Tumor initiating activity of 9- and 10-fluoro-7,12-dimethylbenz[a]-anthracene (DMBA) and the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on tumor initiation by monofluoro derivatives of DMBA in SENCAR mice

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Abstract
The skin tumor initiating activity in SENCAR mice of 6 monofluoro derivatives of 7,12-dimethylbenz[a]anthracene (DMBA) was studied. 9-Fluoro-DMBA (9-F-DMBA) was approximately as active, and 10-F-DMBA was more active than the parent hydrocarbon, DMBA. The difference between DMBA and 10-F-DMBA was most dramatic at the highest initiating doses of 10-F-DMBA tested. 4-F-DMBA, which was only weakly active as an initiator, was also tested as a complete carcinogenic on mouse skin; after 30 wk of treatment of 50 and 100 nmol weekly doses failed to elicit papillomas or carcinomas. Animals treated with 50 nmol DMBA weekly exhibited at 100% papilloma incidence and a 42% carcinoma incidence. Pretreatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) effectively inhibited tumor initiation with all monofluoro derivatives of DMBA tested. The ED50 (dose of TCDD producing half-maximal inhibition) for the inhibition of DMBA initiation in SENCAR mice was 1.8 .times. 10-3 .mu.g/mouse (5.6 pmol). The introduction of a F atom in ring D of DMBA had no effect (positions 9 and 11) or enhanced (position 10) tumor initiating activity. 10-F-DMBA was the 1st example of a hydrocarbon with a fluoro substituent giving rise to increased tumor initiating activity. Structural modifications that altered tumor initiating activity did not alter the ability of TCDD to inhibit tumorigenesis by DMBA.

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