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Approaches to overcome in vivo anti-cancer drug resistance
Abstract:
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.
Insights
Overcoming anticancer drug resistance requires understanding resistance mechanisms. Strategies like improved drug delivery and metabolic modulation show promise, while others like liposomes and VRP modulation are less effective for certain resistances.
Area of Science:
- Pharmacology
- Oncology
- Drug Resistance Mechanisms
Background:
- Anticancer drug efficacy is limited by drug-resistant cells, leading to cross-resistance and fewer treatment options.
- Understanding resistance mechanisms in vitro and in vivo is crucial for developing effective strategies.
- Drug resistance poses a significant challenge in cancer chemotherapy.
Purpose of the Study:
- To investigate mechanisms of anticancer drug resistance and explore strategies to overcome it.
- To evaluate the efficacy of different approaches, including drug delivery modifications and metabolic modulation, against resistant cancer cells.
Main Methods:
- Studied L1210 cells sensitive to cytarabine (araC) transplanted subcutaneously (s.c.) to assess in vivo drug delivery.
- Investigated resistance mechanisms involving deletion of key anabolic enzymes, evaluating collateral sensitivity to 2',2'-difluorodeoxycytidine (DAUR).
- Assessed the effectiveness of liposome encapsulation and Verapamil (VRP) modulation against Adriamycin (AM) resistance in P-388/AM cells.
- Explored metabolic modulation of 5-fluorouracil (FU) using dihydrofolate reductase inhibitors (dLCF).
Main Results:
- Limited drug delivery to solid L1210 tumors was identified as a primary reason for lack of in vivo response to araC.
- Cells with deleted CdR kinase showed collateral sensitivity to DAUR, but liposome encapsulation of araC or araCTP did not overcome this resistance.
- Verapamil (VRP) was ineffective in overcoming high-level Adriamycin (AM) resistance in P-388/AM cells, even with continuous infusion, due to toxicity.
- Metabolic modulation of 5-fluorouracil (FU) by dLCF showed potential but requires further investigation into folate pool modulation.
Conclusions:
- Strategies to improve drug delivery are essential for enhancing the therapeutic selectivity of agents like araC.
- Certain resistance mechanisms, like enzyme deletion, may be overcome by alternative drugs (DAUR), but not all delivery methods (liposomes).
- Verapamil (VRP) and liposome encapsulation are not effective for overcoming high-level AM resistance.
- Metabolic modulation of FU warrants further research for its potential in overcoming resistance.