Modulation of marrow proliferation and chemosensitivity by tumor-produced cytokines from syngeneic pancreatic tumor lines.
OBJECTIVE
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 approximately 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 6alpha or granulocyte macrophage colony-stimulating factor alpha. FLT3-Lalpha reduced marrow proliferation induced by TGP51 medium. Addition of FLT3-L to TGP47 medium additionally enhanced the marrow proliferation. Antitumor necrosis factor alpha additionally increased marrow proliferation induced by TGP47 and TGP51 conditioned medium, whereas addition of tumor necrosis factor alpha 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.


CONCLUSIONS
Tumor-produced cytokines can affect marrow proliferative activity and, thus, chemosensitivity to three distinct classes of chemotherapeutics.
Blumenthal
Rosalyn D
RD
Garden State Cancer Center, Belleville, New Jersey 07109, USA. rblumenthal.gscancer@att.net
Reising
Albert
A
Leon
Evelyn
E
Goldenberg
David M
DM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D003520:Cyclophosphamide / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D007377:Interleukin-3 / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D000077146:Irinotecan; D008565:Membrane Proteins / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D014185:Transplantation, Isogeneic; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D016207:Cytokines; D007375:Interleukin-1; D007377:Interleukin-3; D015850:Interleukin-6; D008565:Membrane Proteins; C084881:flt3 ligand protein; D016179:Granulocyte Colony-Stimulating Factor; D000077146:Irinotecan; D004317:Doxorubicin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D002166:Camptothecin