Vinca vindesine

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. 

Neurologic sequelae with vinblastine are much less common than those seen with vincristine and vindesine. Nonetheless, a causal relationship has been established for seizures, psychotic episodes, and confusional episodes. As common with other vinca agents, absence of reflexes and peripheral neuropathy are well described 23,24). 

The vinca alkaloids comprise vincristine and vinblastine. These complex, heterocyclic alkaloids are derived from the periwinkle plant. Vindesine and vi-norelbine are semisynthetic analogues. These drugs are M-phase specitic. Binding specifically to tubulin they inhibit the polymerization of microtubules. The consequent ineffective chromosome segregation initiates apoptosis for both normal and malignant cells. 

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 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 ... 

Vinca alkaloids (SEDA-28, 538) vinblastine, vincristine, vindesine, vinorelbine. 

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). 

Acute shortness of breath and bronchospasm have been reported after the administration of vinca alkaloids, for example vinblastine and vindesine (30-34). The respiratory effects, including abrupt onset of progressive dyspnea, non-productive cough, pleuritic chest pain, profound wheezing, and diffuse basal crackles, were more common when mitomycin was used concomitantly. The onset of symptoms can be rapid (for... 

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). 

Prestifilippo J, Lewin D. Dyspnea following vinblastine or vindesine administration in patients receiving mitomycin plus vinca alkaloid combination therapy. Cancer Treat Rep 1984 68(7-8) 1029-31. 

Plant derivatives are from several sources. Vinca alkaloids, including vincristine, vinblastine and vindesine, are from... 

Rarely, azathioprine and its major metabohte 6-mercaptopurine have been reported to produce an acute restrictive lung disease. Procarbazine, a methylhydrazine associated more commonly with Loef-fler s syndrome, rarely has been associated with pulmonary fibrosis. The vinca alkaloids vinblastine and vindesine have been reported to produce severe respiratory toxicity in association with mitomycin. The incidence with the combination is 39% and may represent a true synergistic effect between these agents. ... 

Vinorelbine is a semisynthetic vinca alkaloid. Single-agent activity has been demonstrated in advanced NSCLC, with response rates of up to 33%, median survivals of 40 weeks, and 1-year survival rates of 24% to 30%. The combination of vinorelbine plus cisplatin has demonstrated superior efficacy to either agent alone, and to vindesine plus cisplatin in randomized phase in trials. ... 

Vinblastine and vincristine have been used clinically for many years. The major importance of vinblastine is as part of a combination treatment for Hodgkin s disease, while vincristine is used in combination chemotherapy of acute lymphoblastic leukemias and lymphomas. Several analogues of the vinca alkaloids have entered clinical use or clinical trials, including vindesine (3), vinorelbine (4), " the naturally occurring anhydrovin-blastine (5), and vinflunine (6). ° Several synthetic approaches to the vinca alkaloids have been developed, especially by Kuehne, while studies of the chemistry of the alkaloids in super acidic media have yielded new alkaloids such as vinflunine. ... 

Examples of vinca alkaloids are vinblastine, vincristine and vindesine. 

An effect of Vinca alkaloids that may also be important in their anti tumour activity is their antivascular action. It has been shown that vincristine and vindesine are able to reduce the capillaiy network formation by HUVEC cells cultured on Matrigel at non-cytotoxic concentrations, while vinblastine and vinorelbine produce anti-angiogenic effects by direct cytotoxicity [185]. Vinflunine seems to have an antivascular activity consistently superior to that of vinorelbine [25]. 

When incubated with human hepatocytes, vinorelbine was the most rapidly and intensely accumulated Vinca alkaloid followed by vinblastine, vindesine and vincristine, as would be suggested by the lipophilicities of the molecules [187]. Vinflunine is even more lipophilic than vinorelbine and accumulates taster inside cells [23]. 

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