Diltiazem enhances tumor blood flow: MRI study in a murine tumor

Purpose: Diltiazem, a calcium-channel blocker, is known to differentially i nfluence the radiation responses of normal and murine tumor tissues. To elu cidate the underlying mechanisms, the effects of diltiazem on the radiation response of Ehrlich ascites tumor (EAT) in mice have been investigated, an d the hemodynamic changes induced by diltiazem in tumor and normal muscle h ave been studied using magnetic resonance imaging (MRI) techniques. Methods and Materials: Ehrlich ascites tumors were grown subcutaneously in Swiss albino strain A mice. Dynamic gadodiamide and blood oxygen level depe ndent (BOLD) contrast enhanced H-1 MR imaging studies of EAT and normal mus cle were performed after administration of diltiazem in mice using a 4.7 Te sla MR scanner. Tumor radiotherapy experiments (total dose = 10 Gy, 0.4-0.5 Gy/min, single fraction) were carried out with 30 min preadministration of diltiazem (27.5 or 55 mg/kg i.p.) to EAT-bearing mice using a teletherapy machine. Results: The diltiazem+ radiation treated group showed significant tumor re gression (in congruent to 65% of the animals) and enhanced animal survival. MR-gadodiamide contrast kinetics revealed a higher magnitude of signal enh ancement in diltiazem treated groups as compared to the controls. The obser ved changes in the magnitude of kinetic parameters were the same for both t umor and normal muscle, BOLD-MR images at 30 min after diltiazem administra tion showed a 25% and 8% (average) intensity enhancement from their basal v alues in tumor and normal muscle regions, respectively. The control group s howed no significant changes. Conclusion: The present studies demonstrate the radiosensitization potentia l of diltiazem in the mice EAT model. The enhanced radiation response obser ved with diltiazem correlates with the diltiazem-induced increase in tumor blood flow (TBF) and tumor oxygenation, The present results also demonstrat e the applications of BOLD-MR measurements in investigating the alterations in tumor oxygenation status. (C) 1999 Elsevier Science Inc.