Multistage carcinogenesis in mouse skin

The action spectra for delayed erythema and melanogenesis in Caucasian human skin are determined for wavelengths between 250 and 435 nm. The untanned skin of very fair volunteers was observed after single exposures to a range of fluences of monochromatic radiation. At wavelengths longer than 300 nm the two action spectra are indistinguishable, and at wavelengths shorter than 300 nm, they are of similar shape despite a distinct separation. This suggests a common or similar chromophore for initiation of the vascular and pigmentary responses to UV. A broad minimum in the action spectra occurs near 280 nm, a maximum near 296 nm, and for wavelengths longer than 300 nm, increasingly larger fluences of radiation are required to induce delayed erythema and melanogenesis. Between 304 and 334 nm both action spectra exhibit a rapid decrease of almost three orders of magnitude. In contrast, between 334 and 405 nm the spectra decrease by only one order of magnitude, and there is a suggestion of a small maximum at or near 365 nm. Different chromophores, sites of damage, or response mechanisms may be responsible for induction of delayed erythema at these longer wavelengths. After spectral corrections for the optical effects of the stratum corneum, the shape and magnitude of the action spectra are grossly consistent with a mechanism in which DNA is the primary chromophore initiating the response pathways for wavelengths less than 313 nm. Whatever the actual basis for these action spectra may be, they are of practical significance in predicting skin response to sources of ultraviolet radiation.

Erythema and melanogenesis action spectra of normal human skin

An integrative theory is proposed in which environmental carcinogenesis is viewed as a process by which the genetic control of cell divzsion and differentiation is altered by carcinogens. In thzs theory, carcinogens include physical, chemical, and viral "mutagens," as well as chemical and viral gene modulators. Existing explanations of carcinogenesis can be considered either as somatic mutation theories or as epigenetic theories. Evidence seems to support the hypothesis that both mutations and epigenetic processes are components of carcinogenesis. The mutational basis of cancer is supported by the clonal nature of tumors, the mutagenicity of most carcinogens, high mutationfrequencies in cells of cancer-prone human fibroblasts lacking DNA repair enzymes, the correlation of in vitro DNA damage and in vitro mutation and transformationfrequencies with in vivo tumorigenesis, age-related incidences of various hereditary tumors, and the correlation between photoreactivation of DNA damage and the biological amelioration of UV-induced neoplasms. Since both mutagens and gene modulators can be carcinogenic it may be that carcinogens affect genes which control cell division. An integration of the mutation and epigenetic theories of cancer with the "two-stage" theory and Comings's general theory of carcinogenesis is proposed. This integrative theory postulates that carcinogens can affect regulatory genes which control a series of "transforming genes. A general hypothesis is advanced that involves a common mechanism of somatic mutagenesis via error-prone repair of DNA damage which links carcinogenesis, teratogenesis, atherosclerosis and aging. Various concepts are presented to provide aframework for evaluating the scientific, medical, and social implications of cancer. "This innerfragmentation of man mirrors his view of the world 'outside' which is seen as a multitude of separate objects and events. The natural environment is treated as if it consisted of separate parts to be exploited by different interest groups. The fragmented view is further extended to society which is split into different nations, races, religious and political groups. The belief that all thesefragments - in ourselves, in our environment and in our society - are really separate can be seen as the essential reason for the present series of social, ecological, and cultural crises. It has alienated us from nature andfrom our fellow human beings. It has brought a grossly unjust distribution of natural resources creating economic and political dzsorder; an ever rising wave of violence both spontaneous and

An integrative model

Publisher Summary This chapter discusses the possible roles that defective or altered DNA repair may play in a number of human diseases. It is conceivable that a number of other human diseases have—as a fundamental pathogenetic mechanism—alterations in gene structure and/or function arising in somatic cells on a non-heritable basis. The statistical variations in the numerous tests used for measuring DNA repair in normal cells in culture are not yet clearly established. Such differences may arise from one laboratory to another but more importantly may be intrinsic properties of different normal cell lines or of different stages of growth of any single cell line. It is still not well established that some of the techniques that are used for examining repair defects in cells are quantitatively valid—for example, the observation of altered cell survival under conditions of very low plating efficiency can be misleading.

Human Diseases Associated with Defective DNA Repair

Cyclobutyl pyrimidine dimers have been detected in the DNA of human skin following in vivo irradiation with suberythemal doses of ultraviolet (UV) radiation from FS-20 sun lamp fluorescent tubes. Dimers were assayed by treatment of extracted DNA with Micrococcus luteus UV-specific endonuclease, alkaline agarose electrophoresis, and ethidium bromide staining. This technique, in contrast to conventional dimer assays, can be used with nonradioactive DNA and is optimal at low UV light doses. M. luteus endonuclease-sensitive sites were determined after exposure of untanned skin in two volunteers to UV light (0.97, 1.94, or 3.88 X 10(3) J/sq m; lambda, 290 to 360 nm). At 20 min postirradiation (dose, 1.94 X 10(3) J/sq m), fewer M. luteus endonuclease-sensitive sites were found in the DNA than immediately after the irradiation. Even fewer endonuclease-sensitive sites were found at 20 min when the UV-irradiated skin was subsequently irradiated with visible light than when the area was kept in the dark. These data suggest that some dimer disappearance by excision repair occurs within 20 min of UV irradiation and that photoreactivation of dimers can make a contribution to the total repair process.

https://cancerres.aacrjournals.org/content/canres/40/9/3181.full.pdf

Paul Runge

Papers

DNA photoreactivating enzyme from placental mammals. Origin and characteristics