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R B Setlow

Publications and source records attributed to R B Setlow.

At least 19 recordsLinked to original sources
PubMed1998

Localization of a CDKN2 gene in linkage group V of Xiphophorus fishes defines it as a candidate for the DIFF tumor suppressor.

The Xiphophorus hybrid melanoma model represents one of the earliest reported cases of genetically regulated tumor susceptibility. Melanoma formation in Xiphophorus hybrids may be explained by the inheritance of two genes: a sex-linked oncogene, Xmrk, and a putative tumor suppressor locus, termed DIFF, located in Linkage Group V (LG V). Several genetic mapping procedures were used to produce a new Xiphophorus LG V map with 20 loci. All markers, particularly a recently cloned Xiphophorus CDKN2 gene family member, called CDKN2X, were tested for associations of genotype with degree of macromelanophore pigment pattern modification and susceptibility to melanoma formation in backcross hybrids of seven genetic types, involving 1,110 fish and three pigment patterns. Highly significant associations of CDKN2X genotypes with such phenotypic effects suggests that this gene is a strong candidate for the classically defined DIFF tumor suppressor gene. Because published results have documented the involvement of the CDKN2A (p16, MTS1, and INK4A) tumor suppressor gene in human melanoma formation, the possibility of CDKN2 genes acting as tumor suppressors in both man and Xiphophorus is likely.

Animals↗
PubMed1996

Nonmammalian models for sunlight carcinogenesis: genetic analysis of melanoma formation in Xiphophorus hybrid fish.

Genetic hybrids of Xiphophorus fishes have been used for decades to study heritable melanoma formation. In these models, overexpression of pigmentation patterns from melanin-producing pigment cells can lead to genetically regulated melanoma formation in backcross hybrids. In the best studied of these models, the Gordon-Kosswig hybrid melanoma, tumors form spontaneously in all individuals of a subset of backcross hybrids between the platyfish Xiphophorus maculatus Jp 163 A and the swordtail species Xiphophorus helleri. Backcross hybrids susceptible to melanoma formation inherit a sex-linked oncogene, Xmrk, associated with the spotted dorsal (Sd) pigment pattern and have lost both copies of an autosomal gene, DIFF, from the X. maculatus parent. Spontaneous melanoma formation conforms to simple, two-gene Mendelian inheritance in which DIFF behaves as a recessive tumor suppressor gene. Recently, Xiphophorus hybrids in which melanomas can be induced by UV and near-UV visible light exposure have been described. We report here results of genetic linkage analysis of one of these Xiphophorus light-inducible hybrid melanoma models, in backcross hybrids between the two platyfish species X. maculatus Jp 163 B and Xiphophorus couchianus. Our linkage results provide the first estimate of recombination between the tumor suppressor locus, DIFF, and glycerate-2-dehydrogenase (GLYDH) in Xiphophorus linkage group V. Also, they demonstrate that DIFF regulates hyperplasia of spotted side (Sp) pigment cells in this hybrid model, analogous to its regulation of hyperplasia of Sd pigment cells in the "classical" Gordon-Kosswig hybrid. Joint segregation analyses of melanoma-bearing fish indicate that segregation of DIFF is genetically linked to melanoma induction by 405 nm light in this model but that induction of melanomas by UV wavelengths apparently does not depend on segregation of the DIFF locus.

Animals↗
PubMed1994

Temporal changes in the incidence of malignant melanoma: explanation from action spectra.

The incidence of malignant cutaneous melanoma has been increasing for more than 50 years, and is now rising more rapidly than that of any other cancer. This increase is not explicable by changes in the physical environment, particularly by any observed increase in UVB radiation (290-320 nm). The distribution of melanomas on the body differs from the site distribution of nonmelanoma skin cancer (relatively many more melanomas occur on areas of the body not chronically exposed to sunlight, such as the back of the trunk in males, and the legs in females). This localization of melanoma, together with its epidemiology, suggest that a change in lifestyle has contributed to the fast-rising incidence in many countries. There is no convenient mammalian animal model for malignant melanoma. However, certain inter- and intra-specific hybrids of fish of the genus Xiphophorus are very sensitive to light-induced melanomas; we have used them to determine the wavelengths effective in melanoma induction. The action spectrum has a relatively very large component in the UVA region (320-400 nm) compared to human erythema. Hence, if the human and fish spectra were similar, the use of sunscreens that minimize erythema would have little effect in preventing the induction of melanoma, and if people using sunscreens expose themselves to sunlight for longer periods, they will be increasing dramatically their exposure to these melanoma-inducing wavelengths. Such considerations are sufficient to explain the rising incidence of malignant melanoma and its distribution on the body.

Animals↗
PubMed1993

Wavelengths effective in induction of malignant melanoma.

It is generally agreed that sunlight exposure is one of the etiologic agents in malignant melanoma of fair-skinned individuals. However, the wavelengths responsible for tumorigenesis are not known, although DNA is assumed to be the target because individuals defective in the repair of UV damage to DNA are several thousandfold more prone to the disease than the average population. Heavily pigmented backcross hybrids of the genus Xiphophorus (platyfish and swordtails) are very sensitive to melanoma induction by single exposures to UV. We irradiated groups of five 6-day-old fish with narrow wavelength bands at 302, 313, 365, 405, and 436 nm and scored the irradiated animals for melanomas 4 months later. We used several exposures at each wavelength to obtain estimates of the sensitivity for melanoma induction as a function of exposure and wavelength. The action spectrum (sensitivity per incident photon as a function of wavelength) for melanoma induction shows appreciable sensitivity at 365, 405, and probably 436 nm, suggesting that wavelengths not absorbed directly in DNA are effective in induction. We interpret the results as indicating that light energy absorbed in melanin is effective in inducing melanomas in this animal model and that, in natural sunlight, 90-95% of melanoma induction may be attributed to wavelengths > 320 nm--the UV-A and visible spectral regions.

Animals↗
PubMed1993

Ultraviolet radiation-induced DNA damage and its photorepair in the skin of the platyfish Xiphophorus.

Fluence response relationships for the induction of DNA damage in the skin of UV-irradiated Xiphophorus fish were obtained by quantitative gel electrophoresis of unlabeled DNA following extraction and treatment with an enzyme preparation that makes single strand breaks next to cyclobutane pyrimidine dimers. A buffer containing 7 M urea minimized the degradation of DNA during extraction and gave reproducible results. The shapes of fluence response curves for the production of dimers by sun lamp irradiation (lambda > 290 nm) or 302 nm in the dermis of grown fish were similar. Photoreversal of dimers was readily observed by black light exposure or from the longer wavelengths (> 304 nm) from sun lamps. As expected, the number of pyrimidine dimers/incident fluence in young fish skin was considerably higher on the irradiated side of immobilized fish than it was in swimming (randomly moving) fish, and the shape of the fluence response curves was linear for all wavelengths used lambda > 290, 302, and 313 nm. On the other hand, young fish irradiated from above with lambda > 290 nm showed a less than linear relationship between pyrimidine dimers in their skin and radiation fluence because most exposure occurred on the dorsal rim of fish skin; thus, some cells in that skin were exposed to high fluences while others were not, leading to a heterogenous population of cells. Values of dimers produced were also much less than in immobilized fish. The pigment melanin decreased the number of dimers in the epidermis of grown fish exposed to lambda > 290, 302, or 313 nm, or in the dermis of fish following 302 nm, thus conferring protection against this kind of damage. No dimers were detected in the epidermis of fish exposed to 365 nm. The dimers produced at 302 and 313 nm at tumoricidal exposures correspond to 1 dimer in 10(5) base pairs.

Animals↗
PubMed1993

DNA damage, photorepair, and survival in fish and human cells exposed to UV radiation.

The effect of various wavelengths of UVB radiation on the induction of cyclobutane pyrimidine dimers in fish cells and human fibroblasts and the repair of these lesions were studied using an UV-endonuclease to measure dimers (endonuclease sensitive sites) by sedimentation of radioactive DNA, by gel electrophoresis of unlabeled DNA, and by cell survival. The data show that fish cells have an efficient photoreactivation system at wavelength > 304 nm that reverses cytotoxicity and dimer formation after exposure to filtered sunlamp irradiation of a shorter wavelength (lambda > 290 nm). Shorter wavelengths in UVB (> 304 nm) are more effective in photoreversal than longer ones (> 320 nm). As a consequence, 50-85% of dimers induced by these wavelengths in fish are photoreactivated while they are being formed. A major cytotoxicological lesion is the cyclobutane pyrimidine dimers. Cultured human fibroblasts do not possess such a repair system. These results indicate that sunlamp irradiation has wavelengths that both damage and repair DNA.

Animals↗
PubMed1991

X-ray sensitivity of fibroblast cell strains derived from atomic bomb survivors with and without breast cancer.

Fibroblasts were established in vitro from skin biopsies obtained from 55 women and 1 man with or without breast cancer and with or without exposure to radiations from the atomic bomb (A-bomb) explosion in Hiroshima. The radiosensitivity of these cells was evaluated by clonogenic assays after exposure to X-rays. Dose-response curves were fitted to a multitarget model, S/S0 = A[1-(1-e-D/D0)N]. There was no difference in the means or variances of radiosensitivity between exposed and nonexposed groups, or between groups with and without breast cancer.

Breast Neoplasms↗
PubMed1990

Radiosensitivity of skin fibroblasts from atomic bomb survivors with and without breast cancer.

Fibroblasts were established in vitro from skin biopsies obtained from 55 women and 1 man with or without breast cancer and with or without exposure to radiation from the atomic bomb explosion in Hiroshima. The radiosensitivity of these cells was evaluated by clonogenic assays after exposure to X-rays or to fission neutrons from a 252Cf source. Data were fitted to a multitarget model, S/S0 = A [1 - (1 - ekD)N], for both X-ray and neutron dose-survival curves. A single hit model, S/S0 = AekD, fits the neutron dose-survival responses as well. There were no differences in the means or variances of radiosensitivity between exposed and nonexposed groups or between patients with or without breast cancer. Hence, although the sample is not large, it provides no support for the hypothesis that atomic bomb radiation preferentially induces breast cancer in women whose cells in vitro are sensitive to cell killing by radiation.

Adolescent↗
PubMed1989

Animal model for ultraviolet radiation-induced melanoma: platyfish-swordtail hybrid.

Sunlight exposure is strongly indicated as one of the important etiologic agents in human cutaneous malignant melanoma. However, because of the absence of good animal models, it has not been possible to estimate the wavelengths or wavelength regions involved. We have developed a useful animal model from crosses and backcrosses of platyfish (Xiphophorus maculatus) and swordtails (Xiphophorus helleri). Two strains of these fish are susceptible to invasive melanoma induction by exposure to filtered radiation from sunlamps in the wavelength ranges lambda greater than 290 nm and lambda greater than 304 nm. Multiple exposures on 5-20 consecutive days beginning on day 5 after birth or a single exposure of approximately 200 J/(m2.day) of lambda greater than 304 nm result in a tumor prevalence of 20% to 40% at 4 months of age compared with a background rate of 12% in one strain and 2% in another. Exposure of the fish to visible light after UV exposure reduces the prevalence to background. The melanomas are similar in many respects to mammalian melanomas, as judged by light and electron microscopy. The genetics of the crosses determined by others and the high sensitivity of the hybrids to melanoma induction indicate that the UV radiation probably inactivates the one tumor repressor gene (or a small number of tumor repressor genes) in the hybrid fish. The small size of the animals and their high susceptibility to melanoma induction make them ideal for action spectroscopy.

Animals↗
PubMed1989

Inactivation of O6-alkylguanine-DNA alkyltransferase in HeLa cells by cisplatin.

Inactivation of O6-alkylguanine-DNA alkyltransferase (O6-AGT) in HeLa CCL2 cells by cisplatin was studied. HeLa CCL2 cells treated with cisplatin showed a dose-dependent decline in O6-AGT activity. After cisplatin was removed and replaced with fresh medium, the transferase level began to rise slowly. By 72 h slightly more than 80% of the activity was recovered. It seems that the activity of the alkyltransferase can be inactivated by platinated DNA adducts. The data suggest that the O6-platinum-guanine formation and the O6-alkyltransferase depletion are not responsible for cytotoxicity but may result in a base substitution mutation in mammalian cells.

Cell Survival↗
PubMed1987

DNA repair by articular chondrocytes. IV. Measurement of Micrococcus luteus endonuclease-sensitive sites by alkaline elution in rabbit articular chondrocytes.

The ability of resting and dividing rabbit articular chondrocytes to repair low doses of ultraviolet (UV) damage was measured through removal of UV endonuclease-sensitive sites (ESS, pyrimidines dimers) as measured by alkaline elution. The repair of damage was significantly (P less than 0.001) greater in dividing than non-dividing cells. An age-related decrease in repair capability was found in resting chondrocytes, but not in their dividing counterpart. These results support earlier findings of unscheduled DNA synthesis by the same cells. (Mech. Ageing Dev., 32: 39-55, 1985).

Animals↗
PubMed1987

DNA repair by articular chondrocytes. V. O6 methylguanine-acceptor protein activity in resting and cultured rabbit and human chondrocytes.

The level of O6-methylguanine acceptor protein activity was examined in rabbit and human articular chondrocytes of different ages. The activity per microgram of DNA in rabbit chondrocytes was 5-fold lower than in humans. There was no age-dependent decrease in the activity of resting or cultured chondrocytes of either species. The values for resting cells were comparable to those of cultured cells. The lack of age-related differences in methyltransferase activity, in contrast to nucleotide excision repair [Mech. Ageing Dev. 32 (1985) 39-55], indicates that separate repair systems behave differently with respect to chronological aging. The methyl transferase activity may be more essential for survival of articular chondrocytes and therefore more highly conserved with age.

Aging↗