This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Shapiro, W. R. Search for Related Content PubMed PubMed Citation Articles by Shapiro, W. R.

The Effect of Chemotherapeutic Agents on the Incorporation of DNA Precursors by Experimental Brain Tumors¹

Laboratory of Neurological Oncology, Sloan-Kettering Institute for Cancer Research, and Department of Neurology, Cornell University Medical College, New York, New York 10021

A test system is described for chemotherapy of experimental brain tumors based on the effects of the drugs on the uptake and incorporation of DNA precursors. Thirteen to 15 days following intracerebral implantation of murine gliomas, the mice were given chemotherapeutic agents, following which ³H-labeled thymidine (TdR-³H) or deoxyuridine-2-¹⁴C (UdR-¹⁴C) was administered i.p. The effect of the chemotherapeutic agent on the incorporation into newly formed tumor DNA (and frequently that of normal tissues) of the DNA precursors was determined and compared with uptake in a control group of animals not treated with the agent. 1,3-Bis(2-chloroethyl)-1-nitrosourea significantly retarded the uptake of TdR-³H into all three tumors tested. Uptake was retarded from 25 to 50%, depending on the dose of 1,3-bis(2-chloroethyl)-1-nitrosourea. 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea similarly produced retardation in uptake of TdR-³H to approximately 40% of control. Depression began 12 hr after administration of the CCNU and was still evident 72 hr later. Arabinosylcytosine produced marked depression of uptake of TdR-³H at 3 doses tested. At 40 mg/kg, uptake was retarded to 5% of control in the tumor (Glioma 261) and to 0 in lymph node and bone marrow; at doses of 400 and 4000 mg/kg, uptake was retarded to 0 in all tissues tested. Uptake into tumor of TdR-³H was markedly enhanced by methotrexate with maximum effect occurring approximately 30 min after administration of the drug. A combined experiment with UdR-¹⁴C confirmed enhancement of uptake of TdR-³H, while UdR-¹⁴C uptake was markedly retarded. Thirty min after the methotrexate, TdR-³H incorporation increased to 140% of control; UdR-¹⁴C uptake diminished to 23% of control. In murine bone marrow, methotrexate had no effect on uptake of thymidine but produced a prompt fall in uptake of UdR-¹⁴C to 9% of control. This test system permits evaluation of a chemotherapeutic effect in experimental brain tumors, examines possible mechanisms of drug action, and permits inferences on blood-brain barrier function.

¹ Supported in part by National Cancer Institute Grant CA-08748 and American Cancer Society Grant T-537.

² Recipient of Research Career Development Award 5-K4-NS-50,294 from the National Institute of Neurological Diseases and Stroke. To whom requests for reprints should be sent, at Sloan-Kettering Institute, 410 East 68 Street, New York, N. Y. 10021.

Received 2/ 8/72. Accepted 6/22/72.