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The toxicity of the bis-succinyl derivative of the protein antibiotic, neocarzinostatin, was compared with the parent compound, neocarzinostatin (NCS), in rats. The derivative was found to be about two to five fold more active than NCS in vivo. The antitumor activity in rats bearing eleven distinct YOSHIDA hepatoma ascitic cell lines was tested under four possible combinations with regard to sites of drug and tumor cell administration.The results indicate that the antitumor spectrum of the derivative had changed slightly. Antitumor activity in mice was also tested with L1210 and P388 lymphatic leukemia, and with B16 melanocarcinoma. When the effect of the derivative was compared with parental NCS at the molecular level with respect to the inhibition of DNA synthesis in vitro, the specific activities of the two were found to be almost identical. These results were interpreted to indicate that the succinyl derivative of NCS was more stable to inactivation and proteolytic break-down in vivo than NCS as observed previously in in vitro studies.We reported previously the preparation and chemical and biological characterization of the bissuccinyl (NaAla 1, N5Lys 20) neocarzinostatin derivative of the antitumor antibiotic, neocarzinostatin (NCS). It was found in comparison with NCS that modification of the two amino groups in NCS did not alter the effect of the drug against cultured cell lines at 0.25 /tg/ml level, but a considerable decrease was observed in antibacterial activity1,2). Furthermore, the stability of the derivative against proteolytic digestion by blood or serum enzymes was enhanced due to succinylation of the free amino groups in NCS3,4). These results prompted an investigation of the potential usefulness of the derivative in vivo.

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