Robert M. Sayre

Randomized Phase III Study of Trastuzumab, Paclitaxel, and Carboplatin Compared With Trastuzumab and Paclitaxel in Women With HER-2–Overexpressing Metastatic Breast Cancer

PURPOSEnThis randomized, multicenter, phase III trial evaluated the efficacy and safety of trastuzumab and paclitaxel with or without carboplatin as first-line therapy for women with HER-2-overexpressing metastatic breast cancer (MBC).nnnPATIENTS AND METHODSnHER-2 overexpression was defined as immunohistochemical staining scores of 2+ or 3+. Between November 1998 and May 2002, 196 women with HER-2-overexpressing MBC were randomly assigned to six cycles of either trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m2 every 3 weeks (TP), or trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m2 and carboplatin area under the time-concentration curve = 6 every 3 weeks (TPC) followed by weekly trastuzumab alone.nnnRESULTSnBaseline characteristics of the 196 patients were well balanced between study arms. Objective response rate (ORR) was 52% (95% CI, 42% to 62%) for TPC versus 36% (95% CI, 26% to 46%) for TP (P = .04). Median progression-free survival (PFS) was 10.7 months for TPC and 7.1 months for TP (hazard ratio [HR], 0.66; 95% CI, 0.59 to 0.73; P = .03). Improved clinical outcomes with TPC were most evident in HER-2 3+ patients, with an ORR of 57% (95% CI, 45% to 70%) v 36% (95% CI, 25% to 48%; P = .03) and median PFS of 13.8 v 7.6 months (P = .005) for TPC and TP, respectively (HR, 0.55; 95% CI, 0.46 to 0.64). Both regimens were well tolerated, and febrile neutropenia and neurotoxicity occurred infrequently; grade 4 neutropenia occurred more frequently with TPC (P < .01).nnnCONCLUSIONnThe addition of carboplatin to paclitaxel and trastuzumab improved ORR and PFS in women with HER-2-overexpressing MBC. This well-tolerated regimen represents a new therapeutic option.

Photoprotection by melanin—a comparison of black and Caucasian skin

The photoprotective role of melanin was evaluated by comparing the transmission of ultraviolet (UV) radiation through skin samples of blacks and Caucasians, using both biologic and spectroscopic techniques. UVA transmission was measured using fluoranthene, which causes a phototoxic response to UVA wavelength. UVB was measured by monitoring erythema produced by either a 150-watt xenon arc or FS-20 sunlamps. It was found that on the average, five times as much ultraviolet light (UVB and UVA) reaches the upper dermis of Caucasians as reaches that of blacks. Differences in transmission between the stratum corneum of blacks and of Caucasians were far less striking. The main site of UV filtration in Caucasians is the stratum corneum, whereas in blacks it is the malpighian layers. Melanin acts as a neutral density filter, reducing all wavelengths of light equally. The superior photoprotection of black epidermis is due not only to increased melanin content but also to other factors related to packaging and distribution of melanosomes. Not only are these data consistent with epidemiologic evidence, but they also may indicate why blacks are less disposed to phototoxic drug responses as well as less susceptible to acute and chronic actinic damage.

New trends in photobiology: Photoprotection by melanin

Abstract This paper is an attempt to summarize the current state of information on melanin and epidermal melanin pigmentation (EMP) as photoprotective agents. The chemistry and biochemistry of melanin (the particle) and its interaction, in its various forms, with UV radiation are considered. Methods of attenuation of UV radiation are discussed in terms of structure and chemical constituents. Photoprotection by constitutive and facultative pigmentation is reviewed with minimum erythema dose (MED) as the end point. The issue of acclimatization to UV radiation is discussed in terms of UVB phototherapy for psoriasis. Finally, skin cancer is considered as an end point and the reduction of its incidence with pigment level is discussed. It is concluded that whilst EMP provides protection, its extent depends on the end point chosen for evaluation. MED is a convenient photobiological end point but is rather insensitive, whereas skin cancer is sensitive but impractical for laboratory studies. Our current state of knowledge of melanin lacks information on its absorption and scattering coefficients and its refractive index. Methods for the quantitative measurement of EMP are also urgently required.

Constitutive and UV-induced metabolism of melatonin in keratinocytes and cell-free systems

Melatonin, which can be produced in the skin, exerts a protective effect against damage induced by UV radiation (UVR). We have investigated the effect of UVB, the most damaging component of UVR, on melatonin metabolism in HaCaT keratinocytes and in a cell‐free system. Four metabolites were identified by HPLC and LC‐MS: 6‐hydroxymelatonin, N1‐acetyl‐N2‐formy1–5‐methoxykynuramine (AFMK), 2‐hydroxymela‐tonin (the main intermediate between melatonin and AFMK), and 4‐hydroxymelatonin. Concentrations of these photoproducts were directly proportional to UVR‐dose and to melatonin substrate content, and their accumulation was time‐dependent. The UVR‐de‐pendent increase of AFMK and 2‐hydroxymelatonin was also detected in keratinocytes, where it was accompanied by simultaneous consumption of intracellular melatonin. Of note, melatonin and its two major metabolites, 2‐hydroxymelatonin and AFMK, were also detected in untreated keratinocytes, neither irradiated nor preincubated with melatonin. Thus, intracellular melatonin metabolism is enhanced under exposure to UVR. The additional biological activity of these individual melatonin metabolites increases the spectrum of potential actions of the recently identified cutaneous melatoninergic system.—Fischer, T. W., Sweatman, T. W., Semak, L., Sayre, R. M., Wortsman, J., Slominski, A. Constitutive and UV‐induced metabolism of melatonin in keratinocytes and cell‐free systems. FASEB J. 20, E897–E907 (2006)

Melatonin increases survival of HaCaT keratinocytes by suppressing UV-induced apoptosis

Abstract:u2002 Melatonin is a potent antioxidant and direct radical scavenger. As keratinocytes represent the major population in the skin and UV light causes damage to these cells, the possible protective effects of melatonin against UV‐induced cell damage in HaCaT keratinocytes were investigated in vitro. Cells were preincubated with melatonin at graded concentrations from 10−9 to 10−3u2003m for 30u2003min prior to UV irradiation at doses of 25 and 50u2003mJ/cm2. Biological markers of cellular viability such as DNA synthesis and colony‐forming efficiency as well as molecular markers of apoptosis were measured. DNA synthesis was determined by [3H]‐thymidine incorporation into insoluble cellular fraction, clonogenicity through plating efficiency experiments and apoptosis by the terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling (TUNEL) assay. DNA synthesis experiments showed a strong protective effect by preincubation with melatonin at concentrations of 10−4u2003m (Pu2003<u20030.01) and 10−3u2003m (Pu2003<u20030.001). Additional postirradiation treatment with melatonin showed no increase in the pre‐UV incubation protective effect. These results indicate that preincubation is a requirement for melatonin to exert its protective effects. The mechanism of melatonins protective effect (10−6 to 10−3u2003m) includes inhibition of apoptosis as measured by TUNEL assay. Moreover, the biological significance of these effects is supported by clonogenic studies showing a significantly higher number of colonies in cultures treated with melatonin compared to controls. Thus, pretreatment with melatonin led to strong protection against UVB‐induced damage in keratinocytes.

25-Hydroxyvitamin D, cholesterol, and ultraviolet irradiation

Vitamin D deficiency may have implications for cardiovascular health. The purpose of this study was to determine the relationship of 25-hydroxyvitamin D (25[OH]D) to cholesterol and lipoprotein particles and to determine whether increasing 25(OH)D through ultraviolet (UV) irradiation impacted on these parameters in healthy young men and women. This was a randomized trial of 51 adults exposed to suberythemal doses of whole-body irradiation using UV lamps that emitted UV-A and UV-B radiation, compared with a control group, twice weekly for 12 weeks. 25-Hydroxyvitamin D, cholesterol, and lipoprotein subfractions were measured at baseline and after 12 weeks. There was a significant (P < .03) positive association between 25(OH)D and apolipoprotein A-I (Apo A-I) and lipoprotein A-I (Lp A-I). The ratio of low-density lipoprotein to high-density lipoprotein was significantly (P < or = .044) negatively correlated with 25(OH)D levels. The levels of 25(OH)D increased significantly in the treated compared with control group (P < .05). Overall, there were no significant differences between the treated and control groups in any lipoproteins or apolipoproteins after administration of UV irradiation. Subgroup analysis for Apo A-II confined to those with 25(OH)D insufficiency (25[OH]D <75 nmol/L [30 ng/mL]) revealed decreases in Apo A-II in the treated group and increases in the control group that were statistically significantly different between the groups (P = .026). We found a significant positive correlation between 25(OH)D and Apo A-I and Lp A-I and a significant negative correlation between 25(OH)D and the ratio of low-density lipoprotein to high-density lipoprotein. In those with vitamin D insufficiency, we found small decreases in Apo A-II in the treated relative to the control group. Overall, though, twice weekly exposure to UV radiation resulting in an increase in serum 25(OH)D had no significant impact on lipoprotein composition.

Skin type, minimal erythema dose (MED), and sunlight acclimatization

Minimal erythema doses (MEDs) of individuals with different skin types were compared. Each skin type was shown to be statistically different from each other skin type in terms of sunburn sensitivity. Individuals of each skin type who primarily stayed indoors were compared with those who attempted to be outdoors. In the winter there was no difference between the sunburn sensitivity (MEDs) of these groups. During the summer, those who went outdoors were more resistant to sunburn than those who stayed indoors. In effect, acclimatization makes an individual respond to sunlight like a less sensitive skin type. However, acclimatization appears transitory, and benefits can be lost within a month or two.

Ultraviolet radiation regulates cortisol activity in a waveband dependent manner in human skin ex-vivo

Backgroundu2002 11β‐Hydroxysteroid dehydrogenase type 1 (11β‐HSD1), 11β‐hydroxysteroid dehydrogenase type 2 (11β‐HSD2), and glucocorticoids (GC) and their receptor (GR) play a key role in tissue‐specific regulation of GC action.

Holick's rule and vitamin D from sunlight.

Holicks rule says that sun exposure 1/4 of a minimal erythemal dose (MED) over 1/4 of a body is equivalent to 1000 International Units (IU) oral vitamin D3. Webb and Engelsen recently commented that the ultraviolet (UV) spectrum used to establish Holicks rule is unknown. They consequently used a spring midday Boston solar spectrum to estimate ample sunlight exposures for previtamin D3 (preD3) at various locations. Literature review found the source upon which this rule is based was a fluorescent sunlamp (FS lamp). The FS spectrum is known and its relative weighting against the action spectra for erythema and the preD3 is significantly different from the solar spectrum used to derive the standard vitamin D effective dose (SDD). The preD3 effectiveness of the solar spectrum per unit erythemal hazard is greater than the FS lamp by a factor of 1.32. Consequently, UV exposure estimates based on Boston reference sunlight, instead of the UV lamp employed in the originating experiments, over estimate UV exposure equivalent to approximately 1000 IU orally by approximately 1/3. This redefinition of SDD impacts risk/benefit assessments of optimal/feasible sun exposure for vitamin D maintenance and the application of Holicks rule to rational public health messages.

Beta-carotene does not act as an optical filter in skin

Beta-carotene, when orally administered, only slightly increases the sunburn threshold in normal humans but effectively diminishes sunlight risk in patients suffering from erythropoietic protoporphyria. In addition, beta-carotene has been shown to inhibit UV-induced carcinogenesis in mice when administered either orally or intraperitoneally. To examine the photoprotective properties of beta-carotene, SKH-HR1 albino hairless mice received beta-carotene supplemented diets for either two or four weeks. At the end of each treatment period the skins were visibly yellow. Whole skin and epidermis from each animal were studied by forward scattering transmission spectroscopy and compared with age-matched controls. While no major optical differences were seen in the whole skin or in the epidermis, the presence of beta-carotene was optically demonstrated by weak but typical beta-carotene absorption peaks in the epidermis following the two week feeding period. The peaks were also apparent in the four week group. However, the beta-carotene peaks could not be resolved through full thickness skin. Despite the yellow appearance of the skin, the absorbance due to the carotene was insufficient to impart significant photoprotection. These results confirm previous theoretical arguments that oral beta-carotene treatment does not attain a sufficient concentration in the skin to produce a typical sunscreen effect by absorption of radiation. When beta-carotene is effective in the treatment of photosensitivity, it must produce its protectiveness through an alternative mechanism.