Enhancement of methylnitrosourea-induced skin tumorigenesis and carcinogenesis in hairless mice by pretreatment with a mitosis-inhibiting epidermal pentapeptide.

Two groups of 48 hr/hr mice (24 males, 24 females) were pretreated i.p. with 0.03 nmol of a synthetic epidermal mitosis-inhibiting pentapeptide (EPP), pGlu-Glu-Asp-Ser-GlyOH, dissolved in bovine serum albumin solution (BSA) at -6, -3 and 0 h before a topical skin application of 1 mg N-methyl-N-nitrosourea (MNU) in 100 microliters reagent-grade acetone. A control group was pretreated with three solvent injections only -6, -3 and 0 h before application. The results were also compared with a large, historical control group of 333 animals treated once with 1 mg MNU and without any pretreatment. The production of benign and malignant skin tumours was recorded and the results were assessed statistically. There was no statistically significant difference between the large control group without pretreatment and the actual control group pretreated with BSA. Pretreatment with EPP led to significant enhancement of the number of tumour-bearing animals with time and to a very significant increase in the total number of tumours. The group pretreated with EPP also developed more malignant skin tumours. The results are in agreement with earlier findings after i.p. pretreatment with crude skin extracts, hydroxyurea, or when MNU was applied in relation to diurnal rhythms in epidermal cell proliferation. They are also consistent with the assumption that EPP is one of the active growth-inhibitory substances in the epidermal extracts, and support the hypothesis that epidermal basal cells may be more sensitive to MNU-induced carcinogenesis when the rate of cell proliferation is low, because then more cells are in late G1 or early S phase where MNU binding to DNA may be relatively strong.