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Retention of Tritiated Methotrexate in a Transplantable Mouse Glioma¹

Division of Neurosurgery, Medical Sciences Building, University of Toronto, Toronto, Ontario, M5S 1A8 and Division of Neurosurgery, Sunnybrook Medical Centre, Toronto, Ontario, M4N 3M5 Canada

The uptake and distribution of tritiated methotrexate ([³H]MTX) were studied by autoradiography and liquid scintillation counting for up to 7 days after i.v. injection in mice bearing s.c. or intracerebral (i.c.) implants of a transplantable mouse ependymoblastoma.

Autoradiography showed that s.c. tumors took up more [³H]MTX than i.c. tumors. In both s.c. and i.c. tumors, [³H]MTX was mainly intracellular, with very little in interstitial fluid sites. Retention of [³H]MTX gradually diminished with time, with some still being present 7 days after injection. The distribution of [³H]MTX in the i.c. tumors was not uniform, and portions of these tumors were relatively inaccessible to the drug. The uniformity of distribution did not improve with time. Scintillation counting showed that s.c. tumors accumulated much less [³H]MTX and retained a lower proportion of [³H]MTX than many normal tissues.

These studies indicate that [³H]MTX has 3 major short-comings as a chemotherapeutic agent for brain tumors. First, the amount of drug taken up by the transplantable mouse ependymoblastoma was small in comparison with normal tissues and in comparison with other agents taken up by this tumor. Second, the distribution of the drug in the i.c. tumors was nonuniform, with tumor cells in certain areas remaining relatively inaccessible to the drug. Last, the retention of the drug in the tumor was far less than in normal tissues.

¹ Supported by the Ontario Cancer Treatment and Research Foundation Grant 247 and Sunnybrook Hospital, University of Toronto Clinic.

Received 1/ 2/76. Accepted 5/20/76.