Reply to the Letter of H. J. Koch

Abstract

In the investigation quoted by Dr. Koch1 radiosensitivity and local flow in experimental mouse sarcomas were improved by the calcium antagonist flunarizine. This result is not contradictory to our finding that dihydropyridine calcium antagonists such as nifedipine, nimodipine, nitrendipine, and isradipine and the benzothiazepine calcium antagonist, diltiazem, protect mice against lethal radiation (1, 2). Flunarizine, which is a piperazine calcium antagonist, did not display radioprotective effects in our work (1, 2), and neither did the phenylalkylamine calcium antagonist verapamil. It thus appears that radioprotection is not a general property of Ca2+ channel blockers, but that a certain degree of specificity within the class is needed. The evidence that radioprotective or radio-enhancing effects of calcium antagonists are connected to their effects on flow and thus tissue oxygenation does not appear too convincing for several reasons. If calcium antagonists were used as blood flow modifiers and their influence on the radiation response of experimental mouse tumors was studied (3), small doses of nifedipine and verapamil enhanced local flow and radiosensitivity, while large doses of these agents reduced flow and radiosensitivity. However, in our studies, verapamil at a large dose did not reduce radiosensitivity and nifedipine consistently provided radioprotection and failed to sensitize at the lowest dose tested. Flunarizine, which increased radiosensitivity over the whole dose range, afforded a small increase in flow at only one dose (3). Also, the observation that a large array of antihypertensive and vasodilation drugs did not affect the radiosensitivity of mice (1) does not make it possible to ascribe an important role to flow changes. A more direct effect on Ca2' channels or on the interaction of radiation with cells at the biochemical or biophysical level seems more appropriate for explaining radioprotection by calcium antagonists. While Dr. Koch mentions inhibitory effects of calcium antagonists on cell proliferation and multidrug resistance, evidence is also available indicating general cytoprotective properties of calcium antagonists, e.g., with reperfusion injury (4), ischemia (5, 6), toxicity of cytotoxic agents (7), and neurotoxic injuries (8, 9). Finally, it could be argued that in view of differences in radiation response between normal and tumor cells, results obtained with tumors may not necessarily apply to normal tissue. Dr. Koch also addresses the role of the solvent. Since nifedipine and nimodipine had to be applied in a vehicle containing DMSO and ethanol, the possible role of the solvent was investigated in our reports (1, 2). The radioprotection provided by calcium antagonist in the solvent was superior to the protection afforded by the solvent alone. Moreover, nitrendipine and isradipine, which were administered in vehicles displaying no radioprotection, namely distilled water or olive oil, provided significant radioprotection. Diltiazem protected markedly and was applied in a solvent which contained mannitol and distilled water, which have no adioprotective faculties.