristine (leurocristine) (2) is present in C. roseus in approximately 0.0003% yield, the lowest level of any medicinally useful alkaloid produced on commercial basis. Since the initial isolation of 2 45), its structure elucidation has been reviewed 1,3). The final confirmation of structure 2 and the determination of the absolute configurations of the stereo centers of vincristine (2) were achieved by X-ray crystallography of its methiodide derivative 79,80). 

The extremely low yield of vincristine (2) from intact plants has made pursuit of its biosynthesis a very challenging problem, which at this point in time remains unsolved. Kutney et al. have used both anhydrovinblastine (8) (227) and catharanthine N-oxide (107) (233) as precursors to vincristine (2) in a cell-free preparation, but incorporation levels were extremely low. Therefore, the question of whether vinblastine (1) is an in vivo, as well as an in vitro, precursor remains to be answered. Several possibilities exist for the overall oxidation of vinblastine (1) to vincristine (2), including a direct oxidation of the A-methyl group or oxidative loss of the N-methyl group followed by N-formylation. 

X-Ray diffraction analyses of vincristine methiodide (39) and vinzoli-dine 1-naphthalene sulfonate (40) provide atomic coordinates of compounds that are either modified in the velbanamine portion (alkylation at N-6, Fig. 3) or in the vindoline portion (a spiro-fused oxazolidinedione at C-3 and C-23, Fig. 4). These structures show a chair-boat conformation for ring C with C-8 exhibiting an endo pucker. Ring D is clearly in a chair conformation, but, in contrast to the conclusions drawn from C-NMR studies, the N-6 -C-7 bond is axial relative to the piperidine ring. 

Fig. 3. X-Ray crystal structure of vincristine methiodide [coordinates from Moncrief and Lipscomb (39)].

There is little mention of N-6 quatemerization reactions in the literature. N -Methylvincristine, a methiodide of 2, was prepared by reaction of vincristine (2) with iodomethane, but few experimental details are available (59). 

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). 

Treatment of cells with concentrations of vincristine or vindesine that produce relatively little effect on cell viability results in an accumulation of cells in the M and Gj (gap after DNA synthesis) phases of the cell cycle. The cellular effects, as measured by techniques such as flow... 

Vincristine resistance has been studied in Chinese hamster ovary cell lines cells resistant to vincristine also are resistant to vinblastine and vindesine. Suggestions were made that, in cells with relatively low levels of drug resistance, at least two prominent mechanisms of resistance can occur (22). In the first instance, cellular resistance may be attributable to membrane alterations that are reversible, functionally, by treatment with verapamil. In the second, resistance has been postulated to be due to an altered sensitivity of tubulin to the effects of the drugs the primary basis for postulating an altered interaction with tubulin was that a subgroup of cells resistant to vincristine showed enhanced sensitivity to taxol, a drug that can stabilize microtubules. It should be emphasized that differential sensitivities of tubulins from different tumor cells to the effects of vincristine or vinblastine has been proposed as a basis for the susceptibilities of cells to the cytotoxic effects of such drugs (23). Differences have been described in the electrophoretic patterns for tubulins obtained from vin-... 

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. 

Effect of Quinacrine on Activity of Vincristine against Vincristine-Resistant P388 Leukemia in Mice... 

Studies of the metabolism of vincristine and vinblastine have been complicated by chemical alterations of the drugs that occur during processing of samples for analysis. Extraction of these compounds under acidic conditions has been reported to minimize chemical degradation, and HPLC studies of the metabolism of vincristine indicate that microsomal preparations from mouse liver, but not those from human rhabdomyosarcoma tissue, convert vinblastine to 4-deacetyl vinblastine in vitro (38). 

The disappearance of tritiated vindesine from the blood of rats has been reported to be biphasic, with half-life estimates of 15 min (distribution) and 10 hr (elimination) (59) it is likely that the prolonged elimination phase represents a hybrid between the second elimination phase described above for vincristine and the prolonged third phase evident on inspection of log concentration-time plots for vincristine in the rat. Biliary excretion contributes heavily to the elimination of vindesine in the rat. The bioavailability of vindesine in the rat appears to be very poor. The distribution of vincristine to different tissues in the mouse has been correlated with the estimated concentration of tubulin in the tissues (40). Tubulin concentration was measured by the capacity of a tissue to bind colchicine (40) comparable relationships between tissue concentrations of vincristine and colchicine binding capacity were observed for the dog and the monkey, but it should be emphasized that the correlations were based on the assumption that tissue tubulin content is closely similar in the mouse, dog, and monkey. 

Houghton and colleagues found that tumor tissue sensitive to the inhibitory effects of vincristine retains the drug much longer than some normal... 

Johnson and colleagues made a provocative observation in the course of exploratory preclinical toxicological studies of vincristine, namely, that folinic acid (Leucovorin citrovorum factor 5-formyl-5,6,7,8-tetrahy-drofolic acid) was able to protect mice from the toxicity of high doses of vincristine lb). Vincristine, at a dose of 2.5 mg/kg administered intravenously, resulted in a mortality of 90% over a period of 30 days, but treatment with folinic acid lowered the mortality to 25%. The protection against vincristine toxicity did not occur when folic acid was substituted for folinic acid. A report has appeared (45) indicating that there is no specific protective effect of folinic acid against vincristine toxicity in mice and that the protection can be observed by comparable treatment with isotonic saline solution. As discussed in Section Vll, there is not conclusive evidence that folinic acid is able to ameliorate vincristine toxicity in humans (46). 

Half-lives estimated after the administration of vinblastine to patients were 4 min, 1.6 hr, and 25 hr, indicating rapid distribution of the drug to most tissues, relatively rapid clearance, and a subsequent slow terminal elimination process. The distribution and initial clearance phase for vincristine are kinetically comparable to those observed for vinblastine half-lives for these phases have been reported to be 4 min and 2.3 hr in studies with vincristine. The terminal elimination phase for vincristine has been reported to be three to four times longer than that estimated for vinblastine, and the slow elimination of vincristine from susceptible neuronal tissue has been suggested to play a role in the neurotoxicity commonly observed in clinical settings with vincristine but not with vinblastine 51). 

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). 

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