Comparative study of lung carcinogenesis, promoting action in leukaemogenesis and initiating action in skin tumorigenesis by urethane, hydrazine and related compounds

Abstract

Urefhane, N-hydroxyurefhane, hydrazine and sume related compounds were tested in C57BL/6 and S W R mice for activity as lung carcinogens, promoters of X-ray leukaemogenesis, and skin tumour initiators. Equimolar doses were used where possible. N-hydroxyurethane (ethyl hydroxycarbamate) was as strongly coleukaemogenic as urethane, and equally or less active than urethane as a lung carcinogen. Methyl and n-propyl hydroxycarbamates were inactive in all three tests, which suggests that the chemical specificity of urethane is not due to an ethyl-specific N-hydroxylating system. Acetylurethane showed considerable lung-carcinogenic and coleukaemogenic activities, and N-methoxyurethane (ethyl methoxycarbamate) and n-propyl carbamate showed weak lung-carcinogenic activities. Earlier reports that hydroxyurea is not a lung carcinogen were confirmed, but a weak coleukaemogenic effect war apparent. Hydrazine sulphate showed a weak but definite activity as lung carcinogen despite the low dose used, and on a molar basis appeared to be almost as active a s urethane. Methylhydrazine sulphate was inactive.The effects of single injections on the thymus weight of C57BL/6 mice were compared for four of the test compounds. N-hydroxyurethane produced an earlier and stronger depression of thymus weight than urethane, n-propyl hydroxycarhamate showed a definite but short-lived effect, and n-propyl carbamate was almost inactive. The results suggest that hydroxycarbainates exert a direct action on thymus weight, in addition to an action via conversion into the corresponding carbamates.

Inhibition of both skin and lung tumorigenesis by Car‐R mouse‐derived cancer modifier loci

“…Tumors were initiated in SWR/J mice, which are highly susceptible to both lung and skin cancer 3 and in Car-R and (SWR/JxCar-R)F1 mice using urethane, a multi-organ carcinogen that can initiate both lung and skin tumorigenesis. 5,6 Analysis of urethane-initiated and TPA-promoted Car-R, SWR/J and (SWR/JxCar-R)F1 mice revealed resistance to both skin and lung carcinogenesis in the Car-R line and F1 hybrids, showing that the genetic resistance of Car-R mice to both tumor types is dominant over the susceptibility of the SWR/J strain. Linkage disequilibrium (LD) and haplotype analyses showed that Car-R mice carry the Pulmonary adenoma susceptibility 1 (Pas1 s ) allele despite their resistance to lung tumorigenesis.…”

Morphological and Biochemical Effects of 1,2-Dimethylhydrazine and 1-Methylhydrazine in Rats and Mice

“…1,2-Dimethylhydrazine methylates nucleic acids in vivo in the organs where tumours arise, in both rats and mice (Hawks, Swann and Magee, 1971;Hawks and Magee, 1974). Earlier publications (Kelly and O'Gara, 1965;Roe, Grant and Millican, 1967;Kelly et al, 1969;Mirvish et al, 1969;Hawks and Magee, unpublished work) have reported that the closely related compound 1-methylhydrazine was not carcinogenic in rats and mice, and it is a considerably less active alkylating agent in vivo (Hawks and Magee, 1974). More recently, 1-methylhydrazine has been reported to increase the number of pulmonary tumours in Swiss mice (Toth, 1972) and to induce histiocytomata of the liver and some tumours of the caecum in hamsters (Toth and Shimizu, 1973).…”

The Alkylation of Nucleic Acids of Rat and Mouse In Vivo by the Carcinogen 1,2-Dimethylhydrazine

“…In contrast, the unsymmetrical isomer did induce pulmonary adenomata in female Swiss mice (Roe, Grant and Millican, 1967) and has recently been shown to induce vascular tumours in lung, kidney and liver of mice of the same strain (Toth, 1972b). 1 -Methylhydrazine (monomethylhydrazine) has been reported not to be car-cinogenic in mice (Kelly and O'Gara, 1965;Roe et al, 1967;Kelly et al, 1969;Mirvish et al, 1969). However, it has recently been reported that the monomethyl derivative increased the incidence of pulmonary adenomata in Swiss mice (Toth, 1972c) and induced malignant histiocytomata of the liver, and increased the incidence of adenomata and adenocarcinomata of the caecum in Syrian golden hamsters (Toth and Shimizu, 1973).…”