Probable superoxide therapy of experimental cancer with d-penicillamine

SHINICHI OKUYAMA, HITOSHI MISHINA
1981 Tohoku journal of experimental medicine  
A sublethal dose of D-penicillamine (DP) induced hyperlipoperoxidemia and hypocupremia in old rats. Treatment of cancer cells in vitro and in vivo with DP resulted in appreciable suppression of cell multiplication and a remarkable inhibition of tumor growth. Erythropoiesis did not seem to be affected by DP. The selective effect of DP seems to have resulted from the reduced superoxide dismutase activity and/or defective Mn superoxide dismutase. ----superoxide therapy; experimental cancer;
more » ... ntal cancer; D-penicillamine In mammalian cells, two types of superoxide dismutase (SOD) are known; Cu-Zn SOD, and Mn SOD. Malignant cells are suspected of lacking Mn SOD (Oberley and Buettner 1979). Then, a selective superoxide toxicity to cancer cells can be expected if Cu-Zn SOD could sufficiently be copper-chelated. The present investigation was undertaken to see whether D-penicillamine (DP) induces any appreciably selective toxic effects on cancer cells. Fasted female Donryu rats, 6 months of age, were intraperitoneally injected with DP in a dose of 1 g/kg body weight and were bled 24 hr later. The serum copper levels, which were determined by atomic photoabsorptiometry, were 1.68+0.38 µg/ml (mean+s.D.) for 10 untreated rats and 1.22+0.26 for 13 DP-treated (p<0.01). Plasma lipoperoxide concentrations determined by Yagi's method (1976), as expressed in terms of malondialdehyde, were 2.08+0.60 for 4 untreated and 3.70+1.03 for 5 DP-treated rats (p<0.01). Thus, DP increases the superoxide radicals. The FM3A adenocarcinoma cells from C3H mouse were cultured in MEM medium supplemented with 10% calf serum. Fig. 1 shows that there is a small fraction of cells that are sensitive to DP, and that most of the cells are more or less resistant as estimated at 48 hr of DP. Fifteen Donryu rats, 10 weeks of age, were implanted in the right footpad with AH 109A adenocarcinoma cells and therapeutic effects of DP were evaluated as described elsewhere (Okuyama 1978) . Eight of the 15 were intraperitoneally injected with DP (1 g/kg) on day 3 of the implantation. The tumor growth by weight 5 days later was inhibited to 70% of the saline control (p<0.005). Effects of DP on the cell renewal system i.e., on hemopoiesis in the rat femoral marrow, were tested. There was no significant difference in the cellularity, myeloid/ erythroid ratio (1.58 +0.32 vs. 1.79 +0.13) or erythroid mitotic index (1.86+0.70 vs. 2.20+ 0.54) between the DP-treated (3 rats) and nil control (3 rats) as studied on day 6 of DP in a dose of 1 g/kg. The present experimental data suggest that cancer cells are more vulnerable to DP Received for publication, February 14, 1981. Abbreviations : SOD, superoxide dismutase; DP, D-penicillamine. Request reprints to: S. Okuyama, M.D., Tohoku Rosai Hospital, Sendai 980, Japan. 215
doi:10.1620/tjem.135.215 pmid:7330869 fatcat:7lqnxeq3n5e5pbbn7rq24uku7m