Effects of histamine type-2 receptor antagonists on indomethacin and IL-2 immunotherapy of metastasis.
Histamine type-2 receptor antagonists (H-2RA) have been used chronically to prevent dyspepsia in cancer patients subjected to immunotherapy with chronic indomethacin (Indo) and intermittent IL-2 in our cancer centre. We tested the effects of these agents during immunotherapy of C3H/HeJ mice transplanted s.c. with 5 x 10(5) C3L5 mammary adenocarcinoma cells. Tumor-transplanted mice were divided into groups receiving: (1) Indo (14 micrograms/ml); (2) H-2RA, i.e. (a) ranitidine at 28.6 micrograms/ml (Ran-lo) or 143 micrograms/ml (Ran-hi), or (b) famotidine (Fam) at 4.3 micrograms/ml, or (c) cimetidine (Cim) at 107 micrograms/ml, all in the drinking water on days 5-24; (3) IL-2 (1.5 x 10(3) Cetus U i.p. every 8 h on days 10-14 and 20-24); (4) combinations of H-2RA + Indo; or (5) combinations of H-2RA + Indo + IL-2. Animals were killed on day 24 for examination of primary s.c. tumor growth, secondary lung metastasis and splenocyte cytotoxicity against YAC-1 lymphoma cells (51Cr release assay). Results revealed: (1) primary tumor growth was reduced in mice treated with Fam + Indo, Indo + IL-2 and any of the H-2RA + Indo + IL-2 (no difference observed within the last two groups); (2) lung metastases decreased in mice treated with IL-2 alone, Indo + IL-2, and Indo + IL-2 + Ran-hi; (3) splenic cytotoxicity was suppressed in tumor-bearing controls, with partial restoration seen in Ran (both doses), Ran-lo + Indo, Ran-lo + Indo + IL-2, and Cim + Indo + IL-2 treated groups. Nearly complete restoration was seen in Cim, Cim + Indo, Indo + IL-2, Ran-hi + Indo + IL-2, and Fam + Indo + IL-2 groups. Thus, addition of H-2RA did not alter the overall therapeutic efficacy of the standard Indo + IL-2 tumor immunotherapy.
Saarloos
M N
MN
Department of Anatomy, University of Western Ontario, London, Canada.
Khoo
N K
NK
Lala
P K
PK
D000230:Adenocarcinoma / Q000556:secondary* / Q000628:therapy; D000276:Adjuvants, Immunologic; D000818:Animals; D002927:Cimetidine / Q000627:therapeutic use; D015738:Famotidine / Q000627:therapeutic use; D005260:Female; D006635:Histamine H2 Antagonists / Q000627:therapeutic use*; D016219:Immunotherapy, Adoptive; D007213:Indomethacin / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000556:secondary* / Q000628:therapy; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008809:Mice, Inbred C3H; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011899:Ranitidine / Q000627:therapeutic use
D000276:Adjuvants, Immunologic; D006635:Histamine H2 Antagonists; D007376:Interleukin-2; D015738:Famotidine; D002927:Cimetidine; D011899:Ranitidine; D007213:Indomethacin