Adriamycin (AdR) and related anthracyclines are important antitumor agents in the management of human malignancies. Their clinical use is compromised by slow intracellular transport, dose limiting cardiotoxicity and emergence of drug resistance. Our work has focused on studies related to the mechanism of action of and cellular resistance to AdR and some of its newer clinically important analogs both in vitro and in vivo. We have developed and modified techniques which allow us to study AdR transport and resistance, cytokinetic effects and cytotoxicity in individual cells and sub-populations from heterogeneous solid tumors.
The specific aims of this continuation proposal are: To correlate intracellular anthracycline fluorescence with effects on clonogenicity of drug sensitive and resistant cells, sub-populations from heterogeneous tumors and in relation to cell cycle phase and proliferation status. To analyze effect of selected drugs used in combination chemotherapy on anthracycline transport and cytotoxicity. To study correlation between easily measurable parameters such as cell size, nuclear/cytoplasmic ratio, DNA, RNA, protein content, presence or absence of drug resistance-related proteins, and tumor associated antigens and intracellular anthracycline transport characteristics. These parameters will be used for isolation of sub-populations for further study in soft agar and as xenografts. From the planned studies, we will obtain data which will allow us to better understand the relation between transport, role of drug resistance related proteins and the response of sub-populations in a heterogeneous solid tumor to anthracyclines.
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