Vinca cell resistance

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. 

In cultured tumor cells, resistance to taxanes is associated in some lines with increased expression of the mdr-1 gene and its product, the P-glycoprotein other resistant cells have P-tubulin mutations, and these latter cells may display heightened sensitivity to vinca alkaloids. Other cell lines display an increase in survivin, an antiapoptotic factor or aurora kinase, an enzyme that promotes completion of mitosis. The basis of clinical drug resistance is not known. Cell death occurs by apoptosis, but the effectiveness of paclitaxel against experimental tumors does not depend on an intact p53 gene product. 

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). 

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. 

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. 

Etoposide and teniposide are semisynthetic podophyllotoxin derivatives (see Table 124-13). Podophyllin is extracted from the mayapple or mandrake plant. Like the vinca alkaloids, podophyllin itself binds to tubulin and interferes with microtubule formation. Unlike the parent compound, however, etoposide and teniposide damage tumor cells by causing strand breakage through inhibiting topoisomerase Resistance may be caused by differences in topoisomerase II levels, by increased cell ability to repair strand breaks, or by increased levels of P-glycoproteins. Etoposide and teniposide are usually clinically cross-resistant. They are cell-cycle phase-specific and arrest cells in... 

Inhibitors of Eg5 are currently in development as anticancer drugs because, like taxol and the vinca alkaloids, they arrest cells in mitosis by activating the spindle checkpoint. The efficacy of these drugs, as demonstrated by recent studies, requires a prolonged, checkpoint-dependent mitotic arrest [42, 19]. Drug resistance is conferred by a compromised spindle checkpoint, for example, through reduced expression of Mad2. 

---