2004 Dr. Gary J. Becker Young Investigator Award: Relative Thermosensitivity of Cytotoxic Drugs Used in Transcatheter Arterial Chemoembolization

Abstract

Large hepatocellular carcinoma tumors are being treated increasingly with a combination of transcatheter arterial chemoembolization (TACE) and radiofrequency (RF) ablation. However, the high temperatures reached during RF ablation may reduce the cytotoxic effects of antineoplastic agents, but this has not been studied. Therefore, in the present study, the relative thermosensitivity of cytotoxic drugs commonly used in TACE was studied. The relative cytotoxic effects of cisplatin, doxorubicin HCl, and mitomycin on the growth of human colon HT29 and lung A549 adenocarcinoma cells before and after heating each drug in solution was determined from the standpoints of different durations of exposure (15, 30, 60, 90, and 120 minutes) at a fixed temperature (120 degrees C) and exposure to different temperatures (60 degrees C, 80 degrees C, 100 degrees C, and 120 degrees C) for a fixed period of time (2 hours). After 72 hours of exposure of the cells to each drug, relative cell growth inhibition was assessed by MTT assay, and 50% inhibitory concentration (IC(50)) values were calculated for each cytotoxic agent. Finally, the heat-dependent degradation of mitomycin and doxorubicin was analyzed with use of tandem electrospray mass spectrometry. The relative cytotoxic activities (shown by cell growth inhibition and IC(50) values) of cisplatin, doxorubicin, and mitomycin heated to 120 degrees C for 2 hours decreased by factors of 1.35 (range, 1-1.75), 9.5 (range, 8.5-10.5), and 7.05 (range, 3.5-12), respectively. The cytotoxic activities of doxorubicin and mitomycin continued to decrease with incremental increases in temperature. Similarly, with incremental increases in the duration of exposure to heat, the cytotoxic activities of doxorubicin and mitomycin decreased. Mass spectrometric analysis of residual drug content showed that a 2-hour exposure to a temperature of 120 degrees C caused doxorubicin and mitomycin to degrade by 95% and 84%, respectively. The cytotoxicity of cisplatin is not affected by heat. The cytotoxicities of doxorubicin and mitomycin are reduced by high temperature and duration of exposure to heat. Although degradation of cytotoxicity starts at 60 degrees C and after 30 minutes of exposure to heat, statistically significant changes are encountered at 100 degrees C and after 90 minutes of exposure.