METABOLIC CHANGES IN THE HEME PATHWAY DRIVEN BY CYCLOPHOSPHAMIDE TREATMENT IN MICE

In previous work we found a 30% increase in the effectiveness of the p hotodynamic treatment of cancer when combined with the administration of cyclophosphamide (CPM). Here we have tried to elucidate the mechani sm responsible for such potentiation. Male Balb/C mice bearing a trans plantable adenocarcinoma were given 2 or 3 doses of 150 mg of CPM/kg w eight intraperitoneally. At 16 and 40 hrs. after the last injection th e animals were sacrified. Tumor and liver were excised and 5-aminolevu linic acid dehydratase and porphobilinogen deaminase activities were d etermined. Intracellular levels of glutathione and cytochrome P450 wer e also measured. A 15 to 30% decrease in liver 5-aminolevulinic acid d ehydratase activity was observed 40 hrs. after the last injection. The tumor enzyme was 30 to 40% inhibited: The activity of liver porphobil inogen deaminase in CPM treated mice decreased to a minimum (15% below the control) at 16 hrs. after administration of the drug and in tumor s a decrease of 20% was shown 40 hrs. post CPM injection. The greater the number of CPM doses administered the higher the decrease in the en zymatic activities. CPM treatment did not change total tumor glutathio ne levels but the reduced/oxidized glutathione ratio was significantly modified in the tumoral tissue. Cytochrome P-450 levels were not incr eased. These data indicate that CPM-induced potentiation of the photod ynamic damage of tumoral tissue is mediated by a mechanism other than that of increased porphyrin synthesis.