Abstract
Growth of a methylcholanthrene-induced fibrosarcoma in BALB/c mice was accompanied by an increase in the activation state of tumour-associated macrophages (TAM), as measured by their FcIgG receptor expression, phagocytic index and beta-glucuronidase levels. All of these parameters were markedly higher in TAM than in peritoneal macrophages (PM) derived from the same animal. On the other hand, PM from tumour-bearing mice showed lower activation parameters than PM from normal animals. We also studied the effect on tumour development of three inhibitors of prostaglandin synthesis: indomethacin, piroxicam and aspirin. Intraperitoneal administration of these drugs during 8 d was followed by the regression of palpable tumours. Indomethacin (90 mg/d) induced 45% regression, while with piroxicam (two 400 mg/d doses and six 200 mg/d doses) and aspirin (1 mg/d) 32% and 30% regressions, respectively, were observed. The growth rate of nonregressing tumours, which had reached different volumes by the end of the treatment, was delayed to a similar extent by the three anti-inflammatory non-steroidal drugs (NSAID). With respect to TAM, the treatment did not induce any significant change in their activation state, though both piroxicam and indomethacin increased slightly the TAM number. In contrast, NSAID administration was followed by a remarkable increase in the activation parameters of PM when compared with PM from tumour-bearing mice receiving no treatment. Indeed, these parameters were in some cases higher than those of PM from normal mice. The leukocytosis (60,000/microliters) with neutrophilia (80%) induced by tumour growth on peripheral blood leukocytes (PBL) was reversed by the treatment to values close to normal, in parallel with the reduction of tumour size. A drop in haematocrit was also noted which was most probably a consequence of tumour growth rather than of the treatment. This study reveals that the three NSAID tested have a remarkable antitumour activity, which correlates with the restoration of PM activity and PBL values.
Full text
PDF






Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Attia M. A., Weiss D. W. Immunology of spontaneous mammary carcinomas in mice. V. Acquired tumor resistance and enhancement in strain A mice infected with mammary tumor virus. Cancer Res. 1966 Aug;26(8):1787–1800. [PubMed] [Google Scholar]
- Bartholeyns J., Freudenberg M., Galanos C. Growing tumors induce hypersensitivity to endotoxin and tumor necrosis factor. Infect Immun. 1987 Sep;55(9):2230–2233. doi: 10.1128/iai.55.9.2230-2233.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bernheim H. A. Is prostaglandin E2 involved in the pathogenesis of fever? Effects of interleukin-1 on the release of prostaglandins. Yale J Biol Med. 1986 Mar-Apr;59(2):151–158. [PMC free article] [PubMed] [Google Scholar]
- Boardman P. L., Hart F. D. Side-effects of indomethacin. Ann Rheum Dis. 1967 Mar;26(2):127–132. doi: 10.1136/ard.26.2.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Breau J. L., Morere J. F., Israel L. Regressions et freinages de croissance de métastases pulmonaires de cancers humains induits par le piroxicam, un inhibiteur de synthèse des prostaglandines. Bull Cancer. 1989;76(3):321–328. [PubMed] [Google Scholar]
- ElMasry M. N., Fox E. J., Rich R. R. Sequential effects of prostaglandins and interferon-gamma on differentiation of CD8+ suppressor cells. J Immunol. 1987 Aug 1;139(3):688–694. [PubMed] [Google Scholar]
- Fulton A. M. In vivo effects of indomethacin on the growth of murine mammary tumors. Cancer Res. 1984 Jun;44(6):2416–2420. [PubMed] [Google Scholar]
- Hardy C. L., Balducci L. Early hematopoietic events during tumor growth in mice. J Natl Cancer Inst. 1986 Mar;76(3):535–540. [PubMed] [Google Scholar]
- Ikeda T., Tozuka S., Hasumura Y., Takeuchi J. Prostaglandin-E-producing hepatocellular carcinoma with hypercalcemia. Cancer. 1988 May 1;61(9):1813–1814. doi: 10.1002/1097-0142(19880501)61:9<1813::aid-cncr2820610915>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
- Imir T., Sibbitt W., Bankhurst A. The relative resistance of lymphokine activated killer cells to suppression by prostaglandins and glucocorticoids. Prostaglandins Leukot Med. 1987 Jul;28(2):111–118. doi: 10.1016/0262-1746(87)90156-9. [DOI] [PubMed] [Google Scholar]
- Klein W. A., Miller H. H., Anderson M., DeCosse J. J. The use of indomethacin, sulindac, and tamoxifen for the treatment of desmoid tumors associated with familial polyposis. Cancer. 1987 Dec 15;60(12):2863–2868. doi: 10.1002/1097-0142(19871215)60:12<2863::aid-cncr2820601202>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
- Kunkel S. L., Chensue S. W., Phan S. H. Prostaglandins as endogenous mediators of interleukin 1 production. J Immunol. 1986 Jan;136(1):186–192. [PubMed] [Google Scholar]
- Kurland J. I., Broxmeyer H. E., Pelus L. M., Bockman R. S., Moore M. A. Role for monocyte-macrophage-derived colony-stimulating factor and prostaglandin E in the positive and negative feedback control of myeloid stem cell proliferation. Blood. 1978 Aug;52(2):388–407. [PubMed] [Google Scholar]
- Lala P. K., Parhar R. S., Singh P. Indomethacin therapy abrogates the prostaglandin-mediated suppression of natural killer activity in tumor-bearing mice and prevents tumor metastasis. Cell Immunol. 1986 Apr 15;99(1):108–118. doi: 10.1016/0008-8749(86)90220-0. [DOI] [PubMed] [Google Scholar]
- Lau S. S., McMahon J. B., McMenamin M. G., Schuller H. M., Boyd M. R. Metabolism of arachidonic acid in human lung cancer cell lines. Cancer Res. 1987 Jul 15;47(14):3757–3762. [PubMed] [Google Scholar]
- McBride W. H. Phenotype and functions of intratumoral macrophages. Biochim Biophys Acta. 1986 Aug 5;865(1):27–41. doi: 10.1016/0304-419x(86)90011-9. [DOI] [PubMed] [Google Scholar]
- McBride W. H., Woodruff M. F., Forbes G. M., Moore K. Effect of C. parvum on the number and activity of macrophages in primary and transplanted murine fibrosarcomas. Br J Cancer. 1982 Sep;46(3):448–451. doi: 10.1038/bjc.1982.224. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Myers M. J., Hanafin W. P., Schook L. B. Augmented macrophage PGE2 production following exposure to dimethylnitrosamine in vivo: relevance to suppressed T cell responses. Immunopharmacology. 1989 Sep-Oct;18(2):115–124. doi: 10.1016/0162-3109(89)90064-7. [DOI] [PubMed] [Google Scholar]
- Otterness I. G., Bliven M. L., Eskra J. D., Reinke M., Hanson D. C. The pharmacologic regulation of interleukin-1 production: the role of prostaglandins. Cell Immunol. 1988 Jul;114(2):385–397. doi: 10.1016/0008-8749(88)90330-9. [DOI] [PubMed] [Google Scholar]
- Parhar R. S., Lala P. K. Prostaglandin E2-mediated inactivation of various killer lineage cells by tumor-bearing host macrophages. J Leukoc Biol. 1988 Dec;44(6):474–484. doi: 10.1002/jlb.44.6.474. [DOI] [PubMed] [Google Scholar]
- Rappaport R. S., Dodge G. R. Prostaglandin E inhibits the production of human interleukin 2. J Exp Med. 1982 Mar 1;155(3):943–948. doi: 10.1084/jem.155.3.943. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reddy B. S., Maruyama H., Kelloff G. Dose-related inhibition of colon carcinogenesis by dietary piroxicam, a nonsteroidal antiinflammatory drug, during different stages of rat colon tumor development. Cancer Res. 1987 Oct 15;47(20):5340–5346. [PubMed] [Google Scholar]
- Snyder D. S., Beller D. I., Unanue E. R. Prostaglandins modulate macrophage Ia expression. Nature. 1982 Sep 9;299(5879):163–165. doi: 10.1038/299163a0. [DOI] [PubMed] [Google Scholar]
- Snyderman R., Pike M. C., Blaylock B. L., Weinstein P. Effects of neoplasms on inflammation: depression of macrophage accumulation after tumor implantation. J Immunol. 1976 Mar;116(3):585–589. [PubMed] [Google Scholar]
- Valdez J. C., de Alderete N., Meson O. E., Sirena A., Perdigon G. Comparative activation states of tumor-associated and peritoneal macrophages from mice bearing an induced fibrosarcoma. Immunobiology. 1990 Nov;181(4-5):276–287. doi: 10.1016/S0171-2985(11)80519-X. [DOI] [PubMed] [Google Scholar]
- Vore S. J., Eling T. E., Danilowicz M., Tucker A. N., Luster M. I. Regulation of murine hematopoiesis by arachidonic acid metabolites. Int J Immunopharmacol. 1989;11(5):435–442. doi: 10.1016/0192-0561(89)90171-9. [DOI] [PubMed] [Google Scholar]
- Wei W. Z., Ratner S., Fulton A. M., Heppner G. H. Inflammatory infiltrates of experimental mammary cancers. Biochim Biophys Acta. 1986 Aug 5;865(1):13–26. doi: 10.1016/0304-419x(86)90010-7. [DOI] [PubMed] [Google Scholar]
- Young M. R., Hoover C. S. Inhibition of spleen cell cytotoxic capacity toward tumor by elevated prostaglandin E2 levels in mice bearing Lewis lung carcinoma. J Natl Cancer Inst. 1986 Aug;77(2):425–429. [PubMed] [Google Scholar]
- Yurochko A. D., Pyle R. H., Elgert K. D. Changes in macrophage populations: phenotypic differences between normal and tumor-bearing host macrophages. Immunobiology. 1989 Feb;178(4-5):416–435. doi: 10.1016/s0171-2985(89)80063-4. [DOI] [PubMed] [Google Scholar]
