The early effects of a single application of acetone and various doses of 7,12-dimethylbenz(alpha)anthracene on CD-1 and hairless mouse epidermis. A cell kinetic study of so-called initiation and complete carcinogenesis (initiation plus promotion) in chemical skin tumor induction.
To study the early kinetic effects of different single doses of 7,12-dimethylbenz(alpha)anthracene (DMBA) on hairless mouse epidermis, about 1,800 female CD-1 mice and 340 hairless mice of both sexes were treated with a topical skin application of acetone alone or with various doses of from 4.3 to 200 micrograms DMBA in 200 microliter reagent grade acetone for the CD-1 mice, and with 0.5, 5 and 50 micrograms DMBA for the hairless mice. Five cell kinetic variables were measured at different times, from 6 h up to 14 days, after the application: cell counts in 40 vision fields of basal and suprabasal cells, [3H]TdR-labeling indices, DNA-specific radioactivity, and mean grain count after flash labeling with [3H]TdR, fractions of cells in S and G2 by flow cytometry, and the mitotic rate with the Colcemid method. The idea was to see whether there are significant (qualitative, or clearly stepwise) differences between small (allegedly) only initiating single doses of DMBA and larger, completely carcinogenic (and hence allegedly also promoting) doses of the same carcinogen. Higher doses of DMBA (25.6-200 micrograms) led, as expected, to an initial reduction in both DNA synthesis and mitotic activity. The reduction in DNA synthesis seemed more to be due to a low rate of cellular DNA synthesis than to a block at the entrance of cells into the S phase. The decreases lasted for about 3-5 days, and was followed by a period of increased rate of cell proliferation. The number of suprabasal cells (after a very short initial peak after 51.2 micrograms DMBA) was then reduced, probably due to toxic cell death. Subsequently a pronounced hyperplasia developed, which was dose-dependent as regards both size and time pattern. At medium doses, 8.5-12.8 micrograms DMBA, the pattern of reaction changed gradually. The reduction in DNA synthesis and mitotic activity was less pronounced and lasted somewhat shorter, and the ensuing hyperplasia was more moderate. After the lowest doses, 4.3 and 6.4 micrograms DMBA, an initial, short-lasting decrease in the mitotic rate only was observed, but an initial inhibition of DNA synthesis could not be observed in the CD-1 mice. Instead, an early, moderate increase in overall cellular DNA synthesis and in the fraction of G2 cells was observed, concomitant with an almost immediate increase in the number of suprabasal cells. Hence, after these small doses a primary moderate increase in the number of suprabasal cells developed, remaining for at least 10 days. After a temporary reduction the MR increased to normal or slightly above.(ABSTRACT TRUNCATED AT 400 WORDS)
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage*; D000096:Acetone / Q000008:administration & dosage*; D000818:Animals; D002453:Cell Cycle; D003043:Cocarcinogenesis; D004261:DNA Replication / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008940:Mitotic Index; D012867:Skin / Q000166:cytology / Q000187:drug effects*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology; D013997:Time Factors
D000096:Acetone; D015127:9,10-Dimethyl-1,2-benzanthracene