Purine-2(3H),6(1H)-dione

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity, other

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Comparative Inhibiting Effects of Methylxanthines on Urethan-induced Tumors, Malformations, and Presumed Somatic Mutations in Mice

Author:

Nomura T

Year:

1983

Bibliographic source:

Cancer Research, 43:1342-1346

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Methylxanthines were given i.p. at 6-hr intervals during a period of 0 to 24 hours after urethan.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Purine-2(3H),6(1H)-dione

EC Number:

200-718-6

EC Name:

Purine-2(3H),6(1H)-dione

Cas Number:

69-89-6

Molecular formula:

C5H4N4O2

IUPAC Name:

xanthine

Specific details on test material used for the study:

Purity: not reported

Test animals

Species:

mouse

Strain:

other: ICR/Jc1, PT, or HT

Remarks:

Jc1

Administration / exposure

Route of administration:

intraperitoneal

Duration of treatment / exposure:

0-36 hours

Frequency of treatment:

7 i.p. injections given at 6 hour intervals 0-36 hours after urethan treatment

Doses / concentrations

Dose / conc.:

0.38 other: %

Results and discussion

Effect levels

Remarks on result:

other: No significant increase was observed in lung tumors in tumor-bearing mice when 0.38% was given i.p. after urethan treatment.

Applicant's summary and conclusion

Conclusions:

No significant increase was observed in lung tumors in tumor-bearing mice when 0.38% was given i.p. after urethan treatment.

Executive summary:

The inhibiting effects of methylxanthines on urethan-induced lung tumors, malformations, and presumed somatic mutations in mice were studied to determine the contribution of mutational and physiological changes to chemically induced neoplasia and malformation. When young adult or pregnant ICR/Jc1 mice were treated with urethan and then methylxanthines were given, caffeine (1,3,7-trimethylxanthine) and theobromine (3,7-dimethylxanthine) greatly suppressed urethan-induced tumorigenesis and teratogenesis, while the theophylline (1,3-dime-thylxanthine) did not. Of the three monomethylxanthines (methylated at positions 1, 3, or 7), 7-methylxanthine was most effective for inhibiting tumors and malformations, indicating that the methyl group at position 7 is most active. Contribution of cyclic adenosine 3': 5' monophosphate was ruled out, since urethan-induced tumorigenesis and teratogenesis were not affected by the theophylline which elevates the cellular level of cyclic adenosine 3':5'-monophosphate by inhibiting phosphodiesterase more effectively than caffeine does; instead, tumorigenesis and teratogenesis were greatly inhibited by the theobromine and 7-methylxanthine,which do not alter the level of cyclic adenosine 3':5'-monophosphate.To test the mutational origin of cancer and malformation ,the effects of caffeine on urethan induction of somatic mutations in PTXHTF-, mice were examined, because caffeine is known to inhibit ultraviolet and 4-nitroquinoline 1-oxide-initiated mutagenesis in Escherichia coli by inhibiting error-prone repair. In mice, however, caffeine did not inhibit urethan induced somatic mutations. Furthermore, theophylline, an inhibitor of error-prone repair, did not reduce the yields of tumors and malformations. Anti-neoplastic and antiteratogenic effects of caffeine may be caused not by the inhibition of the mutational change but by the inhibition of the subsequent process for expressing tumors and malformations.