Abstract
The antitumor and antimetastatic activities of a thymic factor, thymostimulin (TP-1), with or without cyclophosphamide (CPA) were examined in C57BL/6 mice inoculated with Lewis lung carcinoma (3LL).
Tumor growth was followed by determining the tumor diameter after tumor implantation. TP-1 given to mice every 2 days after tumor implantation significantly inhibited tumor growth without affecting the survival rate.
For induction of spontaneous pulmonary metastases, 3LL cells were implanted into the footpads of mice, and the implanted tumor was removed on day 9. The antimetastatic effect of TP-1 on pulmonary metastases after removal of the primary tumor was evaluated by counting the number of pulmonary surface nodules. TP-1 showed antimetastatic activity depending on its time of administration and dose. Combined therapy with TP-1 plus CPA significantly prolonged the survival of mice with pulmonary metastases.
The cytolytic activities of spleen cells on 3LL cells were enhanced in mice treated with TP-1 and/or CPA and the cytolytic activity of nonadherent spleen cells, the T-cell population, was enhanced.
The role of cytolytic spleen cells in inhibiting and preventing metastases was discussed.
Keywords: Primary Tumor, Tumor Growth, Cyclophosphamide, Lung Carcinoma, Spleen Cell
Abbreviations
- TP-1
thymic factor, thymostimulin
- 3LL
Lewis lung carcinoma
- CPA
cyclophosphamide
- CCNU
1- (2-chloroethyl)-3-cyclohexyl-1-nitrosourea
- BCNU
1,3-bis (2-chloroethyl)-1-nitrosourea
- FCS
fetal calf serum
- SD
standard deviation
- SE
standard error
Footnotes
This work was supported in part by grants from the Ministry of Education, Science and Culture of Japan
References
- 1.Allison AC, Tayler RB. Observations on thymectomy and carcinogenesis. Cancer Res. 1967;27:703. [PubMed] [Google Scholar]
- 2.Bernengo MG, Capella G, DeMatteis A, Tovo PAG, Zina G. The in vitro effect of a calf thymus extract on the peripheral blood lymphocytes of 66 melanoma patients. Clin Exp Immunol. 1979;36:279. [PMC free article] [PubMed] [Google Scholar]
- 3.Bernengo MG, Fra P, Lisa F, Meregalli M, Zina G. Thymostimulin therapy in melanoma patients: Correlation of immunologic effects with clinical course. Clin Immunol Immunopathol. 1983;28:311. doi: 10.1016/0090-1229(83)90098-3. [DOI] [PubMed] [Google Scholar]
- 4.Carnaud C, Hoch B, Trainin N. Influence of immunologic competence of the host on metastases induced by the 3LL Lewis tumor in mice. J Natl Cancer Inst. 1974;52:395. doi: 10.1093/jnci/52.2.395. [DOI] [PubMed] [Google Scholar]
- 5.Chirigos MA (1978) In vitro and in vivo studies with thymosin. In: Chirigos MA (ed) Immune modulation and control of neoplasia by adjuvant therapy. p 305 (Progress in cancer research and therapy, vol 7)
- 6.Chretien PB, Lipson SD, Makuch R, Kenady DE, Cohen MH, Minna JD (1978) Thymosin in cancer patients: In vitro effects and correlations with clinical response to thymosin immunotherapy. Cancer Treat Rep 62:1787 [PubMed]
- 7.Cohen MH, Chretien PB, Ihde DC, Fossieck BE, Makuch R, Bunn PA, Johnston AV, Shackney SE, Matthews MJ, Lipson SD, Kenady DE, Minna JD. Thymosin fraction V and intensive combination chemotherapy prolonging the survival of patients with small-cell lung cancer. JAMA. 1979;241:1813. doi: 10.1001/jama.241.17.1813. [DOI] [PubMed] [Google Scholar]
- 8.Costanzi JJ, Gagliano RG, Delaney F, Harris N, Thurman GB, Sakai H, Goldstein AL, Loukas D, Cohen GB, Thomson PD. The effect of thymosin on patients with disseminated malignancies. A phase 1 study. Cancer. 1977;40:14. doi: 10.1002/1097-0142(197707)40:1<14::aid-cncr2820400105>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
- 9.Cupissol D, Touraine JL, Serrou B. Ability of lymphocytes treated with thymic factor to decrease lung metastasis in tumor-bearing mice. Thymus. 1981;3:9. [PubMed] [Google Scholar]
- 10.Falchetti R, Bergesi G, Caprino L (1976) Isolation, partial characterization and biological effects of a thymus factor. Third European Immunology Meeting, Copenhagen, August 25–27
- 11.Falchetti R, Bergesi G, Eshkol A, Cafiero C, Adorini L, Caprino L. Pharmacological and biological properties of a calf thymus extract (TP-1) Drugs Exp Clin Res. 1977;3:39. [Google Scholar]
- 12.Gabizon A, Trainin N. Effect of a thymic hormone, THF, on tumor-bearing mice and tumor-resected mice. Cancer Immunol Immunother. 1981;10:105. [Google Scholar]
- 13.Grant GA, Miller JFAP. Effect of neonatal thymectomy on the induction of sarcomata in C57BL mice. Nature. 1965;205:1124. doi: 10.1038/2051124a0. [DOI] [PubMed] [Google Scholar]
- 14.Havas HF, Schiffman G. Effect of cyclophosphamide on the immune response of BALB/c mice bearing an immunoglobulin M plasmacytoma (TEPC-183) Cancer Res. 1981;41:801. [PubMed] [Google Scholar]
- 15.Hengst JCD, Mokyr MB, Dray S. Importance of timing in cyclophosphamide therapy of MOPC-315 tumor-bearing mice. Cancer Res. 1980;40:2135. [PubMed] [Google Scholar]
- 16.Kagawa K, Yamashita T, Tsubura E, Yamamura Y. Inhibition of pulmonary metastases by Nocardia rubra cell wall skeleton, with special reference to macrophage activation. Cancer Res. 1984;44:665. [PubMed] [Google Scholar]
- 17.Klein AS, Shoham J. Effect of the thymus factor, thymostinulin (TP-1), on the survival rate of tumor-bearing mice. Cancer Res. 1981;41:3217. [PubMed] [Google Scholar]
- 18.Klimpel GR, Henney CS. BCG-induced suppressor cells. 1: Demonstration of a macrophage-like suppressor cell that inhibits cytotoxic T cell generation in vitro. J. Immunol. 1978;120:563. [PubMed] [Google Scholar]
- 19.Lau CY, Goldstein G. Functional effects of thymopoietin (TP5) on cytotoxic lymphocyte precursor units (CLP-U). 1: Enhancement of splenic CLP-U in vitro and in vivo after suboptimal antigenic stimulation. J Immunol. 1980;124:1861. [PubMed] [Google Scholar]
- 20.Law LW. Immunologic responsiveness and the induction of experimental neoplasms. Cancer Res. 1966;26:1121. [PubMed] [Google Scholar]
- 21.Lipson SD, Chretien PB, Makuch R, Kenady DE, Cohen MH. Thymosin immunotherapy in patients with small cell carcinoma of the lung. Cancer. 1979;43:863. doi: 10.1002/1097-0142(197903)43:3<863::aid-cncr2820430313>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
- 22.Martelli MF, Velardi A, Rambotti P, Cernetti C, Bertotto A, Spinozzi F, Bracaglis AM, Falini B, Davis S. The in vitro effect of thymic factor (thymostimulin) on immunologic parameters of patients with untreated Hodgkin's disease. Cancer. 1982;50:490. doi: 10.1002/1097-0142(19820801)50:3<490::aid-cncr2820500318>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
- 23.Martinez C. Effect of early thymectomy on development of mammary tumor in mice. Nature. 1964;203:1188. doi: 10.1038/2031188a0. [DOI] [PubMed] [Google Scholar]
- 24.Rinehart JJ, Lange P, Gormus BJ, Kaplan M. Human monocyte-induced tumor cell cytotoxicity. Blood. 1978;52:211. [PubMed] [Google Scholar]
- 25.Sanford BH, Kohn HI, Daly JJ, Soo SF. Long-term spontaneous tumor incidence in neonatally thymectomized mice. J Immunol. 1973;110:1437. [PubMed] [Google Scholar]
- 26.Shoham J, Theoder E, Brenner HJ, Goldman B, Lusky A, Chaitchick S. Enhancement of the immune system of chemotherapy-treated cancer patients by simultaneous treatment with thymic extract, TP-1. Cancer Immunol Immunother. 1980;9:173. [Google Scholar]
- 27.Yamamoto T, Yamashita T, Tsubura E. Inhibition of pulmonary metastasis of Lewis lung carcinoma by a glucan, schizophyllan. Invasion and Metastasis. 1981;1:71. [PubMed] [Google Scholar]
- 28.Zaizov R, Vogel R, Wolach B, Cohen IJ, Varsano I, Shohat B. The effect of THF in lymphoproliferative and myeloproliferative diseases in children. Ann NY Acad Sci. 1979;332:172. doi: 10.1111/j.1749-6632.1979.tb47110.x. [DOI] [PubMed] [Google Scholar]