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 photodynamic treatment of cancer when combined with the administration of cyclophosphamide (CPM). Here we have tried to elucidate the mechanism responsible for such potentiation. Male Balb/C mice bearing a transplantable adenocarcinoma were given 2 or 3 doses of 150 mg of CPM/kg weight intraperitoneally. At 16 and 40 hrs. after the last injection the animals were sacrificed. Tumor and liver were excised and 5-aminolevulinic acid dehydratase and porphobilinogen deaminase activities were determined. Intracellular levels of glutathione and cytochrome P450 were also measured. A 15 to 30% decrease in liver 5-aminolevulinic acid dehydratase activity was observed 40 hrs. after the last injection. The tumor enzyme was 30 to 40% inhibited. The activity of liver porphobilinogen deaminase in CPM treated mice decreased to a minimum (15% below the control) at 16 hrs. after administration of the drug and in tumors 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 enzymatic activities. CPM treatment did not change total tumor glutathione levels but the reduced/oxidized glutathione ratio was significantly modified in the tumoral tissue. Cytochrome P450 levels were not increased. These data indicate that CPM-induced potentiation of the photodynamic damage of tumoral tissue is mediated by a mechanism other than that of increased porphyrin synthesis.
Casas
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Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP) FCEyN, University of Buenos Aires, Argentina.
Fukuda
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Del C Batlle
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D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D011163:Hydroxymethylbilane Synthase / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000623:Porphobilinogen Synthase / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D006418:Heme; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D011163:Hydroxymethylbilane Synthase; D000623:Porphobilinogen Synthase; D005978:Glutathione