Vinca vinorelbine

Ngan VK, Bellman K, Hill BT et al (2001) Mechanism of mitotic block and inhibition of cell proliferation by the semisynthetic Vinca alkaloids vinorelbine and its newer derivative vinflunine. Mol Pharmacol 60 225-232... 

Vinca alkaloids Vinorelbine Myelosuppression Fatigue, nausea, vomiting, ulceration necrosis with extravasation... 

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. 

Three classes of plant-derived drugs, the vinca alkaloids (vincristine, vinblastine, and vinorelbine), the epipodo-phyllotoxins (etoposide and teniposide and the tax-anes (paclitaxel and taxotere), are used in cancer chemotherapy. These classes differ in their structures and mechanisms of action but share the multidrug resistance mechanism, since they are all substrates for the multidrug transporter P-glycoprotein. 

Vinca dimer indole alkaloids (e.g., vinblastine) act as spindle poison. They bind tubulin, inhibiting polymerization into microtubules, major elements of the cytoske-Vinblastine itself and its analogue vinorelbine (Navelbine ) are marketed for cancer therapies (Figure 4.48). Because of the obvious difficulty in synthesizing such highly complex structures, there were no reports on the preparation of fluorinated derivatives until the remarkable work of Jacquesy s group on the synthesis in super-acidic media. 5 ... 

Vinflunine (Javlor ) is a member of the second-generation Vinca dimer alkaloids. This 4 -difluoro analogue is more active than vinorelbine in several cancers. It is now in Phase III clinical trials as a chemotherapeutic agent targeted at a variety of cancers (non-small-cell lung and bladder cancers). However, the role of fluorine substitu-... 

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. 

Vinca alkaloids and analogs vinblastine sulfate vincristine sulfate vinorelbine tartrate... 

Two dimeric Vinca alkaloids, vinorelbine and anhydrovinblastine, have also been investigated using the CHCl3-HF-SbF5 system.550-552 In both cases, the corresponding products difluorinated in the ethyl side chain (140) were isolated in modest yields [Eq. (5.206)]. The mechanistic pathway suggested that the transformation includes steps already depicted in Schemes 5.57 and 5.58. 

A rare but well-known adverse effect of vinca alkaloids, including vinorelbine, is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (1195-1197). The diagnosis is usually based on clinical and laboratory... 

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. 

Vincristine [vin KRIS teen] and vinblastine [vin BLAST een] are structurally-related compounds derived from the periwinkle plant, Vinca rosea. They are therefore referred to as the vinca alkaloids. A structurally related new (and less toxic) agent, vinorelbine [vye NO rel been] shows promise in the treatment of advanced non-small cell lung cancer. 

CLARITHROMYCIN, ERYTHROMYCIN VINCA ALKALOIDS -VINBLASTINE, VINCRISTINE, VINORELBINE t adverse effects of vinblastine and vincristine Inhibition of CYP3A4-mediated metabolism. Also inhibition of P-gp efflux of vinblastine Monitor FBCs. Watch for early features of toxicity (pain, numbness, tingling in the fingers and toes, jaw pain, abdominal pain, constipation, ileus). Consider selecting an alternative drug... 

Figure 1 Structures of the vinca alkaloids vinblastine, vincristine, videsine, and vinorelbine.

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

Vinorelbine is the only vinca congener that can also be used orally. Its oral availability averages 43% and is not affected by food (19). The interpatient variability in blood concentrations is in the same range as after intravenous administration (15). 

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). 

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