Iwao Umezawa

Antitumor activity of a nitrosourea derivative, CNUA, on murine tumors.

SummaryThe antitumor activity of a new derivative of nitrosourea, 3-[3-(2-chloroethyl)-3-nitrosoureido]-3-deoxy-d-allose (CNUA), against murine tumors was studied. CNUA showed significant antitumor activity against L1210 leukemia, Lewis lung carcinoma, B-16 melanoma and autochthonous lung tumor induced by 1-ethyl-1-nitrosourea. The effect of CNUA, chlorozotocin, and ACNU on the peripheral white blood cell count (WBC) in normal CDF1 mice was examined. The lowest WBC count occurred 3 days after administration at the therapeutic dose level and the decreased value returned to the normal level 7–14 days following administration of CNUA and chlorozotocin. CNUA also exerted a depressive action on both humoral and cell-mediated immune response to sheep red blood cells determined by the serum hemagglutinin titer, plaque-forming cells in the spleen, and delayed-type hypersensitivity reaction, while the suppression was almost the same or less than that obtained with chlorozotocin when compared at the dose resulting in similar antitumor activity. These findings suggest that the antitumor activity of CNUA was not at all inferior to those of other nitrosoureas. The bone marrow toxicity was moderate and did not last long.

Histopathological studies on antitumor effect of sporamycin

SummaryMice that had received transplants of sarcoma-180 followed by treatment with sporamycin were examined histopathologically at periodic intervals. A marked degeneration of tumor cells was observed at an early stage after the administration of sporamycin, but the degeneration subsequently ceased and regrowth of the tumor was seen. Marked infiltration of lymphoid cells, granulation tissue, and fibrosis was seen in the stroma or surrounding tissue of the tumor at a late stage after the administration of sporamycin, and the regression of tumor cells became marked. With a few exceptions the mice were completely cured by about the 40th day.In the peripheral lymphoid tissues, a transitory decrease in the number of cells was observed after the administration of sporamycin, but this was followed by regeneration of the cells, followed by a marked increase in the B cell system. On the other hand, lymphoid cell depletion of the thymus had persisted.Transplantation of intact sarcoma-180 to mice preliminarily inoculated with sporamycin-treated sarcoma-180 cells resulted in inhibition of tumor growth in most of the mice, and qualitatively the same tissue reactions as those in mice cured of sarcoma-180 by sporamycin were seen.The results suggest that enhancement both of antigenicity of the tumor (cells) and of the subsequent immune response of the host by sporamycin may be involved in the cure of the experimental tumor.

Mechanism of action of acetyl kidamycin. I. Interaction with DNA.

Acetyl kidamycin, an antitumor antibiotic, was strongly bound to DNA in vitro, consequently, the melting temperature of DNA was significantly increased, and its buoyant density was decreased. From these results, it was suggested that acetyl kidamycin stabilized residual links between complementary strands by binding to DNA. An additional action was observed in that acetyl kidamycin caused single-strand scission of DNA in an alkaline sucrose density gradient solution.

Effect of antitumor agents on sarcoma-180 tumor cells transplanted to liver, kidney, and lung.

The survival time of animals, inhibition of the incorporation of thymidine-[6-3H] (3H-TdR) into DNA, and histopathological observation were made after the injection of Mitomycin-C, Bleomycin, cyclophosphamide, Daunomycin, Actinomycin-D, or 5-fluorouracil into mice transplanted with sarcoma-180 to their liver, kidney, and lung. The most prolonged survival time was obtained by the injection with cyclophosphamide and a moderate prolonged survival by Bleomycin and Actinomycin-D. In the case of 5-fluorouracil and Daunomycin, there were extreme variations in the survival time depending on the site of tumor growth. Cyclophosphamide and 5-fluorouracil showed greater and longer lasting inhibition of the incorporation of 3H-TdR into DNA of the tumor tissue, whereas the remaining agents caused transient inhibition on the tumor tissue. Inhibitory ratio and duration of the incorporation of 3H-TdR into DNA of normal site of the tissue of tumor-bearing organ were found to be more increased or almost the same compared with those of the tumor tissue. The most rapid recovery of the incorporation of 3H-TdR into DNA was observed in the small intestine among various organs and tumor in any treatment groups. From the histopathological observation, the degree of tumor cell damage by the agent was almost in agreement with inhibition of the incorporation of 3H-TdR up to 72 hr after the treatment.