Neurotoxicity vinca alkaloids

Vinca alkaloids (vincristine, vinblastine, vindesine) are derived from the periwinkle plant (Vinca rosea), they bind to tubulin and inhibit its polymerization into microtubules and spindle formation, thus producing metaphase arrest. They are cell cycle specific and interfere also with other cellular activities that involve microtubules, such as leukocyte phagocytosis, chemotaxis, and axonal transport in neurons. Vincristine is mainly neurotoxic and mildly hematotoxic, vinblastine is myelosuppressive with veiy low neurotoxicity whereas vindesine has both, moderate myelotoxicity and neurotoxicity. 

Vinca alkaloids are derived from the Madagascar periwinkle plant, Catharanthus roseus. The main alkaloids are vincristine, vinblastine and vindesine. Vinca alkaloids are cell-cycle-specific agents and block cells in mitosis. This cellular activity is due to their ability to bind specifically to tubulin and to block the ability of the protein to polymerize into microtubules. This prevents spindle formation in mitosing cells and causes arrest at metaphase. Vinca alkaloids also inhibit other cellular activities that involve microtubules, such as leukocyte phagocytosis and chemotaxis as well as axonal transport in neurons. Side effects of the vinca alkaloids such as their neurotoxicity may be due to disruption of these functions. 

Vinblastine is another vesicant vinca alkaloid that causes myelo-suppression and less neurotoxicity than vincristine. The pharmacokinetics of vinblastine are best described by a three-compartment model, with an a half-life of 25 minutes, a 3 half-life of 53 minutes, and a terminal half-life of 19 to 25 hours.12 Vinblastine has shown activity in the treatment of bladder, breast, and kidney cancer, as well as some lymphomas. The doses of vinblastine tend to be higher on a milligram per meter squared basis than vincristine. Nausea and vomiting are minimal with vinblastine. Other side effects include mild alopecia, rash, photosensitivity, and stomatitis. 

Vincristine -vinca alkaloid inhibits tubulin polymerization G2 phase specific -neurotoxicity—peripheral neuropathy -vesicant if extravasated -nausea and vomiting -bone marrow suppression—mild -transient transaminase elevation -constipation (often secondary to neuropathy induced ileus) —intrathecal injection is ALWAYS FATAL... 

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. 

The best known drugs acting as antimitotics are the vinca alkaloids, vincristine (7.90) and vinblastine (7.91). They are very complex indole derivatives that nevertheless have been synthesized. Both are quite effective in various leukemias and in Hodgkin s lymphoma, but show considerable neurotoxicity. Vinblastine and vincristine bind specifically to the microtubular protein tubulin in dimeric form, precipitating depolymerization of the microtubules and functionally acting as a mitotic poison. Vinorelbine (7.92) is a semisynthetic vinca alkaloid functionally identical to vinblastine. 

Vinorelbine is a semisynthetic vinca alkaloid whose mechanism of action is identical to that of vinblastine and vincristine, ie, inhibition of mitosis of cells in the M phase through inhibition of tubulin polymerization. Despite its similarities in mechanism of action, vinorelbine has activity in non-small cell lung cancer and in breast cancer. Myelosuppression with neutropenia is the dose-limiting toxicity, but nausea and vomiting, transient elevations in liver function tests, neurotoxicity, and SIADH are also reported. 

CICLOSPORIN VINCA ALKALOIDS High doses of ciclosporin (7.5-1 Omg/kg per day intravenously) t plasma concentrations of vincristine. The predominant toxic effect of vincristine is peripheral neuropathy, and of the others, myelosuppression Due to a combination, to varying degrees, of inhibition of CYP3A4 metabolism and P-gp inhibition. Vinblastine and vincristine are known substrates of P-gp Monitor for neurotoxicity and myelosuppression. The dose-limiting effect of all vinca alkaloids is myelosuppression. Monitor blood counts and clinically watch for and ask patients to report infections... 

Enhanced and potentially life-threatening neurotoxicity of vinca alkaloids through concomitant therapy with itraconazole has been the subject of several compelling... 

The melanocortin Org 2766, an ACTH analogue, which is not yet available for clinical use, alleviates neurotoxicity due to vinca alkaloids and cisplatin, perhaps by enhancing neural repair. However, whereas preliminary results suggested some neuroprotection in women with ovarian cancer treated with cisplatin, these results were not confirmed in a randomized, multicenter, double-blind, placebo-controlled dose-finding study, even with higher doses of Org 2766 (113). 

The concomitant or previous use of potentially neurotoxic drugs (for example paclitaxel, vinca alkaloids, or hexam-ethylmelamine) can increase the risk of peripheral neuropathy due to platinum compounds (68,69). 

All four vinca alkaloids block mitosis with metaphase arrest. Their antitumor activity is based on their high binding affinity to intracellular tubulin, which is the protein subunit of the spindle microtubules. The binding constants of vincristine, vinblastine, and vindesine for tubulin are 8, 6, and 3.3 nmol/1 respectively (9,10). The formation of complexes between the vinca alkaloids and tubulin prevents the polymerization of the tubulin subunits to microtubules, which results in depolymerization of microtubules and inhibition of microtubule assembly. Based on the fact that microtubule assemblies also play a pivotal role in the movement of neurotransmitter substances along neuronal axons, vinca alkaloids can cause neurotoxicity, particularly at higher concentrations (9,10). 

The most commonly reported dose-limiting toxic effect of vinca alkaloids is a mixed sensorimotor polyneuropathy (35). Vincristine has been associated with highest incidence, followed by vindesine and vinblastine vinorelbine canses less neurotoxicity than the other congeners (2,5,8,36). The neurotoxic effects of vinca alkaloids are reversible (5). 

The vinca alkaloids may have synergistic effects on the nervous system. Amongst 17 patients with metastatic breast cancer given the four-drng combination, vincristine -I- vinblastine -I- doxorubicin + cyclosphosphamide, there was a high incidence of acute neurotoxicity at half the usual therapeutic dose of vincristine and vinblastine (37). 

Finally, the aminothiol amifostine has been proposed to be effective in preventing vincristine-induced neurotoxicity however, clinical data are still lacking to assess its role as a neuroprotective agent in terms of vinca alkaloids (5). 

Stewart DJ, Maroun JA, Lefebvre B, Heringer R. Neurotoxicity and efficacy of combined vinca alkaloids in breast cancer. Cancer Treat Rep 1986 70(5) 571-3. 

E All of the above. Vinblastine is hepatically eliminated and must be dose adjusted for hepatic dysfunction. Because vinca alkaloids may cause neurotoxicity (including paralytic ileus), it is important... 

A genetic profile on the basis of SNPs would be more than useful for Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) risk stratification, prior to start treatment. CIPN is a potentially severe and long-lasting side effect of commonly employed anticancer drugs platinum compounds, taxanes, proteasome inhibitors, vinca alkaloids, and epothilones they are used every day to treat... 

Despite only a minor difference in the chemical structures of vinblastine and vincristine, the clinical effects differ considerably. Surprisingly there is no clinical evidence of cross resistance between them, or with radiation and other presently known oncolytic agents. The rise and fall of the blood activity level of vincristine is steeper than that of vinblastine.The dosage requirements of both alkaloids differ markedly the weekly intravenous dose of vinblastine for humans is 0.1—0.2 mg per kg, that of vincristine, however, is approximately one tenth of this. Concerning the side-effects, vincristine shows more neurotoxic effects and vinblastine is considered to have more potency in bone-marrow depression. This is not without consequences on human therapy therapy is limited by bone-marrow depression with vinblastine and neuromuscular effects, with vincristine. Early symptoms of side-effects are vomiting, fever, and exanthemes. Late symptoms are C.N.S. disturbances, alopecia, and leukopenia. C.N.S. disturbances are manifested by various symptoms such as paresthesias, neuritis, paresis, and muscular atrophy, accompanied by quenched reflexes. Even behaviour may be affected after a long period of treatment. But why do all these side-effects happen, when Vinca alkaloids are unable to pass the blood-brain barrier The only explanation we have at hand is that they are possibly caused by metabolites or breakdown products of the normal biochemical pathways, which are disturbed by the alkaloids. 

These drugs are used to treat leukaemia, lymphoma, testicular cancer and lung cancer. Adverse reactions of vinca alkaloids are relatively mild. Some are due to the inhibition of other functions of microtubules. Thus migration of white blood cells and axonal transport in neurons are inhibited leading increased susceptibility to infection and neurotoxicity respectively. 

In addition to their key role in the formation of mitotic spindles, microtubules are found in high concentration in the brain and are essential to cellular functions such as movement, phagocytosis, and axonal transport. Side effects of the vinca alkaloids, such as their neurotoxicity, may be due to disruption of these functions. 

The vinca alkaloids, vincristine and vinblastine, inhibit tumor growth by destroying microtubules which are essential for cell structure and mitosis. They differ in that vinblastine "blasts" bone marrow while vincristine spares marrow. Vincristine however, causes peripheral neuropathy which is manifested by decreased reflexes, foot drop, weak fingers and decreased autonomic function. Another vinca alkaloid, vindesine is being investigated for the treatment of nonsmaU cell lung cancers. Vindesine causes both marrow suppression and neurotoxicity. 

The manufacturers of voriconazole advise caution if it is given to patients treated with the vinca alkaloids (vincristine and vinblastine are named) because of the risk of neurotoxicity.The US manufacturer recommends that dose adjustments of the vinca alkaloids should be considered. ... 

Previous exposure to potentially neurotoxic chemotherapeutic agents, such as platinum compounds and vinca alkaloids, does not appear to increase the risk of neurotoxicity with paclitaxel [5 ]. However, patients with co-existing medical illnesses associated with peripheral neuropathy, such as diabetes mellitus and alcohol abuse, may be more likely to develop a peripheral neuropathy. 

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. 

Vincamine, vinblastine and vincristine are very important clinic alkaloids. They are produced naturally by plants vincamine by Vinca minor, and vinblascine and vincristine by Madagascar periwinkle Catharanthus roseus). The vindoline synthesis pathway starts with strictosidine and, via dehydrogeissoschizine, preakuammicine, stemmadenine and tabersonine, is converted to vindoline and vincristine (Figure 42). Conversion from vindoline to vinblastine is based on the NADH enzyme activity. Vinblastine and vincristine are very similar alkaloids. The difference is that vincristine has CHO connected to N, whereas vinblastine in the same situation has only CO3. This synthetic structural differences influence their activity. Vinblastine is used to treat Hodgkin s disease (a form of lymphoid cancer), while vincristine is used clinically in the treatment of children s leukaemia. Vincristine is more neurotoxic than vinblastine. 

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