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Multisystem Stem Cell Failure after Apparent Recovery from Alkylating Agents¹

Joint Center for Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02115

Failure of cell renewal systems is rarely a cause of death in mammals since these systems have a proliferative capacity that far exceeds the life span of the mammals. While permitting seemingly complete recovery, exposure to systemic chemotherapy may cause sufficient stem cell depletion to limit subsequent proliferative capacity. We tested this hypothesis in 8- to 12-week-old male C3H/HeJ mice receiving five to six weekly i.p. Injections of busulfan, L-phenylalanine mustard, or cyclophosphamide. Mice treated with busulfan demonstrated permanent damage in bone marrow proliferative capacity when tested by serial transplantation and endogenous spleen colony formation for as long as 95 weeks after drug administration the last time tested. These mice also exhibited a decreased antibody response to primary immunization with sheep erythrocytes, early graying of their fur, and an increased incidence of cataract formation. Mice treated with L-phenylalanine mustard demonstrated a moderate defect in hematopoletic proliferation, showed a depressed immunological response, and have also developed a significantly higher incidence of leukemia and Harderian gland tumors. Although cyclophosphamide-treated mice do not show a hematopoletic defect, early graying of fur an an impaired immunological response to sheep erythrocytes have been noted. These results support the theory that reserve cells of renewal tissues have limited proliferative capacity. With the increasing role of adjuvant therapy in cancer management, one must be concerned with the risk of developing late complications secondary to failure of cell renewal tissues.

¹ Study supported in part by USPHS Grants CA-12662, CA-10941, and CA-09078.

² To whom requests for reprints should be addressed.

Received 11/ 7/77. Accepted 3/28/78.

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