"High single-dose' European PUVA regimen also causes an excess of non-melanoma skin cancer

Bruynzeel, Ineke; Bergman, Wilma; Hartevelt, H. M.; Kenter, Charlotte; Velde, E.A. Van De; Schothorst, A.A.; Suurmond, D.

doi:10.1111/j.1365-2133.1991.tb03281.x

Cited by 111 publications

(82 citation statements)

References 16 publications

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“…To prevent recurrences PUVA therapy is usually administered on a long-term basis. However, several studies have demonstrated that high-dose exposure to PUVA increases significantly the risk of the development of squamous-cell carcinoma (SCC) [2, 3, 4, 5, 6]. Although initially large-scale European studies, in contrast to US studies, did not reveal an increased risk of SCC unless the patient belonged to the risk group with prior exposure to other potential carcinogens, a positive correlation has been found lately [7].…”

Section: Introductionmentioning

confidence: 99%

Widespread Cutaneous Carcinomas Associated with Human Papillomaviruses 5, 14 and 20 after Introduction of Methotrexate in Two Long-Term PUVA-Treated Patients

et al. 2001

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Background: PUVA treatment for patients with severe psoriasis has been demonstrated to be highly effective. However, an increased risk of nonmelanoma and melanoma skin cancers has been reported. It is generally accepted that the risk of squamous-cell carcinoma (SCC) is significantly increased in patients with long-term PUVA therapy. The role of methotrexate (MTX) and infection with oncogenic human papillomaviruses which may act as cocarcinogens is poorly documented. Case Reports: Two cases of multiple SCCs associated with numerous PUVA keratoses and PUVA freckles after long-term PUVA therapy and subsequent treatment with MTX are presented. In 1 case, the tumor progressed to metastatic SCC. Tumors and scrapings of psoriatic skin lesions were analyzed for the presence of oncogenic human papillomavirus (HPV) genotypes. The genotype of HPV-5, -14 and -20 was detected in scrapings and skin tumors using PCR amplification. Conclusion: These observations support the concept that long-term PUVA treatment is carcinogenic and rise questions concerning an additional influence of MTX in the development and progression of skin cancer. The risk of metastatic SCC seems to be underestimated in high-dose PUVA-treated patients due to longer latency for developing metastases and the small number of studies with long-term follow-up. Treatment with MTX should be considered cautiously in patients previously exposed to high doses of PUVA. The presence of oncogenic HPVs in carcinomas and psoriatic skin lesions detected only with the highly sensitive nested PCR method is not necessarily a proof of their implication in skin carcinogenesis.

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Section: Introductionmentioning

confidence: 99%

Widespread Cutaneous Carcinomas Associated with Human Papillomaviruses 5, 14 and 20 after Introduction of Methotrexate in Two Long-Term PUVA-Treated Patients

et al. 2001

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“…In primates receiving 2-18 mg kg-' 8-MOP orally, only dosedependent emesis, but no organ damage was observed [20]. Chronic surveillance of PUVA therapy has failed to identify any clinically relevant toxicity [16,21]. Also, a prospective study over 5 years examining ophthalmological findings in patients receiving PUVA indicated a small risk of ocular damage in patients who received at least 100 PUVA treatments [22].…”

Section: Pharmacokinetic Analysis Linearity Analysis Figures 1 and 2 mentioning

confidence: 99%

The pharmacokinetics of 8‐methoxypsoralen following i.v. administration in humans [see comments]

Billard

Gambús

Barr

et al. 1995

Brit J Clinical Pharma

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1. 8‐methoxypsoralen (8‐MOP) is a naturally occurring photoreactive substance which, in the presence of u.v. light, forms covalent adducts with pyrimidine bases in nucleic acids. For many years, 8‐MOP has been used in PUVA therapy for treatment of psoriasis. Recently, the drug has been found to inactivate effectively bacteria spiked into platelet concentrates. The purpose of this study was to determine the pharmacokinetics and safety of 8‐MOP administered intravenously in the bactericidal dosage range. 2. Eighteen volunteers were divided into three treatment groups to receive, respectively, 5, 10, and 15 mg 8‐MOP infused over 60 min. Frequent arterial samples were gathered, and the blood and plasma were assayed for 8‐MOP concentration. The pharmacokinetic parameters were determined by moment and compartmental population analysis, the latter performed with the program NONMEM. Haemodynamics, ventilatory pattern, and subjective effects were recorded throughout the study. 3. The intravenously administered 8‐MOP was well tolerated in all individuals, and no acute toxicity was observed. 4. The pharmacokinetics of 8‐MOP were best described by a three‐compartment mammillary model in which the volumes and clearances were proportional to weight. The mean pharmacokinetic parameters for the plasma concentrations were: V1 = 0.045 1 kg‐1, V2 = 0.57 1 kg‐1, V3 = 0.15 1 kg‐1, CL1 (systemic) = 0.010 1 kg‐1 min‐1, CL2 = 0.0067 1 kg‐1 min‐1, CL3 = 0.012 1 kg‐1 min‐1. The mean pharmacokinetic parameters for the blood concentrations were: V1 = 0.061 1 kg‐1, V2 = 1.15 1 kg‐1, V3 = 0.21 1 kg‐1, CL1 (systemic) = 0.015 1 kg‐1 min‐1, CL2 = 0.011 1 kg‐ 1 min‐1 and CL3 = 0.015 1 kg‐1 min‐1. 5. The plasma pharmacokinetic model described the observations with a median absolute error of 17%, and the blood pharmacokinetic model described the observations with a median absolute error of 18%. Analysis of the relative concentration of 8‐MOP between plasma and red blood cells suggested concentration‐ dependent partitioning. 6. The addition of 7.5 mg 8‐MOP to 300 ml platelet concentrate would produce bactericidal concentrations of 25 micrograms ml‐1. Simulations based upon our data show that intravenous administration of 7.5 mg over 60 min would result in systemic concentrations of 8‐MOP similar to those observed with conventional PUVA therapy. We conclude that the extensive safety history established in PUVA therapy will be applicable to this new application of 8‐MOP.

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“…Other tumors of lower incidences, including basal cell carcinomas and melanomas, have been reported (Stern et al, 1984;Bruynzeel et al, 1991;Stern et al, 1997Stern and Lunder, 1998;McGinnis et al, 2003). The International Agency for Research on Cancer (IARC) has classified PUVA as a group I carcinogen (IARC, 1980(IARC, , 1987.…”

Section: Introductionmentioning

confidence: 97%

Analysis of p53 Tumor Suppressor Gene, H-ras Protooncogene and Proliferating Cell Nuclear Antigen (PCNA) in Squamous Cell Carcinomas of HRA/Skh Mice Following Exposure to 8-Methoxypsoralen (8-MOP) and UVA Radiation (PUVA Therapy)

Lambertini¹,

Surin²,

Ton³

et al. 2005

Toxicol Pathol

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Treatment with 8-methoxypsoralen (8-MOP) and ultraviolet radiation (primarily UVA), called PUVA therapy, has been used to treat different chronic skin diseases but led to a significant increased risk for skin cancer. The National Toxicology Program (NTP) performed a study in mice treated with PUVA that showed a significant increase in squamous cell carcinomas of the skin. In the present study, we evaluated the protein expression of p53 and PCNA and DNA mutations of p53 and H-ras genes in both hyperplastic and neoplastic squamous cell lesions from the NTP study. By immunohistochemical staining, protein expression of both p53 and PCNA was detected in 3/16 (19%) of hyperplastic lesions and 14/17 (82%) of SCCs in groups treated with both 8-MOP and UVA. The mutation frequency of p53 in SCCs from mice administered 8-MOP plus UVA was 15/17 (88%) with a predominant distribution of mutations in exon 6 (14/15 -93%). No H-ras mutations were detected in the hyperplastic lesions/tumors. The mutagenic effect of PUVA on the p53 tumor suppressor gene may lead to a conformational modification and inactivation of the p53 protein, which are considered critical steps in PUVA-induced skin carcinogenesis. The p53 mutational frequency and patterns from our study were different from those reported in human PUVA-type tumors.

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"High single-dose' European PUVA regimen also causes an excess of non-melanoma skin cancer

Cited by 111 publications

References 16 publications

Widespread Cutaneous Carcinomas Associated with Human Papillomaviruses 5, 14 and 20 after Introduction of Methotrexate in Two Long-Term PUVA-Treated Patients

Widespread Cutaneous Carcinomas Associated with Human Papillomaviruses 5, 14 and 20 after Introduction of Methotrexate in Two Long-Term PUVA-Treated Patients

The pharmacokinetics of 8‐methoxypsoralen following i.v. administration in humans [see comments]

Analysis of p53 Tumor Suppressor Gene, H-ras Protooncogene and Proliferating Cell Nuclear Antigen (PCNA) in Squamous Cell Carcinomas of HRA/Skh Mice Following Exposure to 8-Methoxypsoralen (8-MOP) and UVA Radiation (PUVA Therapy)

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