Probable superoxide therapy of experimental cancer with d-penicillamine.

Abstract

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; 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

Intratumoral doxycycline for skin metastases of human malignancies.

“…On account of the biological differences, the protein synthesis of eukaryotic cells may not be directly affected by doxycycline (Alberts et al 1983). Therefore, the anti-cancer effects may first be arising from cell kill through chelation of heavy metals and resultant inactivation of relevant vital enzymes such as superoxide dismutase (Okuyama and Mishina 1981) and DNA polymerase (Slater et al 1971), and through deprivation of HDL-cholesterol from the cell membranes, presumably resulting in disintegration of cancer cells (Bierman and Glomset 1981). They may secondly be related to the tendency to revert along the line of evolution of neoplastic cells 1985a, b, 1986Selata 1984).…”

Intracellular Delivery of the Reactive Oxygen Species Generating Agent d-Penicillamine upon Conjugation to Poly-l-glutamic Acid

“…Based on the results of studies above, it was concluded that PGA− d -pen was able to successfully deliver d -pen to cancer cells. Although high doses of the conjugate ( d -pen equivalent) are required to achieve beneficial effect if used alone, it has been reported that tumorigenic cells are 30- to 100-fold more sensitive to treatment with d -pen compared to normal cells. , This in-built selectivity makes d -pen a potential agent for development as an anticancer drug. However, it may be essential to combine it with a standard chemotherapy regimen when used in the clinic.…”

“…Although high doses of the conjugate (D-pen equivalent) are required to achieve beneficial effect if used alone, it has been reported that tumorigenic cells are 30-to 100-fold more sensitive to treatment with D-pen compared to normal cells. 42,47 This in-built selectivity makes D-pen a potential agent for development as an anticancer drug.…”

Single intratumoral injection of long-acting benzyl ester of D-penicillamine inhibits the growth of melanoma tumor in mice

“…The scheme does not include the reported effects on activation of angiostatin by SH groups of DPA [34], which may explain the angiosuppressive properties of DPA. Okuyama and Mishina [23] suggest that DPA inhibits the activity of superoxide dismutase, thus increasing the peroxidative damage to cells.…”

“…1). after systematic administration in the diet or parenteral injection [18][19][20][21][22][23][24]. The high water solubility of these drugs and their fast metabolism temper their efficacy due to the fast synthesis of LOX.…”