Vinblastine 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. 

Fig. 7. Effects of vinblastine, vindesine, vincristine, vinzolidine, and vinepidine on neuronal processes in cultured rat midbrain cells [data from Boder et at. (9i)).

VP Vinblastine/vindesine, cisplatinum Non-small cell lung cancer... 

The plant alkaloids (vincristine, vinblastine, vindesine and vinorelbine) and taxoids (paclitaxel, docetaxel) inhibit microtubule assembly and cause cell cycle arrest in mitosis. They particularly cause bone marrow depression, peripheral neuropathy (vincristine) and alopecia. Etoposide blocks the cell cycle before mitosis. 

Catharanthus roseus India Vincristine, vinblastine, vindesine... 

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]. 

A syndrome of acute pulmonary toxicity, characterised by severe shortness of breath, can occur when vinblastine, vindesine or vinorelbine is given with mitomycin. Fatalities have occurred. 

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. 

The structural modification of natural products is useful in several ways. The known pharmacology of bisindole alkaloids is enriched by the diversity of chemical structures that are made available by structure modification and total synthesis. These molecules have served as biochemical probes in several areas of biology, especially in those of microtubule assembly and drug resistance. The most elusive prize, however, has remained the discovery of new compounds with clinical activity. In recent years several compounds have been evaluated in clinical trials, but vinblastine and vincristine remain the only bisindole alkaloids approved for the treatment of cancer in the United States. These compounds are joined by vindesine in Europe, and at least two new derivatives are the subject of ongoing clinical trials. Considering the breadth of chemical research in this area, the overall yield as measured by new compounds with clinical activity has been relatively low, but this observation is not unique in history of analog development in cancer research. Nevertheless, the search continues, and this chapter details the chemical endeavors to discover a new bisindole alkaloid with clinical activity. 

Reaction of vinblastine (1) with excess ammonia in anhydrous methanol in a sealed pressure vessel at 100°C for 60 hr produces a mixture of products which gives, after chromatography on silica gel, 4-deacetylvin-blastine amide (vindesine, VDS, 59) and 4-deacetyl-18 -decarbomethoxy-vinblastine amide (60) in yields of 42 and 15%, respectively (53). A much improved preparation of vindesine (59) was realized by hydrazinolysis of... 

The alkaloids vinblastine and vincristine (Fig. 1) have attained a significant role in cancer chemotherapy. A relatively large number of analogs of these alkaloids have been evaluated for biological activity, but very few have advanced beyond initial clinical trials. Vindesine and vinzoli-dine (Fig. 2) are examples of compounds that have been clinically evaluated. These compounds represent structural modifications of the lower portion (vindoline) of the dimeric molecule at position 3. Thus, vinde-... 

Vinblastine, vincristine, and structurally related analogs inhibit microtubule polymerization by 50% at concentrations in the range 0.1-1 xM, and the process of tubulin addition to preformed microtubules, at steady state, is comparably sensitive to inhibition by these agents (5). As shown in Table I, the differences in values for inhibition of steady-state tubulin addition by vinblastine, vincristine, vindesine, and vinepidine were relatively small, but the pattern of activity in the tubulin addition system did not parallel that observed when the compounds were evaluated for effects on the proliferation of B16 melanoma cells in vitro. Vinepidine was more than twice as potent as vinblastine as an inhibitor of steady-state tubulin addition but nearly 10-fold less potent than vinblastine as an inhibitor of cell growth (i). 

Beck has contributed an incisive review of investigations from his laboratory and those of other scientists on the cellular pharmacological aspects of resistance to vinblastine and related compounds (76). Important cellular characteristics that are frequently associated with resistance to vinblastine include cross-resistance, not only to closely related compounds such as vincristine and vindesine but also to other basic naturally occurring compounds. Concomitant resistance to vinblastine and representative anthracyclines (e.g., doxorubicin) may involve reduced abilities... 

Cells that exhibit high (several hundredfold) levels of resistance to vinblastine, vincristine, and vindesine have an extremely limited capacity to accumulate radiolabeled vinblastine for example, essentially no increase in radioactivity associated with human leukemic lymphoblastic cells resistant to vinblastine could be detected over a 60-min incubation period in the presence of concentrations of tritiated vinblastine that were cytotoxic to parent cells. The parent cells, highly sensitive to vinblastine, were observed to accumulate vinblastine to levels seven-fold higher than those observed for the resistant cells (76). 

Vincristine resistance has been studied in Chinese hamster ovary cell lines cells resistant to vincristine also are resistant to vinblastine and vindesine. Suggestions were made that, in cells with relatively low levels of drug resistance, at least two prominent mechanisms of resistance can occur (22). In the first instance, cellular resistance may be attributable to membrane alterations that are reversible, functionally, by treatment with verapamil. In the second, resistance has been postulated to be due to an altered sensitivity of tubulin to the effects of the drugs the primary basis for postulating an altered interaction with tubulin was that a subgroup of cells resistant to vincristine showed enhanced sensitivity to taxol, a drug that can stabilize microtubules. It should be emphasized that differential sensitivities of tubulins from different tumor cells to the effects of vincristine or vinblastine has been proposed as a basis for the susceptibilities of cells to the cytotoxic effects of such drugs (23). Differences have been described in the electrophoretic patterns for tubulins obtained from vin-... 

An interesting difference in the experimental antitumor spectra of vinblastine and vincristine was noted in that vinblastine was inactive against the Ridgeway osteogenic sarcoma in mice whereas vincristine strongly inhibited the growth of this tumor. Vindesine inhibited the Ridgeway os-... 

Estimates for the apparent volumes of distribution for vinblastine, vincristine, and vindesine are extremely high the mean value for vinblastine is approximately 2000 liters (for a 70-kg individual), and those for vincristine and vindesine are approximately 600 liters (5/). Such high estimates... 

The toxicological profile for vindesine includes effects observed with both vinblastine and vincristine. Among the effects observed with vindesine are bone marrow depression, alopecia, and peripheral neurotoxicity. 

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). 

As opposed to vinblastine, vincristine s hematologic effects are minimal. In fact, thrombocytosis is often seen following vincristine administration (10,25,26). Alopecia occurs in from 13 to 22% of patients given full doses of vincristine. Cutaneous effects are, however, more unusual and are a practical problem only when the drug is extravasated (21,22). The spectrum of vindesine side effects is similar to that seen with vincristine. 

Catharanthus roseus Ajmalicine Catharan thine Vindoline Vinblastine Vincristine Vindesine Alioline... 

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. 

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