Approaches to overcome in vivo anti-cancer drug resistance.

Therapeutic efficacy of anticancer drugs against malignant diseases is limited because of the selection and regrowth of drug resistant cells. This problem is compounded by the development of cross-resistance to other useful chemotherapeutic agents which severely limits treatment alternatives. Development of approaches to overcome and/or circumvent drug resistance will depend on the precise understanding of the mechanism(s) of resistance not only at the target tumor cell level (in vitro) but also in vivo. The data on L1210 sensitive to araC transplanted s.c. demonstrated that although target cells are highly sensitive to araC, the lack of in vivo response of solid L1210 cells (s.c.) is primarily due to limited drug delivery to the target. Approaches that would modify these processes should improve on the therapeutic selectivity of this agent. In contrast, in cells where the mechanism of resistance is deletion of a key anabolic enzyme (e.g. CdR kinase), these cells are collaterally sensitive in vitro and in vivo to DAUR. This type of resistance, however, could not be overcome by liposome encapsulation of araC or araCTP. With respect to AM resistance, the concentration of VRP for in vitro reversal of resistance of P-388/AM was difficult to achieve in vivo without significant host toxicity. Continuous infusion of VRP, however, demonstrated that at the maximally tolerated doses of VRP it was not possible to achieve any significant therapeutic effects against P-388/AM. The use of liposomes or modulation by VRP does not appear to be a fruitful approach in overcoming AM resistance, especially in cells which possess a high degree of resistance. Metabolic modulation of FU by dLCF appears to be a promising area of investigation and deserves further investigation concerning quantitation of the intracellular pools of folate and ways to modulate them.