Vinblastine toxicity

Information seems to be limited to this report. On the basis of their findings the authors suggest that erythromycin should be avoided at the time of vinblastine infusion. Use with clarithromycin may be safe. The UK manufacturers of vincristine and vindesine have warned that caution should be exercised in patients taking any drugs known to inhibit the CYP3A subfamily because of the risk of an earlier onset and/or increased severity of adverse effects. One manufacturer of vinblastine states that erythromycin may increase vinblastine toxicity. Note that itraconazole, another CYP3A4 inhibitor, is known to increase the toxicity of vincristine, see Vinca alkaloids -i- Azoles , p.668. 

In an attempt to reduce relapse rate and late toxicity, combined-modality therapy using lower doses of radiation and an abbreviated course of chemotherapy has been evaluated.16 The goal of decreased relapse rate has been achieved, but no overall survival benefit has been documented. A limitation of this approach is exposing patients to the additive toxicities of chemotherapy. Trials that have investigated this approach typically have incorporated between two and four cycles of a standard regimen for HL, such as ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with involved-field radiation. At present, combined-modality therapy is considered to be a standard of care for stage I/II HL. 

The use of triphenylethylene SERMs as Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration, which is likely due to the involvement of proteins with the ability to bind these compounds. For instance, toremifene is able to reverse MDR and to sensitize human renal cancer cells to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular a 1-acid glycoprotein (AAG), which may limit its tissue availability (Braybrooke et al. 2000). In agreement with this, Chatterjee and Harris (1990) have shown that tamoxifen and 4-OH-tamoxifen were similarly potent in reversing MDR in Chinese hamster ovary (CHO) cells with acquired resistance to adriamycin. However, the addition of AAG (0.5 to 2 mg/ml, the range found in vivo) to cell cultures decreased the effect of tamoxifen on reversing MDR, and at the highest AAG concentration there was a complete reversal of the effects of... 

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. 

A new effective metal-ffee radical approach by Murphy et al generates the free radical by treatment with tetrathiafulvalene (TTF).1491 As depicted in scheme 16 the aromatic amine 79 is transformed into the diazonium salt 81 which on treatment with TTF leads to the radical 82. The following stereoselective cyclization gives the hexahydrocarba-zole scaffold 80, a substructure of alkaloids like aspi-dospermidin, strychnin and vinblastin. Also the non-toxic tris(trimethylsilyl)silane was employed for domino reactions, eg. for the preparation of the alkaloid aspidospermidin. 

Although toxicity was observed at 20 mg/kg, good dose responses were observed in the dose range 2.5-10.0 mg/kg. At the highest dose, test/con-trol values in excess of 300% were consistently observed with five cures in one instance and four cures in another. In a parallel test, vinblastine (1) showed TIC 309% at 0.5 mg/kg with five survivors. According to these data leurosine A b-oxide is one of the most active compounds in the B16 test system isolated thus far. 

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... 

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. 

In animals a prominent toxic effect is depression of white blood cell counts. This leukopenia is reversible and is dose related in rats treated with vinblastine. Early observations indicated that the death of animals treated with vinblastine was attributable to an overwhelming bacterial in-... 

Johnson and colleagues have summarized the major toxicological observations made after administration of vinblastine or vincristine to other animals Ib). In rabbits and cats intravenous doses of 0.2 mg/kg vincristine were lethal after the second to the fifth dose on a schedule involving drug administration two to three times a week. Signs consistent with neurotoxicity were observed in rabbits and cats for example, a head drop phenomenon, characteristic of neuromuscular dysfunction, was observed in rabbits, and clonic convulsions were observed in cats. Vincristine is lethal to dogs when administered at 0.05 mg/kg, intravenously, five times in a 1-week period. Vincristine is lethal to monkeys when administered five times on a schedule of 1 mg/kg weekly comparable toxicity is observed when the drug is administered more frequently (daily) at lower doses (e.g., 0.2 g/kg). 

Both vincristine and vinblastine are administered by intravenous injection, and this reflects the relatively poor bioavailability of the drugs indicated in preclinical studies. Oral administration of a vinblastine derivative, vinzolidine (Fig. 2), has been shown to produce some antitumor activity in clinical trials, but investigations of this oral agent have been discontinued because of unpredictable toxicity (50). 

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). 

Incidents of vincristine overdosage have been reported relatively frequently in the medical literature. Some of these have involved inadvertent administration of the intravenous formulation into the central nervous system by the intrathecal route this produces devastating results by a combination of chemical damage to sensitive neuronal tissue as well as biochemical perturbations. Two representative cases of vincristine overdose were described (46) involving administration of vincristine to patients scheduled to receive vinblastine. In one patient toxicity initially involved vomiting and diarrhea with subsequent constipation and paralytic ileus (inhibition of motor activity in the small intestine). Muscle pain... 

Vincristine displays limited myelosuppression but its neurotoxicity is dose limiting. On the other hand the most important toxicity of vinblastine is myelosuppression while it lacks serious risks for neurotoxicity. The toxicity spectrum of vindesine and of vinorelbine is between these two extremes. The vinca alkaloids can cause inappropriate secretion of antidiuretic hormone. 

Vincristine (Oncovin) and vinblastine (Velban) are both produced by the leaves of the periwinkle plant. Despite their structural similarity, there are significant differences between them in regard to clinical usefulness and toxicity. 

Neurological toxicity is the major dose-limiting toxicity of vincristine, whereas bone marrow toxicity is limiting for vinblastine. Severe neutropenia occurs in approximately half of the patients receiving vinorelbine. Severe leukopenia is the major side effect of vinblastine. These drugs are potent local blistering agents and will produce tissue necrosis if extravasated. 

The main dose-limiting toxicity is neurotoxicity, usually expressed as a peripheral sensory neuropathy, although autonomic nervous system dysfunction with orthostatic hypotension, urinary retention, paralytic ileus, or constipation, cranial nerve palsies, ataxia, seizures, and coma have been observed. While myelosuppression occurs, it is generally milder and much less significant than with vinblastine. The other potential adverse effect that can develop is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). 

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