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Modulation of Marrow Proliferation and Chemosensitivity by Tumor-produced Cytokines from Syngeneic Pancreatic Tumor Lines¹

Garden State Cancer Center, Belleville, New Jersey 07109

Purpose: A dynamic process exists in which hematopoietic progenitor andstromal cells interact to maintain normal hematopoiesis or to adjust to hematopoietic needs under "stress" situations. The effect that tumor-produced growth factors have on hematopoiesis has not been addressed. We postulate that an excess of tumor-produced stimulatory or inhibitory cytokines could impact marrow proliferation and sensitivity to cytotoxic agents.

Methods: We used two tumor lines (TGP47 and TGP51) taken from a panel of syngeneic murine pancreatic carcinomas, in which each produces a unique array of cytokines, and evaluated their effect in vitro on marrow proliferation and chemosensitivity.

Results: TGP51- and TGP47-conditioned medium increased [³H]thymidine incorporation into cultured marrow cells by 12-fold and 4.8-fold, respectively. The percent of cells in the S + G₂-M phases of the cell cycle increased by 110% (TGP51) and 44% (TGP47), and the MCF for proliferating cell nuclear antigen expression increased by 104% (TGP51) and 45% (TGP47). Marrow proliferation of untreated cells could be reduced by interleukin 6 but not by granulocyte macrophage colony-stimulating factor neutralization. Conditioned medium-induced stimulation was unchanged by either interleukin 6 or granulocyte macrophage colony-stimulating factor . FLT3-L reduced marrow proliferation induced by TGP51 medium. Addition of FLT3-L to TGP47 medium additionally enhanced the marrow proliferation. Antitumor necrosis factor additionally increased marrow proliferation induced by TGP47 and TGP51 conditioned medium, whereas addition of tumor necrosis factor reduced marrow proliferation associated with TGP51 medium. The TGP51-induced increase in marrow proliferation resulted in increased marrow chemosensitivity to three myelosuppressive drugs: doxorubicin, cyclophosphamide, and CPT-11, decreasing the IC₅₀ by 46%, 38%, and 95%, respectively.

Conclusion: Tumor-produced cytokines can affect marrow proliferative activity and, thus, chemosensitivity to three distinct classes of chemotherapeutics.

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