Metabolic response of AH13r rat tumours to cyclophosphamide as monitored by pO2 and pH semi-microelectrodes.

The composition of the microenvironment has an important influence on the cellular response to cytotoxic agents. Using pH and pO2 semi-microelectrodes, we have monitored metabolic changes in AH13r rat tumours as a function of time after subcurative chemotherapy. Prior to therapy, tumours contained large areas considered hypoxic (mean pO2 approximately 4 mmHg) and are characterised by a marked accumulation of acidic metabolites (mean pH 6.65). Administration of cyclophosphamide (40 mg/kg body weight) resulted in tumour regression to 15% of pretreatment volumes and a growth delay of 12 days. Concomitant with volume reduction, tumours became reoxygenated (mean pO2 approximately 7 mmHg), with maximum values being reached within 2-4 days, paralleled by a shift of pH to more alkaline values (0.17 U on average). These changes coincided with the development of subtotal necrosis. During early tumour regrowth, the pH and pO2 histograms returned to control values. These data corroborate and extend the results of previous studies in which noninvasive techniques had been applied for the monitoring of treatment-induced metabolic changes in malignant tumours in vivo. In addition, these results support the notion that the effectiveness of anticancer therapy might be improved by selecting and scheduling therapeutic agents in consideration of physiological changes caused by preceding courses of treatment.