Vinca resistance

The vinca alkaloids vinblastine and vincristine are capable of producing the MDR phenotype in a wide variety of cell types. Furthermore, cells that are made resistant to antitumor drugs such as doxorubicin, actinomy-cin D, or the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26) are often resistant to the effects of the bisindole alkaloids. The structural and mechanistic diversity of these compounds is even more striking against the backdrop of collateral resistance. 

Drug resistance in vitro and probably in vivo results both from inhibition of influx of the vinca alkaloids and, perhaps more frequently, from promotion of their efflux out of cells (34,35). Until relatively recently, the former mechanism was thought to predominate, and, indeed, certain acquired drug-resistant states are clearly associated with the loss of membrane proteins which can be shown to bind and transport agents into cells (34). However, other resistant states have been shown to be associated with the acquisition of membrane transport proteins which remove toxins (and, therefore, chemotherapeutic agents) both from normal and malignant cells. 

Augmented drug extrusion increased synthesis of the P-glycoprotein that extrudes drugs from the cell (e.g., anthracyclines, vinca alkaloids, epipodophyllotoxins, and paclitaxel) is re-ponsible for multi-drug resistance (mdr-1 gene amplification). 

In principle there is no cross-resistance among the individual vinca alkaloids. However cells which are multidrug-resistant due to an activated efflux pump may display cross-resistance to vinca alkaloids, the epipodophyllotoxins, anthracyclines. 

Dactinomycin (actinomycin D, Cosmegen) is one of a family of chromopeptides produced by Streptomyces. It is known to bind noncovalently to double-strand DNA by partial intercalation, inhibiting DNA-directed RNA synthesis. The drug is most toxic to proliferating cells, but it is not specific for any one phase of the cell cycle. Resistance to dactinomycin is caused by decreased ability of tumor cells to take up and retain the drug, and it is associated with cross-resistance to vinca alkaloids, the anthracyclines, and certain other agents (multidrug resistance). 

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. 

Resistance to vinca alkaloids has been correlated with a decreased rate of drug uptake or an increased drug efflux from these tumor cells. Cross-resistance usually occurs with anthracycUnes, dactinomycin, and podophyllotoxins. 

Etoposide (VePesid) is a semisynthetic derivative of podophyllotoxin that is produced in the roots of the American mandrake, or May apple. Unlike podophyllotoxin and vinca alkaloids, etoposide does not bind to microtubules. It forms a complex with the enzyme topoiso-merase II, which results in a single-strand breakage of DNA. It is most lethal to cells in the S- and Gj-phases of the cell cycle. Drug resistance to etoposide is thought to be caused by decreased cellular drug accumulation. 

Vincristine is an alkaloid derivative of Vinca rosea and is closely related in structure to vinblastine. Its mechanism of action, mechanism of resistance, and clinical pharmacology are identical to those of vinblastine. Despite these similarities to vinblastine, vincristine has a strikingly different spectrum of clinical activity and safety profile. 

Beck WT, Cirtain MC. Continued expression of vinca alkaloid resistance by CCRF-CEM cells after treatment with tunicamycin or pronase. Cancer Res 1982 42 (1) 184-189. 

Fig. 7 The location on tubulin of residues that modulate the sensitivity to MT-destabilizing agents and the location of exogenous inhibitor and nucleotide sites on P tubulin. The a subunit is in semitransparent pink together with a composite P-subunit color-coded as in Fig. 3a with ball-and-stick models of bound taxol (orange), colchicine (yellow) and GDP (magenta). Ball-and-stick models of vinblastine (cyan) are drawn on the two partial vinca sites on a and on P tubulin. The sulfur atom of Cys P12 is highlighted as a yellow sphere. The sites of nine amino acid substitutions [49] that both confer resistance to vinblastine and colchicine and stabilize MTs are depicted as red (on a tubulin) or green (on P tubulin) spheres. Two residues of the P H10 helix whose mutations enhance the sensitivity to colchicine site ligands and destabilize MTs [71] are also shown as blue spheres...

Resistance Resistant cells have been shown to have enhanced binding of vinblastine to the P-glycoprotein, which is responsible for the efflux of vincristine and vinblastine and several other drugs. Alterations in tubulin structure may also affect binding of the vinca alkaloids. 

Resistance Like the vinca alkaloids, resistance has been associated with the presence of amplified P-glycoprotein, or a mutation in tubulin structure. 

Resistance to vinca alkaloids can be mediated by glycoprotein B, a transmembrane pump that is part of the multidrug resistance (MDR) phenotype (5). 

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