Vindesine

USP (Oncovin) vindesine sulfate [59917-39 ] C43H55N5O7 -H2S0 852.01 (50) chil-dren lymphocytic leukemia Hodgkin s disease non-Hodg-kin s lymphomas Wilm s tumor neuroblastoma rhabdomyosarcoma, investigational dmg (paresthesias, foot drop, double vision, etc) constipation ileus alopecia leu-kopenia (occasional) ... 

Quingestanol acetate Stanzolol Tegafur Tiopronin Tocainide Vindesine Xipamid 2oxazo lamina Ammonium acetate Cyclopentamine HCl Ammonium carbonate Aminosalicylic acid Phenytoin... 

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. 

Many drugs have been conjugated to antibodies or their fragments, including daunomycin [113], cyclosporine [114], platinum [115], chlorambucil [116], and vindesine [117], When choosing a drug for this type of... 

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 Phase I studies of vindesine determined the maximum tolerated dose of the compound to be 3-4 mg/m (body surface area) when given once weekly (i.v.) 78). Mild leukopenia ensues, reaching a nadir after about 4 days, and is accompanied by neurotoxicity. Several patients responded to drug treatment during this initial trial, including several complete responders with acute leukemias and partial responders with malignant melanoma and non-Hodgkin s lymphoma. Subsequent studies indicated that vindesine was active in vincristine-resistant childhood lymphocytic leukemia and, when combined with cisplatin, was effective in... 

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

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). 

Treatment of cells with concentrations of vincristine or vindesine that produce relatively little effect on cell viability results in an accumulation of cells in the M and Gj (gap after DNA synthesis) phases of the cell cycle. The cellular effects, as measured by techniques such as flow... 

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-... 

The disappearance of tritiated vindesine from the blood of rats has been reported to be biphasic, with half-life estimates of 15 min (distribution) and 10 hr (elimination) (59) it is likely that the prolonged elimination phase represents a hybrid between the second elimination phase described above for vincristine and the prolonged third phase evident on inspection of log concentration-time plots for vincristine in the rat. Biliary excretion contributes heavily to the elimination of vindesine in the rat. The bioavailability of vindesine in the rat appears to be very poor. The distribution of vincristine to different tissues in the mouse has been correlated with the estimated concentration of tubulin in the tissues (40). Tubulin concentration was measured by the capacity of a tissue to bind colchicine (40) comparable relationships between tissue concentrations of vincristine and colchicine binding capacity were observed for the dog and the monkey, but it should be emphasized that the correlations were based on the assumption that tissue tubulin content is closely similar in the mouse, dog, and monkey. 

In addition to leukopenia and manifestations of neurotoxicity (tremor, ataxia), monkeys treated with vincristine had degenerative changes in the liver and kidney. Vindesine at doses in the range of 0.1-0.3 mg/kg weekly produced leukopenia and reduced spermatogenesis in rats but apparently did not alter neural function 42). The acute intravenous LD50 for vindesine in mice is 6.3 mg/kg, and that for the congener in which two vindesine units are linked by a disulfide bridge is 6.9 mg/kg 32). 

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