Effect of resiniferatoxin pretreatment on the inflammatory response to phorbol-12-myristate-13-acetate in mouse strains with different susceptibilities to phorbol ester tumor promotion.
All tumor-promoting phorbol esters induce inflammation in mouse skin. The correlation between promoting and inflammatory activities is only partial, however, indicating that only some events in inflammation may be closely coupled to the process of tumor promotion. Resiniferatoxin (RTX), an extremely inflammatory phorbol-related diterpene, acts as an ultrapotent analog of capsaicin to stimulate and then to block the neurogenic inflammatory pathway. In CD-1 mice, we have used pretreatment with RTX to show that the erythema and edema responses to phorbol and 12-deoxyphorbol esters in significant part involve this neurogenic inflammatory pathway. We report here that mouse strains with differing sensitivities to phorbol-ester-induced promotion displayed marked differences in the effect of pretreating with RTX on the edema response following phorbol-12-myristate-13-acetate (PMA) application. In the highly promotion-sensitive SENCAR mouse, RTX pretreatment had little inhibitory effect; the edema response to PMA was similar with or without RTX pretreatment 6 h before PMA application. On the other hand, in C57BL/6J mice, which are resistant to promotion by phorbol esters under the usual protocols, the edema response to PMA was totally eliminated by RTX pretreatment during the first 8 h after PMA administration. DBA/2J mice, which are similar to CD-1 mice in their susceptibility to PMA promotion, responded similarly to CD-1: the edema response was blocked partially by RTX pretreatment during the early phase (up to 8 h) of inflammation. Our results suggest that the RTX-resistant component of PMA-induced edema may correlate better with the sensitivity to promoting action than does the overall inflammatory response.
Szallasi
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A
Molecular Mechanisms of Tumor Promotion Section, National Cancer Institute, Bethesda, MD 20892.
Blumberg
P M
PM
D000818:Animals; D002273:Carcinogens; D004224:Diterpenes / Q000494:pharmacology*; D004487:Edema / Q000139:chemically induced; D005260:Female; D007249:Inflammation / Q000139:chemically induced*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D013997:Time Factors
D002273:Carcinogens; D004224:Diterpenes; C024353:resiniferatoxin; D013755:Tetradecanoylphorbol Acetate