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Protection by S-2-(3-Aminopropylamino)ethylphosphorothioic Acid against Radiation- and Cyclophosphamide-induced Attenuation in Antitumor Resistance¹

Department of Experimental Radiotherapy, The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77030 [L. M., N. H., H. I.], and Department of Bacteriology, University of Edinburgh, University Medical School, Edinburgh, Scotland [W. H. M.]

Studies were performed to investigate whether S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) can protect antitumor immune rejection responses against the damaging effect of whole-body irradiation (WBI) and cyclophosphamide (CY). Among these damaging effects were radiation-induced enhancement of s.c. tumor take and radiation- and CY-induced enhancement of lung colonization by tumor cells injected i.v. The ability of WR-2721 to protect against WBI-induced decreased radioresponse of solitary tumors was also investigated. All experiments were performed with an immunogenic fibrosarcoma syngeneic to C3Hf/Kam mice. WR-2721 was given i.p. at a dose of 400 mg/kg 30 min before WBI with -rays or CY injection. WBI with 650 rads reduced the number of tumor cells needed for tumor take in 50% of animals from 5.1 x 10⁴ cells in normal mice to 2.0 x 10². WR-2721 given before WBI almost entirely abolished the effect of WBI: the number of tumor cells needed for tumor take in 50% of animals was 1.4 x 10⁴. Treatment of mice with WBI or CY increased the number of tumor nodules in the lung generated by fibrosarcoma cells injected i.v. 5 days later, in linear dose response. WR-2721 greatly reduced this metastasis enhancement effect of WBI and CY with protection factors of 2.5 for WBI and 1.8 for CY. Fibrosarcomas of 8 mm in diameter exhibited a decreased radiocurability when growing in WBI mice: the dose of irradiation yielding local tumor control in 50% of animals in these mice was 5950 compared to a dose of irradiation yielding local tumor control in 50% of animals of 4160 rads in normal mice. WR-2721 given before WBI inhibited this effect of WBI: the dose of irradiation yielding local tumor control in 50% of animals was 5210 rads. The proportion of macrophages in tumors growing in WBI mice was significantly reduced, but not when WR-2721 was first given. WR-2721 greatly reduced the damaging effects of WBI and CY on natural killer cell activity. Therefore, WR-2721 was capable of protecting the immune mechanisms involved in antitumor resistance against WBI and CY. This might be of therapeutic benefit when WR-2721 is combined with radio- or chemotherapy.

¹ This investigation was supported in part by Grants CA-06294 and CA-16672, awarded by the National Cancer Institute, Department of Health and Human Services. Animals used in this study were maintained in facilities approved by the American Association for Accreditation of Laboratory Animal Care and in accordance with current regulations and standards of the United States Department of Agriculture and Department of Health and Human Services, NIH.

² To whom requests for reprints should be addressed.

Received 11/21/83. Accepted 3/ 6/84.