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Role of Corticosteroid Hormones in the Control of Cell Proliferation in Residual Tumor after Surgical Cytoreduction¹

Department of Experimental Therapeutics [P. G. B., L. M. S.], AMC Cancer Research Center, Lakewood, Colorado 80214, and Cancer Research Laboratories [H. L. T.], Allegheny Singer Research Corporation, Pittsburgh, Pennsylvania 15212

Changes in tumor cell proliferation in local and distant residual tumor were studied after subtotal surgical cytoreduction in three experimental tumor models varying in corticosteroid receptor content, cell proliferation, and animal host. In residual s.c. RIF-1 anf R3230AC tumors, proliferation was inhibited within 24 hr after 75% resection. Subsequently, intervals of increased proliferation, characterized by increases in tritiated thymidine ([³H]dThd) labeling index, primer-dependent DNA polymerase labeling indices, and S-phase clonogenic fractions, were observed. In RIF-1 "artificial" lung metastases. [³H]dThd uptake in tumor-bearing lungs increased by about 70% at 3 days after amputation of "primary" tumor-bearing legs. When dexamethasone was given every 12 hr during the postsurgical recovery interval, changes in [³H]dThd labeling indices and [³H]dThd uptake per lung indicated that the proliferative recovery was delayed until after cessation of dexamethasone treatments. Other studies with RIF-1 tumors indicated that postsurgical tumors indicated that postsurgical proliferation inhibition was dependent on intact adrenal function and that the initiation of postsurgical proliferative recovery was preceded by reestablishment of normal serum corticosterone levels and presurgical levels of saturable glucocorticosteroid receptor. The effectiveness of cyclophosphamide 5-fluorouracil after surgery was time dependent in residual local and distant tumor, with the most efficacious intervals being coincident with postsurgical proliferative recovery. Our results indicate that, in these experimental tumor models, changes in endogenous corticosteroid hormones resulting from the surgica trauma, cellular corticosteroid hormone receptor levels and cytoreduction may influence the time course of the proliferative response in residual tumor after surgical cytoreduction.

¹ This work supported by Department of Health, Education, and Welfare Grants CA 34961 and CA 26020, and grants to the AMC Cancer Research Center from John E. Fuller, Sr., and Fred T. Davine.

² To whom requests for reprints should be addressed.

Received 5/ 2/83. Accepted 9/ 2/83.