Browsing by Author "Runger, T. M."

Resistance to chemotherapy is a common phenomenon in malignant melanoma. In order to assess the role of altered DNA repair in chemoresistant melanoma, we investigated different DNA repair pathways in one parental human melanoma line (MeWo) and in sublines of MeWo selected in vitro for drug resistance against four commonly used drugs (cisplatin, fotemustine, etoposide, and vindesine). Host cell reactivation assays with the plasmid pRSVcat were used to assess processing of different DNA lesions. With ultraviolet-irradiated plasmids, no significant differences were found, indicating a normal (nucleotide excision) repair of DNA photoproducts. With singlet oxygen-treated plasmid, the fotemustine- and cisplatin-resistant lines exhibited a significantly increased (base excision) repair of oxidative DNA damage. With fotemustine-treated plasmid, the fotemustine-resistant subline did not exhibit an increased repair of directly fotemustine-induced DNA damage. Similar results were obtained with cisplatin-induced DNA crosslinks in the cisplatin-resistant line. The fotemustine- and etoposide-resistant sublines have been shown to exhibit a reduced expression of genes involved in DNA mismatch repair. We used a 'host cell microsatellite stability assay' with the plasmid pZCA29 and found a 2.0-fold to 2.5-fold increase of microsatellite frameshift mutations (p less than or equal to 0.002) in the two resistant sublines. This indicates microsatellite instability, the hallmark of an impaired DNA mismatch repair. The increased repair of oxidative DNA damage might mediate an increased chemoresistance through an improved repair of drug-induced DNA damage. In contrast, a reduced DNA mismatch repair might confer resistance by preventing futile degradation of newly synthesized DNA opposite alkylation damage, or by an inability to detect such damage and subsequent inability to undergo DNA-damage-induced apoptosis.

The purpose of this randomized trial was to evaluate the efficacy of combination chemoimmunotherapy compared with chemotherapy alone. A total of 124 patients were randomized to receive intravenous cisplatin (35 mg m(-2), days 1-3), carmustine (150 mg m-2, day 1, cycles 1 and 3 only), dacarbacine (220 mg m-2, days 1-3) and oral tamoxifen (20 mg m-2, daily) in combination with (n=64) or without (n=60) sequential subcutaneous IL-2 and IFN-alpha. In those patients who received sequential immunothenapy, each cycle of chemotherapy was followed by outpatient s.c. IL-2 (10x 10(6) IU m(-2), days 3-5, week 4; 5 x 10(6) IU m(-2), days 1, 3, 5, week 5) and s.c. IFN-alpha (5 x 10(6) IU m(-2), day 1, week 4; days 1, 3, 5, week 5). The overall response rate of patients treated with the combination of chemotherapy and IL-2/IFN-a was 34.3% with seven complete responses (10.9%) and 15 partial responses (23.4%). In patients treated with chemotherapy, only, the overall response rate was 29.9% with eight complete responses (13.3%) and 10 partial responses (16.6%). There was no significant difference in median progression free survival (0 months vs 4 months) and in median overall survival (12 months vs 13 months) for combined chemoimmunotherapy and for chemotherapy, respectively. (C) 2002 The Cancer Research Campaign.

An infant girl presented at birth with multiple, large nodular xanthogranulomas. Her monozygotic twin sister was not affected. The congenital tumors were up to 1.5 cm in diameter, done-shaped and mainly located on the head and the upper half of the body. Histologically the cells were characterized as CD68+ non-langerhans histiocytes. Followup for 18 months showed no new tumors and regression of the existing ones. No extracutaneous manifestations were observed. Knowledge of the differential diagnosis, especially the group of Langerhans cell histiocytosis, is essential for prognosis estimation.

Purpose: The comet assay has been used to visualize DNA damage in single cells after exposure to UV light. These comets are commonly thought to reflect transient, repair-induced DNA breaks. The goal of the work presented here was to further characterize the nature of UV-induced comets and to further elucidate DNA damage formation by different wavelengths of ultraviolet light. Materials and methods: Detailed dose-response and time-course experiments with comet formation were carried out with normal and nucleotide excision repair (NER)-deficient xeroderma pigmentosum (XP) lymphoblasts. Irradiation was carried out with low, intermediate, or high doses of UVAl or UVB, comet formation was observed, cell survival and viability were determined, and UV-induced apoptosis was measured. Results: All responses were dose-dependent. With the intermediate dose of UVAl, a pronounced comet formation was observed without subsequent growth inhibition. Raising levels of porphyrins, which act as photosensitizers, by preincubation with 5-amino-levulinic acid increased comet formation with UVA, but not with UVB. UVAl-sensitivity and comet formation in XP cells was not significantly different from the normal cells. With UVB no comet formation was seen without subsequent apoptotic cell death. XP cells exhibited the known UVB-hypersensitivity, but their comet formation was not significantly different from that of normal cells. Conclusions: The findings are compatible with the hypothesis that UV-induced comets represent transient repair-induced DNA breaks. Both, the NER of dimers and the base excision repair of oxidative DNA modifications are thought to contribute to comet formation.