memo - Magazine of European Medical Oncology

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Clinical importance of DNA repair inhibitors in cancer therapy

Hosoya, N.; Miyagawa, K.

2008 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-008-0081-7

The efficacy of cancer chemotherapy and radiotherapy relies on generation of DNA damage. Since intrinsic DNA repair pathways enable cancer cells to survive by repairing these damaged lesions, inactivation of DNA repair coupled with chemotherapy and radiotherapy has a potential to enhance the effect of these therapies. Small molecule compounds that inhibit specific DNA repair proteins have been developed, and early clinical trials are ongoing. While DNA repair inhibitors have been tried mostly as a part of combination therapies with cytotoxic agents, recent reports highlighted a new concept in cancer therapy where DNA repair inhibitors could be used as single agents to selectively kill cancer cells. This concept is based on the findings that cancer cells are frequently defective in particular DNA repair pathway(s) and the presumption that inhibition of the compensatory repair pathway(s) in such cells might be useful to kill them. For example, poly(ADP-ribose) polymerase (PARP) plays a critical role in DNA base-excision repair, and inactivation of this protein increases the number of single-strand breaks, leading to double-strand breaks that require to be repaired by homologous recombination (HR) mediated by BRCA1 and BRCA2. Recently, BRCA1- or BRCA2-defective tumour cells were shown to be sensitive to PARP inhibitors alone. This treatment may be tumour-specific because only the BRCA1−/− or BRCA2−/− tumours in the BRCA1+/− or BRCA2+/− patients are completely defective in HR repair. The following short review aims at summarizing the basic mechanisms of DNA repair and the therapeutic options using DNA repair inhibitors in cancer therapy.
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Disruption of telomere homeostasis as a new cancer treatment strategy

Herbert, B.-S.

2008 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-008-0080-8

Telomeres are critical for the protection of chromosomal ends and genomic integrity. Telomeres can be maintained by their associated proteins (collectively termed as telosome or shelterin) as well as the telomerase complex containing a reverse transcriptase component. While most somatic human cells lack telomerase activity to sufficiently maintain telomeres, the majority of all cancer cells express telomerase activity. The maintenance of telomeres contributes to the immortal phenotype seen in most cancers. Therefore, it has been proposed that targeting telomere maintenance should result in a highly specific and universal treatment for cancer. Here the topic of targeting the immortal phenotype of cancer by disrupting telomere homeostasis is discussed as well as the current status, and challenges, of clinical trials.
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Challenges and pitfalls in HNPCC: a pedigree of an Austrian HNPCC family beyond four generations!

Winder, T.; Mündlein, A.; Gasser, K.; Lingg, G.; Walser, J.; Karner-Hanusch, J.; Dirschmid, K.; Drexel, H.; Lang, A.

2008 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-008-0083-5

In this study we present an Austrian family with HNPCC, which was diagnosed by clinical criteria (Amsterdam I). Subsequent to the diagnosis, genetic counselling and testing was offered to all family members. A causal mutation was detected in exon 12 of the MLH1 gene by determining the genomic sequence. The mutation had resulted in the deletion of an adenine nucleotide at position 1343 (c.1343delA; respective cDNA NCBI accession number: NM_000249), creating a new reading frame (p.E448fs). Within this pedigree it was possible, with frequent colonoscopy screening, to detect an early-stage tumour localised in the coecum. Furthermore, there is evidence for genetic anticipation. The median ages at diagnosis of colorectal cancer decreased from 51.5 in the second generation to 33.5 in the third generation.
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The expression of EGFR, HER2 and EpCam in Head and Neck squamous cell carcinomas

Schartinger, V. H.; Schmutzhard, J.; Wurm, M.; Schwentner, I. M.; Obrist, P.; Oberaigner, W.; Sprinzl, G. M.

2008 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-008-0082-6

PURPOSE: Head and Neck squamous cell carcinomas show an increasing incidence and make up to 5% of all malignancies. In this work three cell surface proteins are investigated, which could be possible targets in currently arising tailored cancer treatment: Epithelial cell adhesion molecule (EpCam), the epidermal growth factor receptor (EGFR, c-erbB-1 or HER1) and HER2/neu (c-erbB-2). MATERIALS AND METHODS: In this study, specimens from 114 histologically verified squamous cell carcinoma of pharynx and oral cavity were analysed. The surface proteins were tested with pharmacodiagnostic kits. RESULTS: With 44.7% (51/114) EGFR was found to be overexpressed most frequently in this cohort. A usable distribution for EpCam and nearly lacking of HER2 was shown in 22.8% (26/114) and 3.5 % (4/114), respectively. CONCLUSION: These data show that EGFR and EpCam might have a relevant role for the biology of this disease. Its relevance for a therapeutic application cannot yet be concluded.
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