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Carbodiimide Enhancement of Complement-dependent Antibody-mediated Tumor Cell Lysis in Vitro and Antitumor Activity in Vivo¹

Donner Laboratory, Lawrence Berkeley Laboratory, University of California, Berkeley, California 94720

The water-soluble carbodiimide salt 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide·HCl (EDCI·HCl) has been shown to increase the complement-dependent lysis of cultured mouse neuroblastoma C1300 cells by two types of antibody: (l) natural antibodies in the sera of normal (nonimmunized) rabbits, and (b) serum antibodies from syngeneic tumor-bearing A/HeJ mice. In the latter case, both the level of serum antibodies and the extent of carbodiimide enhancement of immune lysis were demonstrated in vitro to be substantially greater with sera from mice bearing 21-day-old tumors relative to 4-day-old tumors. The carbodiimide EDCI·HCl has also been found to increase the complement-dependent lysis of cultured TA3 carcinoma cells by serum antibodies from isogeneic LAF₁/J mice bearing ascites tumors in advanced stages of growth. Finally, it has been shown that EDCI·HCl exerts an antitumor activity in vivo that is significantly greater against 21-day-old than against 4-day-old neuroblastoma C1300 tumors. The increase in EDCI·HCl activity with tumor age is contrary to the response that would be expected if this drug were serving as an antimetabolite. This is evidenced by data showing that the antimetabolite 6-thioguanine is most effective against young, rapidly growing neuroblastoma C1300 tumors. The correlation between carbodiimide antitumor activity and host production of cytotoxic antibodies suggests that EDCI·HCl may operate in vivo by an immunological mechanism comparable to that demonstrated in vitro.

¹ This research was supported by the United States Atomic Energy Commission Contract W-7405-eng-48 with the Lawrence Berkeley Laboratory.

² Gratefully acknowledges support from a Bay Area Heart Committee Postdoctoral Fellowship (1969–1971) and National Cancer Institute Postdoctoral Fellowship 5-FO3-CA52469-02 (1971–1973).

³ Present address: Northwestern University Medical School, Chicago, Ill. 60201.

Received 3/ 4/74. Accepted 11/22/74.