Does P-glycoprotein play a role in clinical resistance of malignant astrocytoma?

P-glycoprotein (P-gp) is a 170 kDa transmembrane glycoprotein which plays a significant role in modulating pleomorphic or multiple drug resistance (MD R) in a wide variety of human cancers like renal and colorectal carcinoma. However, its role in modulating drug resistance in other types of cancer is less well defined. The purpose of this review is to critically examine the evidence that P-gp plays an important role in producing drug resistance in astrocytic gliomas. Malignant astrocytoma is clinically resistant to most types of cytotoxic drugs, including those associated with the MDR phenotype and the cross-resistance patterns of short-term cultures derived from mali gnant glioma are consistent with this phenotype. Consequently, it might be expected that this tumor would express high levels of P-gp, However, immuno histochemical findings from a number of previous studies have provided conf licting data about the expression of P-gp in these tumors, although P-gp ha s been consistently detected in normal brain in the endothelial cells in ce rebral blood vessels and is thought to contribute to the blood-brain barrie r phenomena. In order to determine if P-gp contributes to drug resistance i n malignant astrocytoma, we undertook a study of P-gp expression in a panel of short-term cultures derived from these tumors in which we determined th e in vitro chemosensitivity. However, immunocytochemical studies with a pan el of antibodies which recognize both internal and external epitopes of the P-gp molecule have consistently failed to show the characteristic membrane staining associated with MDR in any of the cultures, including those marke dly cross-resistant to vincristine and doxorubicin, One antibody, JSB-1, sh owed heterogeneous granular cytoplasmic staining which was unrelated to a p articular pattern of drug resistance. This is probably because this antibod y cross-reacts with a widely distributed cytoplasmic antigen, pyruvate carb oxylase, which is present in abundance in normal astrocytes, The unexpected ly poor specificities of many of the antibodies thought to be specific for P-gp is reviewed in the context of malignant astrocytoma. In conclusion, th e role of P-gp in producing drug resistance in malignant astrocytoma is que stionable and further studies might more profitably concentrate on the mech anisms of resistance to DNA-damaging agents like the nitrosoureas, methylat ing agents or platinum-based drugs. [(C) 1999 Lippincott Williams & Wilkins .].