The Photocarcinogenesis of Antibiotic Lomefloxacin and UVA Radiation Is Enhanced in Xeroderma Pigmentosum Group A Gene-Deficient Mice

Abstract

Lomefloxacin (LFLX) is phototoxic and phototumorigenic, but the mechanisms of phototumorigenesis of quinolone drugs have not been fully elucidated. Formation of cyclobutane pyrimidine dimers (CPD) by UVB radiation is primarily involved in the carcinogenesis of ultraviolet (UV) radiation. On the other hand, UVA region is responsible to photobiologic reactions of quinolone drugs. To know if CPD can be formed by UVA radiation in the presence of LFLX and is involved in the phototumorigenesis, we used xeroderma pigmentosum (XP) group A gene-deficient (XPA-/-) mouse, which is defective in nucleotide excision repair. XPA-/- and XPA+/+ mice were irradiated to 5 J per cm2-UVA with or without the administration of LFLX. In XPA-/- mice treated with LFLX, the first skin tumor appeared after exposures to 75 J per cm2 in 5 wk. In XPA+/+ mice treated with LFLX, the first tumor appeared after exposures to 345 J per cm2 in 23 wk. Immunohistochemically, CPD formation was observed after UVA-exposure in the skin of XPA+/+ as well as XPA-/- mice which had been given LFLX. The CPD disappeared, however, earlier from XPA+/+ mice than from XPA-/- mice. The acute inflammatory reaction after LFLX administration and exposure to UVA were greatly enhanced in XPA-/- mice. These results indicate that UVA exposure induces DNA damage in the form of CPD in the presence of LFLX, which exerts phototoxicity and phototumorigenesis.

Multifocal Aggressive Squamous Cell Carcinomas Induced by Prolonged Voriconazole Therapy: A Case Report

“…Concerning genotoxicity, it has been reported, in an experimental model, that fluoroquinolones, especially lomefloxacin and fleroxacin, associated with UVA radiation, enhanced tumor prevalence and drastically shortened the median latent period of tumor onset compared with UVA alone [22–24]. In UV-irradiated xeroderma pigmentosum group A gene-deficient mice, defective in nucleotide excision repair, the treatment with lomefloxacin induced DNA damage [25]. In our case, no mutation of POLH, a gene predisposing to xeroderma pigmentosum variant, was identified.…”

Photosensitization Reactions of Fluoroquinolones and Their Biological Consequences

“…However, mechanistical studies in the case of a photoclastogenic substance seem to be necessary to support the risk assessment. Indeed, between the FQs resulted positive to the photo‐CA assay, only CIP (4,5), FLE (4–6) and LOM (4,5,133), resulted photocarcinogenic. In addition, in the same experiment for photogenotoxicity described above, rodents deficient in T<>T‐DNA repair systems resulted positive for LOM photoinduced skin tumor, but not for OFL (133).…”

“…For example, ENR is able to photoinduce retinal degeneration and blindness in felines by means of photogenotoxicity in the feline ABCG2 gene (132). Genotoxic damage by means of induction of tumors, ear swelling response, immuno‐histochemical and histological examination as well as sunburn cell formation counting was found in skin cells of LOM and OFL photosensitized rodents (133). The correlation of magnitude in the skin micronucleus test for several FQs is similar to that found in previous in vitro photochemical clastogenicity studies, i.e.…”

Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions†

“…CPDs were also detected by immunoassay in the DNA of fibroblasts, keratinocytes and Caucasian melanocytes upon lomefloxacin photosensitization (150). Evidence has been also provided using an immunohistochemical detection approach for the lomefloxacin-sensitized formation of CPDs in the skin of mice XPA + ⁄ + and XPA ) ⁄ ) upon UVA irradiation (151). Further detailed information was gained on the photosensitizing properties of several fluoroquinolones on the DNA of THP-1 human monocytes (93).…”