Fundamental study of combination treatment of fibrinolytic agents, radiohypersensitizer and repair-inhibitor of DNA to enhance radiation effects on experimental tumor in mice and rabbits.

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To strengthen radiation effects on tumors, each one of fibrinolytic agents and radiohypersensitizers have been used jointly with radiation,however this approach has not always produced good results in cancer patients. Fibrinolytic agents can not improve blood flow in capillary vessels in which micro-thrombus become old and fibrotic. While, radiohypersensitizers are unable to permeate deeply and sufficiently in hypoxic and anoxic areas of large tumor, because this agents have neuro-toxic effects when administered in large amounts.We carried out a combination treatment with fibrinolytic agents (a mixture of Low Molecular Weight Dextran and Urokinase) and a radiohypersensitizer(misonidazol) to supply deficiencys of these agents. In our studies on mouse Ehrlich solid tumor, we found the same result could be obtained with 300 mg/kg of misonidazol as with 500 mg/kg of misonidazol in case of misonidazol, alone a reduction of 40%. However, the effect of this combination treatment had been redu … More ced in experiments when large sized Vx-2 tumors on rabbits were used, and it was thought that permeation of misonidazol was not sufficient in wide hypoxic and anoxic areas of large tumors. In other studies, we foundthat low doses of TNF(Tumor Necrosis Factor) remarkably increased drug accumulation in tumor tissures. From these results, a new combination treatment of fibrinolytic agents, TNF and misonidazol was studied on large Vx-2 tumor. By this new treatment, radiation effects were greatly enhanced, and the effective dosage of misonidazol reduced to 200 mg/kg.By this combination treatment system, RK-28( an improved type substance of misonidazol ) was studied instead of misonidazol, and the same result were obtained. To further augment radiation effects, at the same time, Ara-A( as a repair-inhibitor of damaged DNA ) was studied with this systemic combination treatment of fibrinolytic agents, TNF and RK-28, but it failed to show enhancement of radiation effects.These results indicated that our combination treatment of fibrinolytic agents, TNF and radiohypersensitizers is worthy of clinical trial for cancer therapy. Less