What's new in cytostatic drug resistance and pathology.

A major problem in cytostatic treatment of malignant tumors is the development of chemoresistant cell clones. An increased understanding of chemoresistance related mechanisms, improved methods for the detection and localization of resistant cell populations including predictive conclusions on the effectiveness of cytostatic drugs would contribute to the advancement of anti-tumor strategies. This paper reviews current concepts suggested for the development of cellular resistance to natural product drugs (anthracyclines, Vinca alkaloids, epipodophyllotoxines, antibiotics; so-called multidrug resistance substances), alkylating agents (nitrosureas, busulfan and mitomycin C), heavy metal compounds (cisplatin) and antifolates (5-fluorouracil, methotrexate) and describes the role of drug transporting and binding proteins (P-170-glycoprotein), detoxifying enzymes (glutathion-S-transferase, dihydrofolate reductase), DNA repair enzymes (topoisomerase I and II, polymerase alpha and beta), and genomic alterations (amplification, double minutes and homogeneous staining regions) due to resistance. It is focussed on the employment of morphological methods (light microscopy, immunocytochemistry, electron microscopy, fluorescence analysis, in situ hybridization, computer aided morphometric analysis) which will help to detect resistant cell clones in tumor biopsies. First correlations between histological data and clinical course will be reported. In the future, the morphological determination of chemoresistance may play an important role in applied functional tumor pathology.