Previous findings had shown that the effect of anticancer agents in restoring lowered enzyme activities in the liver and especially that of catalase was not always in parallel with their therapeutic effect. To elucidate this, the possible inhibitory effect of these agents on heme metabolism, with special reference to iron, copper, and δ-aminolevulinic acid metabolism in normal and tumor-bearing mice, was investigated.
The δ-aminolevulinic acid dehydrase activity in the liver of tumor-bearers was lower than that of normal animals and was found to be very low in tumor cells. Of the anticancer agents tested
in vitro, 2, 5-bis(ethyleneimino)-1, 4-benzoquinone and folic acid antagonists were found to inhibit this enzyme activity in normal mice.
On the other hand, carboxamide utilization in which δ-aminolevulinic acid is concerned with the source of a C
1-donor occurred at a much higher rate in tumor cells than in the liver of normal and tumor-bearing mice. In the presence of folic acid antagonists, and
d-catechin and berberine, carboxamide utilization by tumor cells was markedly inhibited
in vitro.
Daily decrease in the serum iron level, blood hemoglobin content, and liver δ-aminolevulinic acid dehydrase activity was observed after tumor transplantation, when the serum copper level increased. Administration of alkylating agents and 8-azaguanine to tumor-bearers restored these metabolic disturbances to normal in parallel with their therapeutic effects. These agents showed no influence on these levels in normal mice. 6-Mercaptopurine, which has a marked anticancer activity with Ehrlich ascites carcinoma, returned the lowered liver δ-aminolevulinic acid dehydrase activity and elevated serum copper level in tumor-bearing animals to normal. However, the lowered serum iron level and blood hemoglobin content in tumor-bearers were further depressed by treatment with 6-mercaptopurine and this depressive action was also found in normal mice. Treatment with aminopterin, which was not effective against Ehrlich ascites carcinoma at the dose level tested, did not restore the altered metabolism of tumor-bearing animals to normal and this agent caused a depression of the blood hemoglobin content in normal mice.
The significance of these results in relation to those in the previous report is discussed.
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