Studies with cyclophosphamide labeled with phosphorus-32: nucleic acid alkylation and its effect on DNA synthesis in rat tumor and normal tissues.

The gross distribution of levels of [32P]cyclophosphamide ([32P]CY) in August female rats was similar in tumor, intestinal mucosa, spleen, bone marrow, and striated muscle tissue, with slightly higher levels in liver and kidney tissue. A triphasic association with nucleic acids was found and actual alkylation of DNA and RNA reached a maximum of 48 hours post treatment. There was no evidence of 32P-label reutilization that could have accounted for prolonged alkylation. We found that 100 mg CY/kg suppressed the incorporation of [3H]thymidine, [3H]deoxyuridine, and [14C]sodium formate into the DNA of the BICR-A15 carcinoma for at least 10 days. This correlated well with the observed regression of tumor volume. Bone marrow and intestinal mucosa, two tissues which limit chemotherapuetic treatment of the tumor, were less affected by 100 mg CY/kg. Bone marrow had regained normal levels of DNA precursor incorporation by 5 days, and intestinal mucosa had regained normal levels by 3 days. Results indicated that this differential in recovery time may assist in the successful scheduling of vital tissue-sparing drug regimens.