This study assessed the selective growth inhibitory effect on cultured
carcinoma cells by
3'-azido-3'-deoxythymidine (AZT), as a single agent, and in combination with delocalized lipophilic
cations (DLCs) that are known to inhibit mitochondrial function. In cytotoxicity assays, treatment of cells with varying concentrations of AZT induced a dose-dependent inhibition of cell growth of the human
carcinoma lines DU-145 (prostate; IC50 at 24 microM), MCF-7 (breast; IC50 at 22 microM), and CX-1 (colon; IC50 at 23 microM), yet caused no significant effect on the growth of the control epithelial cell line
CV-1 (monkey kidney) at a concentration as high as 50 microM AZT. Combination treatment employing a constant concentration (1.25 microM) of the DLC
dequalinium chloride (DECA) plus varying concentrations of AZT (0-50 microM) enhanced the AZT-induced cytotoxicity of
carcinoma cells at least fourfold for MCF-7 and CX-1 cells (IC50 at 5 microM AZT), and twofold for DU-145 cells (IC50 at 11 microM AZT). Similar results were obtained in DU-145 cells using a constant concentration of the DLC
MKT-077 (1.0 microM) and varying concentrations of AZT (IC50 at 12.5 microM). As expected, the
drug combination of constant DLC and varying AZT had no significant effect on the growth of
CV-1 cells. Clonogenic assays demonstrated up to 20-fold enhancement of selective
carcinoma cell killing by combination vs. single agent treatment, depending on the specific
drug combination and concentrations used. It is hypothesized that the efficacy of the AZT/DLC
drug combination in
carcinoma cell killing may be based on a dual selectivity involving inhibition of mitochondrial energy metabolism and inhibition of
DNA synthesis due to limited
deoxythymidine monophosphate availability.