Epidemiological studies on the etiologies of human cancers are exceedingly difficult due to the multiplicity of carcinogens to which humans are exposed, and due to the long latency periods between exposure and the expression of the disease state. The multiplicity of exposures also complicates efforts to predict human cancer risks based on bioassays in which animals are exposed to a single agent. In order to make better predictions for human cancer risks, it is exceedingly important to understand the mechanisms by which low levels of environmental carcinogenic agents interact to promote this disease. We have selected a group of known or suspected carcinogenic agents and propose to measure patterns of interaction for endpoints which are highly correlated with the carcinogenic pathway. Specific agents were chosen based on i) our knowledge of the mechanism by which they produce DNA damage and the type of lesions which result, and ii) either because some of these agents are cancer chemotherapeutic drugs, permitting comparison with human responses, or because the agents are ubiquitous in our environment, and exposures are unavoidable. We propose to examine several endpoints in vitro which include: cytotoxicity, specific locus mutation, sister chromatid exchange, chromosomal aberrations, and inhibition of cell replication kinetics. These last three endpoints will also be studied in vivo and in utero to confirm the validity of in vitro observations. The time interval between exposures is an important parameter in evaluating potential interaction. Our protocols will evaluate both simultaneous and sequential exposure to carcinogenic agents. Simultaneous exposure to interactive agents will determine if acute effects are mitigating, additive or synergistic. Exposures separated by both long (hours) and short (days or greater) intervals will measure how risk factors are affected by histories or previous exposures. These types of data may prove important in predicting human risks involved in exposure to multiple carcinogenic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003644-02
Application #
3251157
Study Section
(SSS)
Project Start
1984-09-01
Project End
1987-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Chang, G; Jacobson-Kram, D; Williams, J R (1988) Use of an established human hepatoma cell line with endogenous bioactivation for gene mutation studies. Cell Biol Toxicol 4:267-79
Dillehay, L E; Denstman, S C; Williams, J R (1987) Cell cycle dependence of sister chromatid exchange induction by DNA topoisomerase II inhibitors in Chinese hamster V79 cells. Cancer Res 47:206-9
Shubber, E K; Jacobson-Kram, D; Williams, J R (1986) Comparison of the Ames assay and the induction of sister chromatid exchanges: results with ten pharmaceuticals and five selected agents. Cell Biol Toxicol 2:379-99
Denstman, S C; Dillehay, L E; Williams, J R (1986) Enhanced susceptibility to HPD-sensitized phototoxicity and correlated resistance to trypsin detachment in SV40 transformed IMR-90 cells. Photochem Photobiol 43:145-7
Lim, M; Liu, L F; Jacobson-Kram, D et al. (1986) Induction of sister chromatid exchanges by inhibitors of topoisomerases. Cell Biol Toxicol 2:485-94
Dearfield, K L; Jacobson-Kram, D; Huber, B E et al. (1986) Induction of sister chromatid exchanges in human and rat hepatoma cell lines by cyclophosphamide and phosphoramide mustard and the effects of cytochrome P-450 inhibitors. Biochem Pharmacol 35:2199-205
Grady, M K; Jacobson-Kram, D; Dearfield, K L et al. (1986) Induction of sister chromatid exchanges by benzidine in rat and human hepatoma cell lines and inhibition by indomethacin. Cell Biol Toxicol 2:223-30
Kim, J P; D'Arpa, P; Jacobson-Kram, D et al. (1985) Ultraviolet-light exposure induces a heritable sensitivity to the induction of SCE by mitomycin-C. Mutat Res 149:437-42
Williams, J R; D'Arpa, P; Opishinski, J et al. (1985) Differential and similar responses between rodent and human cells to DNA-damaging agents: possible implications for cellular aging. Basic Life Sci 35:205-11
Huber, B E; Dearfield, K L; Williams, J R et al. (1985) Tumorigenicity and transcriptional modulation of c-myc and N-ras oncogenes in a human hepatoma cell line. Cancer Res 45:4322-9