Vincristine toxicity

L-asparaginase—be prepared to treat anaphylaxis at each administration giving with or immediately before Vincristine may increase Vincristine toxicity... 

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). 

Gillies J, Hung KA, Fitzsimons E, et al. Severe vincristine toxicity in combination with itraconazole. Clin Lab Haematol 1998 20 123-124. 

Kamaluddin M, McNally P, Breatnach F, O Marcaigh A, Webb D, O Dell E, Scanlon P, Butler K, O Meara A. Potentiation of vincristine toxicity by itraconazole in children with lymphoid malignancies. Acta Paediatr 2001 90(10) 1204-7. 

Asparaginase and vincristine should not be used together on the same day, since simultaneous administration can cause increased vincristine toxicity. It has been suggested that this is due to a deleterious effect of asparaginase on hepatic function, reducing the metabolism of vincristine (5). 

Murphy JA, Ross LM, Gibson BE. Vincristine toxicity in five children with acute lymphoblastic leukaemia. Lancet 1995 346(8972) 443. 

These reports appear to be the only ones implicating isoniazid in an increase in vincristine toxicity, but they serve to emphasise the importance of very close neurological supervision in anyone given both drugs. 

Vincristine Fluconazole (4 mg/kg per day) increased the incidence of vincristine toxicity in children with acute lymphoblastic leukaemia [63 ]. A retrospective analysis suggested also that patients receiving fluconazole had 4.5-fold risk to develop neuropathy. 

Teusink AC, Ragucd D, Shatat IF, Kalpatthi R. Potentiation of vincristine toxicity with concomitant fluconazole prophylaxis in children with acute lymphoblastic leukemia. Pediatr Hematol Oncol 2012 29(l) 62-7. 

Cumulative organ toxicity also presents a significant obstacle for effective chemotherapy. In many cases, the severity of the toxicity impedes the broader use of an agent. Other specific toxicities are associated with specific agents, for example cardiotoxicity with adriamycin (32), renal toxicity with i7j -platinum (28), and neurotoxicity with vincristine (49). 

Nitrogen mustard is clinically used for the treatment of lymphomas and some forms of lung cancer. The major indication for mechlorethamine is Hodgkin s disease as a part of the MOPP regimen (mechlorethamine + vincristine (oncovin) + procarbazine + prednisone). The usual dose consists of 6 mg/m2 on days 1 and 8. This drug has pronounced hematological toxicity (myelo-suppression). 

Increased toxicity has been noted when given concurrently with vincristine and prednisone. Decreased metabolism when used with cyclophosphamide. 

Doxorubicin (Adriamycin) Myelosuppression, alopecia, cumulative dose-limiting toxicity, myocardium damage Given in combination with vincristine and dexamethasone (VAD)... 

Doxorubicin—monitor cumulative dose for cardiac toxicity (not to exceed 550 mg/M2 or 450 mg/M2 with prior chest radiotherapy) vesicant—avoid extravasation use 50% for bilirubin 1.5-3.0 use 25% for bilirubin >3.0 Vincristine—vesicant—avoid extravasation cumulative neurotoxicity—may produce severe constipation maximum 2 mg per administration ... 

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. 

O. van Tellingen, T. Buckle, J.W. Jonker, M.A. van der Valk, and J.H. Beijnen. P-glycoprotein and Mrpl collectively protect the bone marrow from vincristine-induced toxicity in vivo. Br J Cancer. 89 1776-1782 (2003). 

Mayer LD, Bally MB, Loughrey H, Masin D, Cullis PR. Liposomal vincristine preparations which exhibit decreased drug toxicity and increased activity against murine L1210 and P388 tumors. Cancer Res 1990 50 575. 

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. 

The functionality associated with N-1 of the vindoline portion of the bisindole alkaloids confers much biological diversity to these compounds. This property is exemplified by the differences in the cellular pharmacology, antitumor efficacy, and toxicity of vinblastine (1) and vincristine (2). Since 1 is isolated from extracts of Catharanthus in approximately 10-fold greater yield, it is not surprising that several oxidative methods have... 

Multiple single-point modification of both halves of the bisindole framework provided vinepidine (144), a bisindole alkaloid that exhibited experimental antitumor activity similar to vincristine without demonstrating the acute neuronal toxicity of this alkaloid. Ultimately, the vinepidine experience was both educational and an exercise in humility, since the compound showed promise in preclinical neurotoxicology models yet demonstrated considerable neurotoxicity in clinical trials. Nevertheless, vinepidine brings a rich example of the combined effects of ring D conformation (with its associated effect on N-6 basicity) and the presence of an N-1 formyl group. 

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). 

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