Patients undergoing """"""""curative"""""""" cancer surgery occasionally develop distant metastases faster and in greater volume than would be expected from the natural history of their resected tumors. In many animal models surgical stress increases both the number and growth rate of metastases relative to unstressed controls. The object of this study is to determine the impact of surgery on host immune protection against metastases. Mechanisms harmed by surgery will be identified; methods to reverse their surgically induced impairment will be explored. Natural killer cells (NKC) play a crucial role in surveillance and clearance of circulating tumor cells, thereby helping prevent metastases. NKC cytotoxicity is decreased by as much as 68% one day after the application of surgical stress (amputation) in a mouse model using an in vitro 51Cr release assay. Other immune factors are also important in defense against malignancy. Primary and secondary antibody response (as measured by hemagglutination microtiter techniques) and the blastogenic transformation of lymphocytes after mitogen stimulation with PHA and LPS will be studied in control, surgically stressed, and tumor bearing surgically stressed for mice. An in vivo model of surgical stress-induced metastasis is being developed using mice first amputated and then one day later foot pad inoculated with 500,000 Lewis lung tumor cells. The observed surgical impairment of NKC cytotoxicity, and the potential impairment of antibody formation and lymphoblastogenesis may be preventable by preoperative treatment with the biologic response modifier tuftsin. Likewise, preoperative tuftsin may be successful in protecting against stress-induced metastases in vivo. Ultimately, these animal studies may suggest a possible explanation and solution for the dilemma of surgically induced metastasis--a possibility that has direct human application.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA000936-03
Application #
3079406
Study Section
(SRC)
Project Start
1984-04-15
Project End
1987-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Hospitals
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Delsite, Robert L; Rasmussen, Lene Juel; Rasmussen, Anne Karin et al. (2003) Mitochondrial impairment is accompanied by impaired oxidative DNA repair in the nucleus. Mutagenesis 18:497-503
Delsite, Robert; Kachhap, Sushant; Anbazhagan, Ramaswamy et al. (2002) Nuclear genes involved in mitochondria-to-nucleus communication in breast cancer cells. Mol Cancer 1:6
Ding, H F; Bustin, M; Hansen, U (1997) Alleviation of histone H1-mediated transcriptional repression and chromatin compaction by the acidic activation region in chromosomal protein HMG-14. Mol Cell Biol 17:5843-55
DeFranco, C; Damon, D H; Endoh, M et al. (1993) Nerve growth factor induces transcription of NGFIA through complex regulatory elements that are also sensitive to serum and phorbol 12-myristate 13-acetate. Mol Endocrinol 7:365-79
Pollock, R E; Lotzova, E; Stanford, S D (1989) Surgical stress impairment of murine natural killer cell cytotoxicity involves pre- and postbinding events. J Immunol 143:3396-403
Pollock, R E; Lotzova, E (1987) Surgical-stress-related suppression of natural killer cell activity: a possible role in tumor metastasis. Nat Immun Cell Growth Regul 6:269-78
Pollock, R; Ames, F; Rubio, P et al. (1987) Protracted severe immune dysregulation induced by cardiopulmonary bypass: a predisposing etiologic factor in blood transfusion-related AIDS? J Clin Lab Immunol 22:1-5
Pollock, R E; Lotzova, E; Stanford, S D et al. (1987) Effect of surgical stress on murine natural killer cell cytotoxicity. J Immunol 138:171-8
Heilig, J S; Glimcher, L H; Kranz, D M et al. (1985) Expression of the T-cell-specific gamma gene is unnecessary in T cells recognizing class II MHC determinants. Nature 317:68-70