Three-stage tumorigenesis in mouse skin: DNA synthesis as a prerequisite for the conversion stage induced by TPA prior to initiation

Abstract

Recent evidence shows that stage I of tumor promotion in NMRI-mouse skin induced by a single dose of 12-O-tetradecanoylphorbol-13-acetate (TPA) can be effected not only after initiation by 7,12-dimethylbenz(a)anthracene (DMBA) but also several weeks prior to initiation. In view of this partial inversion of the initiation-promotion sequence we proposed to replace the term ‘stage I of promotion’ by the term ‘conversion’. The convertogenic effectivity of a single dose of TPA applied after DMBA can be suppressed in a rather characteristic and non-toxic fashion by hydroxyurea (HU). In the present study we asked whether HU might also interfere with the converting effectivity of a single dose of TPA given prior to DMBA. NMRI mice received a single dose of TPA 3 weeks prior to initiation by DMBA which was followed by twice weekly application of skin irritant 12-O-retinoylphor-bol-13-acetate (RPA) in order to effect stage II of promotion. A single dose of HU given i.p. at different times after TPA was found to interfere with tumor formation exhibiting an almost complete inhibition if administered 18 h after TPA. This inhibition did not prevent a subsequent promotion by repetitive TPA treatment. The data indicate that conversion can be inhibited by HU in the same characteristic fashion regardless of whether TPA was administered after or prior to initiation. The data also support the autonomous character of the conversion process for which epidermal DNA synthesis appears to be obligatory.