Further evidence of the tumor-suppressive effects of cadmium in the B6C3F1 mouse liver and lung: late stage vulnerability of tumors to cadmium and the role of metallothionein.
Previously, we studied the ability of cadmium to initiate or promote tumors in B6C3F1 mice and, contrary to expectation, found that cadmium inhibited development of N-nitrosodiethylamine (NDEA)-initiated and sodium barbital-promoted liver tumors. In this study, the time course of cadmium inhibition of NDEA-initiated tumor formation was studied. A single dose of NDEA (90 mg/kg i.p.) was given at 5 weeks of age (time 0) followed by cadmium (1000 ppm) in drinking water from 2 to 48, 4 to 48, 8 to 48, 16 to 48 and 32 to 48 weeks. The study ended at 48 weeks. NDEA-induced elevations in liver tumor incidence (22 tumor-bearing mice/25 total) over control (5/25) were prevented by cadmium regardless of the period of administration (NDEA + cadmium: 2-48 weeks, 2/25; 4-48 weeks, 1/25; 8-48 weeks, 1/25; 16-48 weeks, 2/25; 32-48 weeks, 6/24). Cadmium alone (2-48 weeks) eliminated (0/25) spontaneously occurring liver tumors (5/25). NDEA-induced lung tumor incidence (25/25) and multiplicity (7.28 tumors/lung) were also reduced by cadmium (maximal decreases 28% and 80%, respectively). Some evidence of a specific deficiency of metallothionein in tumor cells was seen immunohistologically in NDEA-induced hepatic lesions and pulmonary lesions. These results indicate that cadmium prevents or reduces tumor formation in the B6C3F1 mouse liver and lung regardless of the exposure interval and apparently by cell-specific cytotoxicity. Auxiliary studies indicated that in mice bearing multiple liver foci resulting from NDEA treatment there was a marked reduction in basal metallothionein levels and in response to zinc induction.(ABSTRACT TRUNCATED AT 250 WORDS)
Waalkes
M P
MP
National Cancer Institute, PRI/DynCorp, Frederick Cancer Research and Development Center, Maryland.
Diwan
B A
BA
Weghorst
C M
CM
Ward
J M
JM
Rice
J M
JM
Cherian
M G
MG
Goyer
R A
RA
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002104:Cadmium / Q000627:therapeutic use*; D004052:Diethylnitrosamine; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000737:chemistry / Q000517:prevention & control*; D008168:Lung / Q000187:drug effects; D008175:Lung Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D008668:Metallothionein / Q000032:analysis / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D013997:Time Factors
D016588:Anticarcinogenic Agents; D002104:Cadmium; D004052:Diethylnitrosamine; D008668:Metallothionein