Chemotherapy resistance in Acute Leukemia.
Drug resistance markers are often predictive of treatment response and outcome in patients with acute myeloid leukemia. The immunologic detection of drug efflux pumps such as P-glycoprotein (Pgp) and multidrug resistance associated protein 1 (MRP1) rrelate with functional assays of drug resistance and these drug accumulation defects also appear operable in ALL. Other markers such as LRP, bcl- 2, and BRCP, have been described in patients with AML although their pathophysiology and clinical relevance is less clear and methodology for their quantification not well standardized. Preclinical tudies have shown that small molecules capable of reversing efflux can restore drug sensitivity in resistant tumor models. While initial clinical studies were limited by both potency and specificity of the reverser, later studies with more effective reversers have in many instances been limited by pharmacokinetic interactions exacerbating the clinical toxicities of chemotherapy. Nonetheless, one large randomized study using cyclosporine has demonstrated a proven survival advantage without increased toxicity, although the inconsistent results with other modulators raises doubt as to the utility and overall strategy of using drug efflux blockers in patients with established Pgp overexpression. Most of these patients have additional mechanisms of resistance and achieving meaningful clinical responses will likely require more complex clinical strategies. Preventing or delaying development of drug resistance in chemosensitive patientsrepresents another therapeutic strategy to be tested.
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Chauncey