Microcalorimetric evaluation of the effect of combined chemotherapeutic drugs

A study of the effect of combined antineoplastic drugs in vitro was carried out by microcalorimetric monitoring of the metabolic activity of treated cells. Power-time curves of growing T-lymphoma cell suspensions, treated with single or combined drugs, were recorded. The extent of the effect was evaluated by changes in the slopes of the microcalorimetric curves and the kinetics of the drug action were interpreted from the time at which these changes reached their maximum value. The method was validated using two well-established drug combinations, the potentiatory effect of dipyridamole on methotrexate cytotoxicity, and the synergism between methotrexate and 6-thioguanine. In the first case, where one drug is not toxic, the modulation may be evaluated by comparing the inhibition produced by the toxic drug alone and in combination with its modulator. Otherwise, when both drugs are toxic, the combined effect must be evaluated by means of their combination index. The measurement procedure is simple, the electric signal is well suited to automation of data acquisition and the response may be evaluated within 5 to 6 h of drug administration. Moreover, we demonstrate that microcalorimetry is a reliable method for the detection of modulatory effects in combination chemotherapy.