Hypoxic cells comprise 10~20% of tumor cells and are more sensitive to hyperthermia. By decreasing tumor blood flow artificially and thus increasing the hypoxic fraction in the tumor, the cytotoxic effect of hyperthermia can be increased.
Hydralazine is
an antihypertensive drug and its main mechanism is relaxation of the vascular smooth muscle of arterioles rather than veins. Administration of hydralazine causes a decrease in vascular resistance and an increase in blood flow in normal tissue,
but
since
the vasculature of tumor is not responsive to such a drug, blood flow in tumors is decreased because of steal phenomenon. Thus the hypoxic fraction in the tumor is in creased, and the tumor becomes more sensitive to hyperthermia.
Therefore, to evaluate the hydralazine effect on hyperthermia, the tumor growth delay was investigated and the change in the hypoxic fraction of the tumor was estimated using C3H mouse fibrosarcoma(FSaⅡ) with hypoxic fractions of usual range. In
6mm
FSaⅡtumors growing in the dorsum of the foot, administration of 5 or 10mg/kg of hydralazine was followed by 43℃hyperthermia for 60 minutes.
Tumor growth times (TGT) to reach a tumor volume of 500 mm* were 7.11±0.84 days and 7.44±1.13 days for controls and 10mg/kg of hydralazine only. TGT's for hyperthermia alone and administration of 5 or 10mg/kg of hydralazine followed by
hyperthermia
were 10.34±2.17 days. 13.38±1.82 days and 14.47±0.67 days, respectively. Elongation of tumor growth delay by administration of 5 or 10mg/kg of hydralazine in addition to hyperthermia were statistically significant (0.025respectively). Tumor control radiation doses (TCD50) were 69.6 (66.8-72.5) Gy for radiation alone, 80.9(76.2-85.7) Gy for radiation after administration of hydralazine (10mg/kg) and 81.7 (77.7-86.9) Gy for radiation under clamp hypoxia. The
hypoxic
fraction estimated from the TCD50's was 10.6% for controls and this was markedly increased to 86.2% by administration of hydralazine.
From the above results it was confirmed that the cytotoxic effect of hyperthermia was enhanced significantly by administration of hydralazine as a results of fnarked increased in the hypoxic fraction in the tumor.
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