INHIBITION OF ORNITHINE DECARBOXYLASE BY ORAL COMPOUNDS

Project: Research project

Project Details

Description

The overall objective of this proposal is to develop, through a rational
approach, an ideal dose and administration schedule of a drug which can be
administered orally in a prospective chemo-preventive trial in patients at
high risk of developing malignant disease. The observation that forms the
basis of this proposal is that the induction of mouse epidermal ornithine
decarboxylase (ODC) by a phorbol ester tumor promoting agent,
12-O-tetradecanoylphorbol-13-acetate (TPA) is correlated to the promotion
of skin tumor formation in mice. Evidence indicates that the induction of
ODC activity is an essential property of tumor promoters. Topical or
systemic agents that prevent the induction of ODC (eg. retinoids and
prostaglandin synthesis inhibitors) or inhibit the action of ODC
(difluoromethylornithine, DFMO) can prevent skin tumor promotion in mice.
In mice, when administered orally, these antipromoters inhibit TPA caused
ODC activity in vitro in 3 mm punch biopsies of mouse skin. These
observations have now been extended to human skin. Preliminary results
indicate that ODC can be induced by TPA in incubated human skin punch
biopsies and that in vitro retinoic acid inhibits TPA caused ODC induction
in human skin. Further plans are: 1) to define intra-subject and
inter-subject variability of epidermal ODC activity and inducibility by
TPA; 2) to demonstrate in humans the ability of orally administered
nontoxic substances (eg., aspirin, retinoids, or DFMO) to preclude
TPA-caused increased ODC activity; 3) to determine an ideal dose and dose
schedule for such a substance; and 4) to propose a prospective randomized
chemoprevention drug trial in a group of patients with high risk of
developing cancer. Fasting volunteers will be used to determine
TPA-induced ODC activity in vitro in 3 mm skin punch biopsy specimens. To
determine appropriate human chemopreventive agents, doses, and dose
schedules, punch biopsies will be obtained for in vitro induction of ODC by
TPA both before and after oral medications are administered. This in vitro
human assay system will help determine the requisite doses and dose
schedules of certain chemopreventive agents for use in future human
chemoprevention trials.
StatusFinished
Effective start/end date1/1/856/30/85

Funding

  • National Institutes of Health

ASJC

  • Medicine(all)

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