Improved Tumour Oxygenation and Radiosensitization by Combination with Nicotinamide and Pentoxifylline

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Abstract
We hypothesized that the combination of pentoxifylline (PTX) and nicotinamide (NA) can reduce the radioresistance of FSaII murine fibrosarcoma by improving oxygenation of the hypoxic tumour cells. The purpose of this study was to test the hypothesis; first, tumour blood flow after treatment with NA, PTX, and the combination (PTX+NA) was measured using laser Doppler flowmetry. Second, intratumour pO2 after various treatments was measured polarographically using O2 microelectrodes. Third, the radiation response was also measured, i.e. after an exposure to 20 Gy, the time required to reach a four-fold increase in initial tumour volume was 18 days in the saline-treated control group, 21 days in the NA-treated group, 26 days in the PTX-treated group, but was 36 days in PTX+NA treated group. Interestingly, tumour blood flow significantly increased at 10 min after injection of PTX+NA. The mean pO2 in untreated control tumours was 7.5 mmHg, increasing to 13.1 mmHg after 500 mg/kg of NA alone. Repeated injections of PTX with 100 mg/kg/day for 3 days significantly increased intratumour pO2 to 17.2 mmHg. Compared with PTX alone, PTX+NA slightly increased intratumour pO2 from 17.2 to 18.5 mmHg. However, the percentage of regions having values < 2.5 mmHg significantly decreased from 5% with PTX alone to 1% with PTX+NA. In conclusion, single or multiple injections of PTX may increase available O2 in the tumour and thus ameliorate hypoxia in tumour microregions. As previously reported, the subsequent injection of NA may efficiently oxygenate acutely hypoxic cells. Consequently, PTX+NA may increase the radioresponse of tumours by oxygenating chronic as well as acutely hypoxic cells. PTX alone or in combination with NA is potentially useful to radiosensitize tumours.

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