Multidrug drug resistance in pediatric sarcomas

Although P-glycoprotein overexpression is an important cause of multidrug resistance in vitro, whether this resistance mechanism is equally applicable to the clinic has still to be fully established. This review has examined the immunohistochemical and molecular biologic tools used to evaluate soft tissue sarcomas of children and adults, in order to determine whether P-glycoprotein can limit the efficacy of chemotherapy.

Because soft tissue sarcomas are successfully treated by cytotoxic substrates of P-glycoprotein in many, but not all children, these tumors may be useful models for determining whether this drug efflux transporter is a clinically relevant cause of chemoresistance.

Certain studies of acute myelogenous leukemia, lymphoma, and myeloma in adults and rhabdomyosarcoma, neuroblastoma, and acute lymphoblastic leukemia in children have provided the best current evidence for a strong corelation between the expression of P-glycoprotein and outcome of chemotherapy. Based on these observations, several clinical trials have been initiated to determine whether pharmacologic chemosensitization improves chemotherapy responses and cure rates in P-glycoprotein-expressing malignancies. Thus, early identification of lower levels of P-glycoprotein in tumors that still might respond to chemosensitizer-modulated chemotherapy may be highly pertinent to conducting more informative multidrug resistance reversal trials.

The question of whether the multidrug resistance P-glycoprotein is a clinically relevant cause of chemoresistance may ultimately be answered by the successful prevention of chemotherapy failure by chemosensitizers that specifically reverse this drug efflux mechanism.