Non-melanoma skin cancer, sun exposure and sun protection.

The incidence of skin tumors including squamous cell carcinoma (SCC), and its biological precursor, the actinic keratosis, and basal cell carcinoma (BCC) often named together non-melanoma skin cancer (NMSC) is growing all over the world in people of Caucasian ancestry. A plenty of clinical and epidemiological studies have demonstrated the causal relationship with high cumulative solar dosages and number of sunburns, although the hazard may be different for different tumors according to the modalities of ultraviolet (UV) exposure. BCC is much more strongly related to measures of intermittent ultraviolet exposure (particularly those of childhood or adolescence) than to measures of cumulative exposure. In contrast, SCC is more strongly related to constant or cumulative sun exposure. Photobiological studies have clarified that sunlight and UVB radiation are complete carcinogens for AK and SCC although the relationship with UVA exposure is much less known. Also the likelihood of BCC has been related to either sunburns and high lifetime solar, UVA and UVB cumulative doses but the pathogenetic pathways of both UVB and UVA radiation for BCC development need to be clarified so far. The lack of a complete knowledge of the photocarcinogenic pathways of keratinocytes has contributed to the limited results of solar photoprotection strategies, beside the limitations of the available sunscreens and present EU regulations.

Cryotherapy is preferable to ablative CO2 laser for the treatment of isolated actinic keratoses of the face and scalp: a randomized clinical trial.

BACKGROUND: Actinic keratosis (AK) may progress to squamous cell carcinoma. In the case of normal or mildly photodamaged skin, lesion-directed treatments are considered valuable options despite poor published evidence of their therapeutic activity. OBJECTIVES: The aim of this single-centre, open-label, prospective, nonsponsored, randomized, controlled clinical trial was to compare CO2 laser ablation with cryotherapy in the treatment of isolated AKs of the face and scalp. PATIENTS AND METHODS: Patients with isolated (≤ 4) AKs of the face and scalp were randomized to receive CO2 laser ablation or cryotherapy. After 90 days, the overall complete remission (CR) rates of patients and lesions were assessed and correlated with thickness grade. RESULTS: Two hundred patients with a total number of 543 AKs were enrolled. The CR rates of lesions after 3 months were 78·2% with cryotherapy and 72·4% with CO2 laser ablation. Thicker lesions were significantly more responsive to cryotherapy (P = 0·034). Seventy-three patients (71·6%) had CR of all lesions 3 months after cryotherapy and 64 (65·3%) after laser ablation. At 12 months after treatment the number of patients with CR was reduced to 53 with cryotherapy and 14 with laser ablation. CONCLUSIONS: The rate of patients and lesions with CR is similar after 3 months, but more patients remain in stable remission for 12 months after cryotherapy. Cryotherapy is more effective for thick lesions. The cosmetic outcome was good or excellent in almost all patients.

Synergism between narrowband ultraviolet B phototherapy and etanercept for the treatment of plaque-type psoriasis.

BACKGROUND: Previous investigations have demonstrated that a combination of etanercept (ETN) and narrowband ultraviolet B (NB-UVB) phototherapy is more effective than ETN alone. However, it is unclear if this combination is more effective than NB-UVB phototherapy alone. OBJECTIVES: To evaluate whether the combination of NB-UVB phototherapy with ETN improves the efficacy of ETN alone in the treatment of moderate-to-severe psoriasis. METHODS: We enrolled 322 consecutive patients with moderate-to-severe plaque-type psoriasis, who were treated with NB-UVB phototherapy as the first-line treatment option. Patients who did not achieve a 75% improvement in Psoriasis Area and Severity Index (PASI 75) were treated with conventional systemic therapies for psoriasis. If they were ineligible for these, they were treated with ETN 50 mg twice weekly. If they did not achieve PASI 75 within 12 weeks, NB-UVB phototherapy was added. RESULTS: PASI 75 was achieved in 262 patients (81.4%) treated with NB-UVB phototherapy. Sixteen patients (5.0%) dropped out for personal reasons and 24 (7.5%) were treated with at least one of the conventional systemic treatments for psoriasis. Twenty patients (6.2%) were treated with ETN. The combination regimen was needed in eight patients (2.5%) with poor response to both phototherapy and ETN alone. All of these patients achieved PASI 75 and three of them had a complete remission after 14.6 ± 3.3 NB-UVB exposures. The combined treatment was well tolerated without acute adverse events. Unfortunately, all of these patients relapsed, with PASI > 10 within 2.8 ± 1.7 months. CONCLUSIONS: The combined treatment has a synergistic effect for clearing plaque-type psoriasis previously unresponsive to ETN and NB-UVB phototherapy alone. The clearance rate is very high in a very short time without short-term adverse effects. However, concerns regarding potential cocarcinogenicity remain. Therefore the number of patients who require, and could benefit from, the combined treatment is likely to be small.

Advances in photodynamic therapy. A review.

Photodynamic therapy (PDT) has been pioneered in dermatology at the beginning of the 20th century. Today, cutaneous treatments are the most common applications of PDT. Originating from cancer therapy, recent developments have widened the therapeutic spectrum, and now PDT indications range from inflammatory disorders to cosmetic applications. With several photosensitizers approved by regulatory agencies around the world, PDT continues demonstrating its inherent versatility. This review concentrates on aminolevulinic acid-based PDT regimens in dermatology. Recent research has helped to enhance the treatment efficacy of PDT and to further exploit its potential. Evolving strategies are being tested at present experimentally that will increase the power and diversity of cutaneous PDT. Ultimately these regimens will affect future development in clinical applications.

Methotrexate used in combination with aminolaevulinic acid for photodynamic killing of prostate cancer cells.

Photodynamic therapy (PDT) using 5-aminolaevulinic acid (ALA) to drive production of an intracellular photosensitiser, protoporphyrin IX (PpIX), is a promising cancer treatment. However, ALA-PDT is still suboptimal for thick or refractory tumours. Searching for new approaches, we tested a known inducer of cellular differentiation, methotrexate (MTX), in combination with ALA-PDT in LNCaP cells. Methotrexate alone promoted growth arrest, differentiation, and apoptosis. Methotrexate pretreatment (1 mg l(-1), 72 h) followed by ALA (0.3 mM, 4 h) resulted in a three-fold increase in intracellular PpIX, by biochemical and confocal analyses. After exposure to 512 nm light, killing was significantly enhanced in MTX-preconditioned cells. The reverse order of treatments, ALA-PDT followed by MTX, yielded no enhancement. Methotrexate caused a similar relative increase in PpIX, whether cells were incubated with ALA, methyl-ALA, or hexyl-ALA, arguing against a major effect upon ALA transport. Searching for an effect among porphyrin synthetic enzymes, we found that coproporphyrinogen oxidase (CPO) was increased three-fold by MTX at the mRNA and protein levels. Transfection of LNCaP cells with a CPO-expressing vector stimulated the accumulation of PpIX. Our data suggest that MTX, when used to modulate intracellular production of endogenous PpIX, may provide a new combination PDT approach for certain cancers.

Differentiation enhances aminolevulinic acid-dependent photodynamic treatment of LNCaP prostate cancer cells.

Photodynamic therapy using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) may be applied to the treatment of neoplasms in a variety of organs. In order to enhance existing regimens of photodynamic therapy, we investigated the effects of adding differentiation therapy to photodynamic therapy in human prostate cancer cells in vitro. The objective of differentiation therapy per se is to reverse the lack of differentiation in cancer cells using pharmacological agents. The motivation for this study was to exploit the differentiation-dependent expression of some heme enzymes to enhance tumour cell toxicity of ALA-photodynamic therapy. A short course of differentiation therapy was applied to increase PpIX formation during subsequent ALA exposure. Using the synthetic androgen R1881, isomers of retinoic acid, and analogues of vitamin D for 3 to 4 days, exogenous ALA-dependent PpIX formation in LNCaP cells was increased, along with markers for growth arrest and for differentiation. As a consequence of higher PpIX levels, cytotoxic effects of visible light exposure were also enhanced. Short-term differentiation therapy increased not only the overall PpIX production but also reduced that fraction of cells that contained low PpIX levels as demonstrated by flow cytometry and fluorescence microscopy. This study suggests that it will be feasible to develop protocols combining short-term differentiation therapy with photodynamic therapy for enhanced photosensitisation.

PUVA downregulates whn expression in primary mouse keratinocytes.

Psoralen photochemotherapy (PUVA) is one of the most efficient treatment regimens for psoriasis and other skin diseases. In order to evaluate keratinocyte-specific PUVA effects, we investigated the impact of clinically relevant PUVA doses on whn, the 'nude' gene. This transcription factor plays an important role in epidermal homeostasis, and epidermal whn over-expression results in a psoriasis-like phenotype. We demonstrated a persistent down-regulation of whn mRNA 48-72 h after PUVA treatment but not after UVA alone. Using transgenic animals, we also demonstrated dose-dependent down-regulation of whn promoter activity. Finally, whn-null ('nude') keratinocytes were more resistant to PUVA-induced suppression of DNA synthesis than wild-type cells. Our results suggest that whn suppression may be involved in mediating the anti-proliferative effect of PUVA on keratinocytes.

Pegylation of a chlorin(e6) polymer conjugate increases tumor targeting of photosensitizer.

Photodynamic therapy is emerging as a viable modality for the treatment of many cancers. A limiting factor in its use against intracavity tumors such as disseminated ovarian cancer is insufficient selectivity of the photosensitizer for tumor compared with normal tissue. We report on an approach to improve tumor targeting by exploiting differences between cell types and by chemical modification of a photosensitizer conjugate. Attachment of polyethylene glycol (pegylation) to a polyacetylated conjugate between poly-l-lysine and chlorin(e6) increased the relative phototoxicity in vitro toward an ovarian cancer cell line (OVCAR-5) while reducing it toward a macrophage cell line (J774), compared with the nonpegylated conjugate. Surprisingly, the increased phototoxicity of the pegylated conjugate correlated with reduced oxygen consumption. Pegylation also reduced the tendency of the conjugate to aggregate and reduced the consumption of oxygen when the conjugates were illuminated in solution in serum containing medium, suggesting a switch in photochemical mechanism from type II (singlet oxygen) to type I (radicals or electron transfer). Pegylation led to more mitochondrial localization as shown by confocal fluorescence microscopy in OVCAR-5 cells, and, on illumination, produced a switch in cell death mechanism toward apoptosis not seen with J774 cells. Conjugates were injected i.p. into nude mice bearing i.p. OVCAR-5 tumors, and the pegylated conjugate gave higher amounts of photosensitizer in tumor and higher tumor:normal tissue ratios and increased the depth to which the chlorin(e6) penetrated into the peritoneal wall. Taken together, these results suggest that pegylation of a polymer-photosensitizer conjugate improves tumor-targeting and may increase the efficacy of photodynamic therapy for ovarian cancer.

A photobiological and photophysical-based study of phototoxicity of two chlorins.

To understand the fundamental determinants of phototoxic efficacy and absorbed photodynamic dose, the triplet state and photobleaching quantum yields in living cells, cellular uptake, intracellular localization, and correlation with cell viability were studied for the two purpurins tin ethyl etiopurpurin 1 (SnET2) and tin octaethylbenzochlorin (SnOEBC) in ovarian cancer cells (OVCAR5). Although the triplet yields of these two photosensitizers were not significantly affected by cellular incorporation, the photobleaching yields were shown to be 3 orders of magnitude higher for cellular-bound sensitizer than for free or albumin-bound photosensitizer and higher for SnET2 than for SnOEBC for all of the cases. The intracellular concentration of SnOEBC was half that of SnET2 after 3 h- and 24 h-incubation times for both 0.1 microM and 1.0 microM incubation concentrations. Despite the lower concentrations of SnOEBC, the phototoxicity of the two photosensitizers was comparable at 1-microM incubation concentration and was up to 10-fold higher for SnOEBC at the lower concentration. The subcellular localization established using confocal microscopy and molecular probes showed that both photosensitizers were primarily lysosomally localized. SnOEBC, however, had an extra-lysosomal, mitochondrial localization component. The photophysical measurements allowed calculation of the intracellular singlet oxygen production, which indicated that the photosensitizer-light dose reciprocity was limited by photobleaching for SnET2 but only minimally for SnOEBC, and this was confirmed through cell-survival studies. Taken together, these data indicate that the critical determinant of differences in phototoxicity between the two molecules was their relative rates of photobleaching and their subcellular localization. The study points to the importance of combining photosensitizer uptake and localization with photophysical measurements in the relevant biological milieu to reasonably interpret and/or predict photosensitization efficacies.

Scavenger-receptor targeted photodynamic therapy.

Covalent conjugation of a photosensitizer to a ligand that specifically recognized and internalized by a cell-surface receptor may be a way of improving the selectivity of photodynamic therapy (PDT). The class A Type-I scavenger receptor of macrophages, which among other ligands recognizes maleylated serum albumin and has a high capacity is a good candidate for testing this approach. Chlorin(e6) was covalently attached to bovine serum albumin to give conjugates with molar substitution ratios of 1:1 and 3:1 (dye to protein), and these conjugates could then be further modified by maleylation. A novel way of purifying the conjugates by acetone precipitation was developed in order to remove traces of unbound dye that could not be accomplished by size-exclusion chromatography. Conjugates were characterized by polyacrylamide gel electrophoresis and thin-layer chromatography. Photosensitizer uptake was measured by target J774 murine macrophage-like cells and nontarget OVCAR-5 human ovarian cancer cells, and phototoxicity was examined after illumination by a 660 nm diode laser by a tetrazolium assay. All of the purified conjugates were taken up by and after illumination killed J774 cells while there was only small uptake and no phototoxicity toward OVCAR-5 cells. The higher dye:protein ratio and maleylation of the conjugates both produced higher uptakes and lower survival ratios in J774 cells. The uptake and phototoxicity by J774 cells were decreased after incubation at 4 degrees C demonstrating internalization, and confocal microscopy with organelle-specific green fluorescent probes showed largely lysosomal localization. Uptake and phototoxicity by J774 cells could both be competed by addition of the scavenger receptor ligand maleylated albumin. These data show that scavenger receptor-targeted PDT gives a high degree of specificity toward macrophages and may have applications in the treatment of tumors and atherosclerosis.

Laser-induced hyperthermia in rat prostate cancer: role of site of tumor implantation.

OBJECTIVES: To investigate the importance of the site of tumor implantation on the treatment response to laser-induced hyperthermia (LIH) of rat prostate cancer (PCa), because interventional manipulations of PCa have been reported to increase metastatic dissemination. METHODS: Seven to nine days after either subcutaneous or orthotopic implantation of MatLyLu cells, LIH (46.5 degrees C) was induced using pulsed irradiations of a neodymium:yttrium-aluminum-garnet laser. Both local control and distant metastases were evaluated. Plasma metalloproteinase 9 (MMP-9) was tested as a possible marker of PCa progression and LIH response. RESULTS: Twelve days after LIH treatment of subcutaneous tumors, the volumes were reduced by 64% after 8 minutes of irradiation, 73% after 10 minutes, 81% after 15 minutes, and 91.1% after 20 minutes. In the orthotopic model, the corresponding tumor reductions were 44% after 10 minutes, 61% after 20 minutes, and 65% after 30 minutes. Lung metastases were observed in only 1 animal with subcutaneous tumors. In contrast, 86% of the orthotopic tumor-bearing animals treated for 30 minutes had lung metastases compared with 23% of the untreated tumor-bearing rats. MMP-9 expression was detected in both orthotopic and subcutaneous tumor tissue and in the plasma of tumor-bearing rats. The prostate tissue of healthy rats and subcutaneous tumor-bearing rats was devoid of MMP-9. The plasma levels of MMP-9 showed a trend toward direct correlation with local tumor control but no correlation with the incidence of metastasis. CONCLUSIONS: These data emphasize the importance of the site of tumor implantation for evaluation of the efficacy of therapeutic interventions and may warrant further studies before widespread clinical application of LIH as monotherapy.

Synthetic inhibitor of matrix metalloproteinases (batimastat) reduces prostate cancer growth in an orthotopic rat model.

BACKGROUND: Increased concentrations of metalloproteinases are associated with the invasive and metastatic behavior of several human malignant tumors. Normally, enzymatic activity is tightly regulated by nonspecific mechanisms and specific inhibitors. The aim of the study was to determine the potential of a synthetic metalloproteinase inhibitor, batimastat, to show its in vitro effect on MatLyLu cancer cells and its in vivo effect on tumor growth in orthotopic cancer (R3327 Dunning tumor) in rats. METHODS: In vitro, a dose response curve of batimastat was generated over 4 days using the MTT assay. Prostate cancer was injected in vivo in male Copenhagen rats by inoculating R3327 Dunning tumor cells (MatLyLu) into the ventral prostatic lobe of 30 rats. Each of 10 rats received batimastat (30 mg/kg body weight) or vehicle administered once a day by i.p. application beginning the day of cell inoculation. Ten rats remained untreated. The effect on local tumor growth was evaluated by measuring tumor weights 20 days after tumor cell inoculation. RESULTS: Significant inhibition of tumor cell proliferation in vitro occurred at 400 and 4,000 ng/ml batimastat. After orthotopic cell inoculation, tumors grew to mean weights of 18.9 g in the control group without treatment, to 22.3 g in the vehicle group, and to 11.1 g in the treated group. In comparison to the control group and to the vehicle group, tumor weights increased significantly less under treatment with batimastat. CONCLUSIONS: Batimastat is able to reduce tumor growth in the standard prostate cancer model. Using this model, activity against cancer progression of future inhibitory agents can be reliably assessed.

Temperatures reached inside stand-up ultraviolet treatment boxes.

Heat generated within ultraviolet treatment units can exacerbate eczema. To document the actual temperature changes within the treatment units, we measured the air temperatures in standard stand-up psoralen plus ultraviolet A (PUVA), narrowband ultraviolet B (UVB), broadband UVB, and combination UVA/UVB cabinets using a thermocouple thermometer. For the latter unit, we also measured the air temperatures with and without ventilation systems, and actual skin temperatures on individuals undergoing light treatment. The air temperatures rose significantly in all the treatment units, more so with PUVA and narrowband UVB boxes, and were highest with the ventilation systems shut off. Skin temperatures also rose significantly, but less dramatically. Ventilation is essential in maintaining comfortable temperatures within ultraviolet treatment units.

Half-side comparison of erythemogenic versus suberythemogenic UVA doses in oral photochemotherapy of psoriasis.

BACKGROUND: Early American and European multicenter trials on the efficacy of photochemotherapy (PUVA) for psoriasis have clearly shown that the treatment protocol has a crucial impact on the cumulative UVA dose required for clearing patients. Most, if not all, treatment protocols rely on the PUVA-induced erythema as a guideline for UVA dosimetry. OBJECTIVE: Our aim was to investigate whether phototoxic erythema is integral to an optimized PUVA protocol or reflects an unnecessary overexposure of patients. METHODS: A standard high-dose UVA regimen using minimal phototoxic doses (MPD) was compared against two different low-dose regimens. To this purpose a bilateral comparison study was performed on 31 patients and divided in two parts. In the first trial on 14 patients, half of each patient's body was irradiated at each visit with 1 MPD, whereas the other half received only two thirds of the MPD. In the second trial on 17 patients treatment with 1 MPD was compared against treatment with one half of the MPD. RESULTS: A total of 27 patients (12 patients in the first trial, 15 patients in the second trial) completed the study. In both trials the suberythemogenic doses were therapeutically as effective as the minimal phototoxic doses. CONCLUSION: We conclude that PUVA-induced erythema is not a prerequisite for effective psoriasis treatment and that a low-dose UVA regimen is a promising approach to increase the short- and long-term safety of photochemotherapy.

BPD-MA-mediated photosensitization in vitro and in vivo: cellular adhesion and beta1 integrin expression in ovarian cancer cells.

Benzoporphyrin derivative monoacid (BPD-MA) photosensitization was examined for its effects on cellular adhesion of a human ovarian cancer cell line, OVCAR 3, to extracellular matrix (ECM) components. Mild BPD-MA photosensitization (approximately 85% cell survival) of OVCAR 3 transiently decreased adhesion to collagen IV, fibronectin, laminin and vitronectin to a greater extent than could be attributed to cell death. The loss in adhesiveness was accompanied by a loss of beta1 integrin-containing focal adhesion plaques (FAPs), although beta1 subunits were still recognized by monoclonal antibody directed against human beta1 subunits. In vivo BPD-MA photosensitization decreased OVCAR 3 adhesiveness as well. Photosensitized adhesion was reduced in the presence of sodium azide and enhanced in deuterium oxide, suggesting mediation by singlet oxygen. Co-localization studies of BPD-MA and Rhodamine 123 showed that the photosensitizer was largely mitochondrial, but also exhibited extramitochondrial, intracellullar, diffuse cytosolic fluorescence. Taken together, these data show that intracellular damage mediated by BPD-PDT remote from the FAP site can affect cellular-ECM interactions and result in loss of FAP formation. This may have an impact on long-term effects of photodynamic therapy. The topic merits further investigation.

Ultrastructural changes in PAM cells after photodynamic treatment with delta-aminolevulinic acid-induced porphyrins or photosan.

Photodynamic therapy (PDT) is the combination of a photosensitizing drug (Ps) with light in the presence of oxygen leading to the generation of reactive molecular species and destruction of cancer cells. In this study we compared PDT with two Ps, the hematoporphyrin derivative Photosan (Ph) and delta-aminolevulinic acid (ALA)-induced endogenous protoporphyrin IX, with respect to mitochondrial function and ultrastructural alterations. The effects of PDT were investigated in PAM 212 cells after different Ps incubation times, light doses, and post-treatment periods. Both Ps induced a light dose-dependent impairment of the mitochondrial function with the dose-response curve being steep for ALA and flat for Ph. The prolongation of the incubation time from 4 to 20 h resulted in an increased reduction of mitochondrial activity after ALA PDT but not after Ph PDT. Treatment with an irradiation dose that decreased mitochondrial activity by 50% (IC50) led to early and profound changes of mitochondrial morphology in ALA photosensitized cells, whereas photosensitization with Ph resulted in more pronounced alterations of lysosomes. We conclude that at bioequivalent sublethal PDT exposures of PAM 212 cells, ALA-induced damage is primarily restricted to mitochondria, whereas Ph-induced cytotoxicity is mediated by damage of the lysosomal system.

Generalized pustular psoriasis of pregnancy (impetigo herpetiformis).

A 17-year-old woman had a sudden eruption of pustules in her intertriginous areas as well as of erythematosquamous plaques on the scalp, elbows, palms and soles in the third trimester of her first pregnancy. Histopathological evaluation of a biopsy revealed typical changes of pustular psoriasis with parakeratosis and abscesses of neutrophils (Kogoj's spongiform pustules). The diagnosis of pustular psoriasis was established by the typical clinical and histopathological findings. Laboratory parameters showed a highly elevated blood sedimentation rate, hypoferric anemia and decreased albumin levels. Serum concentrations of parathormone and its metabolites were normal. After systemic treatment with glucocorticosteroids and antibiotics, the lesions improved but did not clear. After delivery of a healthy boy, therapy was switched to retinoid photochemotherapy with isotretinoin and PUVA that resulted in rapid and complete clearing of the eruption. The coincidence of plaque-type psoriasis and a pustular eruption as described previously in impetigo herpetiformis supports the view that this dermatosis of pregnancy is a variant of generalized pustular psoriasis.

Differentiation-specific increase in ALA-induced protoporphyrin IX accumulation in primary mouse keratinocytes.

A treatment regimen that takes advantage of the induction of intracellular porphyrins such as protoporphyrin IX (PPIX) by exposure to exogenous 5-amino-laevulinic acid (ALA) followed by localized exposure to visible light represents a promising new approach to photodynamic therapy (PDT). Acting upon the suggestion that the effectiveness of ALA-dependent PDT may depend upon the state of cellular differentiation, we investigated the effect of terminal differentiation upon ALA-induced synthesis of and the subsequent phototoxicity attributable to PPIX in primary mouse keratinocytes. Induction of keratinocyte differentiation augmented intracellular PPIX accumulation in cells treated with ALA. These elevated PPIX levels resulted in an enhanced lethal photodynamic sensitization of differentiated cells. The differentiation-dependent increase in cellular PPIX levels resulted from several factors including: (a) increased ALA uptake, (b) enhanced PPIX production and (c) decreased PPIX export into the culture media. Simultaneously, steady-state levels of coproporphyrinogen oxidase mRNA increased but aminolaevulinic acid dehydratase mRNA levels remained unchanged. From experiments using 12-o-tetradecanoylphorbol-13-acetate, transforming growth factor beta 1 and calcimycin we demonstrated that the increase in PPIX concentration in terminally differentiating keratinocytes is calcium- and differentiation specific. Stimulation of the haem synthetic capacity is seen in primary keratinocytes, but not in PAM 212 cells that fail to undergo differentiation. Interestingly, increased PPIX formation and elevated coproporphyrinogen oxidase mRNA levels are not limited to differentiating keratinocytes; these were also elevated in the C2C12 myoblast and the PC12 adrenal cell lines upon induction of differentiation. Overall, the therapeutic implications of these results are that the effectiveness of ALA-dependent PDT depends on the differentiation status of the cell and that this may enable selective targeting of several tissue types.

Amino acid conjugates of jasmonic acid induce jasmonate-responsive gene expression in barley (Hordeum vulgare L.) leaves.

Leaves of barley (Hordeum vulgare L. cv. Salome) treated with jasmonic acid (JA), its methyl ester (JM), or its amino acid conjugates exhibit up-regulation of specific genes and down-regulation of house-keeping genes. This transcriptional regulation exhibits several specificities. (i) The (-)-enantiomers are more active, and conjugates are mainly active if they carry an L-amino acid moiety. (ii) The various JA-responsive genes respond differentially to enantiomeric and chiralic forms. (iii) Both JA and its amino acid conjugates exhibiting no or negligible interconversion induce/repress genes.