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Rational Selection of Adjuvant Chemotherapy after Cytoreduction Surgery for Murine Neuroblastoma¹

Division of Pediatric Surgery and the Joseph Stokes Research Foundation, The Children's Hospital of Philadelphia [H. N., M. Z.]; and the Departments of Surgery and Pharmacology and the Harrison Department of Surgical Research, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania [K. C. T.]

Improving the prognosis of advanced neuroblastoma remains an important yet unachieved goal of pediatric oncology, a fact which may be related to an insufficient analysis of the role played by cytoreductive surgery. Utilizing strain A mice bearing C-1300 syngeneic neuroblastoma, tumor biology and host immunocompetence were studied after cytoreduction surgery and adjuvant chemotherapy. Cell kinetic analysis in the residual tumor demonstrated an increase of the proliferative fraction 18 to 42 h after operation, but the same peak proliferation was delayed in bone marrow cells to 24 to 96 h. The potential for drug distribution to the tumor after cytoreduction surgery was assessed by injecting Na₂⁵¹CrO₄ and measuring tumor uptake. There were two significant (P < 0.05) peaks of activity at 6 h and 3 days, suggesting local edema and neovascularity, respectively. Injection of both cell cycle specific and nonspecific adjuvant chemotherapeutic agents in a dosage of one-fourth of their 50% lethal dose at 24 or 72 h following surgical cytoreduction did not induce any antitumor activity at either injection time. However, when cyclophosphamide was given in this dose, the C-1300 tumor growth was impaired, an effect which was largely abrogated by first subjecting the tumor bearer to thymectomy and irradiation. The transfer of spleen cells from adjuvant cyclophosphamide-treated mice to tumor-inoculated normal mice significantly delayed tumor appearance when comparison was made with animals treated by operation alone, and such recipients also exhibited a more prolonged survival. These data suggest that the antitumor activity of cyclophosphamide following cytoreduction surgery of C-1300 neuroblastoma is mediated by both pharmacological and immunological mechanisms.

¹ This work was conducted with support from Grant CA 28770 from the National Cancer Institute and with support from the McCabe Research Fund, Grant 2754.

² To whom requests for reprints should be addressed, at Department of Surgery, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104.

Received 7/20/83. Revised 4/29/85. Accepted 5/ 1/85.

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