Thermal enhancement of pirarubicin (THP-Adriamycin) by mild hyperthermia in vitro

Abstract

It has been demonstrated that hyperthermia can enhance the cytotoxicity of several anticancer drugs. Pirarubicin (THP-adriamycin) is a less cardiotoxic derivative of adriamycin. The thermal enhancement of cytotoxicity of pirarubicin was studied at various elevated temperatures in vitro by using a Chinese hamster cell line, V79. Cell survival curves were obtained at elevated temperatures for V79 cells treated with heat given alone or in combination with pirarubicin, and D₀, the treatment time to reduce cell survival from S to S/e, was obtained for each cell survival curve. The relationship between the logarithm of the Do and the treatment temperature for cells treated with heat alone was biphasic with a breaking point at 43°C, although that for cells treated with a combination of heat and pirarubicin was exponential with no breaking point. The slope of this relationship for heat alone > 43°C was −0.72 × 0.094 h/°C which was not significantly different from the slope for combined heat and pirarubicin, -0.64 × 0.032 h/°C. The results indicated that the cytotoxicity of pirarubicin was thermally enhanced specifically by mild hyperthermia. Pirarubicin uptake into the V79 cells during hyperthermia was independent of the treatment temperature (37, 42, and 44°C), suggesting that the thermal enhancement of pirarubicin was not due to the increased drug-uptake at elevated temperatures. Based on these results, it is predictable that hyperthermia combined with pirarubicin is more effective below 43°C which is easily achievable clinically.

Key Words:

• Mild hyperthermia
• pirarubicin
• enhancement
• moderate temperature
• break point