Mechanisms in tumor promotion: guidance for risk assessment and cancer chemoprevention.
In mouse skin, tumor development promoted by 'non-genotoxic' carcinogens is closely related to the wound response. In both cases endogenous factors such as cytokines and eicosanoids released primarily from 'activated keratinocytes' play a key role as mediators of inflammation and cellular hyperproliferation. The liberation of interleukin-1 alpha and arachidonic acid from human keratinocytes has been used as an in vitro parameter of irritancy. The results (from experiments with 15 different chemicals) being validated at present in a clinical study indicate a quantitative relationship between irritancy in vivo and mediator release in vitro. In the course of experimental skin carcinogenesis an overproduction of eicosanoids due to a constitutive overexpression of the corresponding enzymes (i.e. PGH synthase-II and 8- and 12-lipoxygenase) is observed. Enzyme inhibitors, for instance nonsteroidal antiinflammatory drugs (NSAIDs), exert a strong tumoristatic effect. Thus, the approach of multistage skin carcinogenesis provides a suitable animal model for a mechanistic evaluation and further improvement of chemopreventive measures such as the inhibition of colorectal tumor development in humans by NSAIDs ('aspirin effect').
Marks
F
F
German Cancer Research Center, Research Program Tumor Cell Regulation, Department 0235, Heidelberg, Germany.
Fürstenberger
G
G
Heinzelmann
T
T
Müller-Decker
K
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D007375:Interleukin-1 / Q000502:physiology; D051379:Mice; D018570:Risk Assessment; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000517:prevention & control*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D007375:Interleukin-1; D016718:Arachidonic Acid