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Increased Therapeutic Benefit through the Addition of Misonidazole to a Nitrosourea-Radiation Combination¹

Experimental Therapeutics Division and Department of Radiation Oncology, University of Rochester Cancer Center, Rochester, New York 14642

The potential therapeutic advantage of including the radiosensitizer misonidazole (MISO) in a treatment regimen combining systemic chemotherapy and localized radiotherapy was assessed in the KHT sarcoma. Tumor-bearing C3H mice were treated with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, administered either alone or in combination with MISO, 24 h prior to irradiating the tumors with doses ranging from 0–35 Gy. The sensitizer exposure was either a single dose of 2.5 mmol/kg or multiple injections given every 0.5 h for 8 h to maintain a sensitizer blood level of approximately 100 µg/ml. The chemotherapeutic agent was administered simultaneously with the single sensitizer dose or 3 h into the chronic sensitizer dosing schedule. Tumor response to the combined modality treatments was determined using end points of tumor regrowth delay and animal tumor-free survival. Skin reactions in the treatment field were scored as a measure of normal tissue complications. MISO, administered as a single dose in the combined modality therapy, enhanced the tumor response by a factor of 1.8–1.9 while increasing skin reactions 1.1- to 1.2-fold. Combining 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea with chronic MISO administration prior to irradiation increased the resultant tumor control probability 1.5- to 1.8-fold without enhancing normal tissue complications. Consequently using MISO as a chemopotentiator in a 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea-radiation combination can yield a significant therapeutic benefit.

¹ Supported by USPHS Grants CA-20329 and CA-38637, awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Experimental Therapeutics Division, University of Rochester Cancer Center, 601 Elmwood Ave. Box 704, Rochester, NY 14642.

³ Present address: Gray Laboratory, Mt. Vernon Hospital, Northwood, Middlesex HA6 2RN England.

Received 7/11/85. Revised 10/10/85. Accepted 10/14/85.