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Some Effects of 1, 3-Bis(2-chloroethyl)-1-nitrosourea upon the Synthesis of Protein and Nucleic Acids in Vivo and in Vitro¹

Kettering-Meyer Laboratory, Southern Research Institute,² Birmingham, Alabama

In a study of the biochemical effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, NSC 409962) 3 experimental systems were used: L1210 ascites cells in vitro; L1210 solid tumors and host livers in vivo; and plasmacytoma-1 and plasmacytoma-1/cyclophosphamide in vivo in hamsters. Formate-¹⁴C and adenine-8-¹⁴C were used as substrates in each of these systems, and DL-leucine-4,5-³H was also used as a substrate for the L1210 ascites cells in vitro and the L1210 solid tumors in vivo. The following effects of BCNU upon the metabolism of these substrates were observed: (a) inhibition of de novo synthesis of purine ribonucleotides by higher doses of the agent, with resulting inhibition of the incorporation of ¹⁴C from formate-¹⁴C into the purines of both RNA³ and DNA; (b) no inhibition of the conversion of adenine-8-¹⁴C into ribonucleotides; (c) greater inhibition of the conversion of ribonucleotides into components of DNA than into components of RNA; (d) greater inhibition of the synthesis of nucleic acids than of proteins; (e) delayed maximum inhibition of the synthesis of nucleic acids in vivo in solid tumors and host livers (maximum inhibition was observed at intervals of 16–48 hr after administration of the agent).

It was concluded that BCNU has a number of biochemical effects similar to those of several alkylating agents that have been studied in some of the same experimental systems but that much remains to be done to define its site and mode of action precisely.

¹ This investigation was supported by the Cancer Chemotherapy National Service Center, National Cancer Institute, under USPHS Contract SA-43-ph-2433 and by a grant from The John A. Hartford Foundation, Inc.

² Affiliated with Sloan-Kettering Institute for Cancer Research, New York, New York.

Received 3/26/65.