Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that non-cycling (unstimulated) human lymphocytes from normal donors show extreme hypersensitivity to UV-B irradiation, and are killed by an excisable lesion which is not a pyrimidine dimer or 6-4 photoproduct. In this paper we show that addition of the 4 deoxyribonucleosides to the medium, each at 10(-5) M, substantially increased the survival of non-cycling normal human T-lymphocytes following UV-B irradiation and substantially reduced the frequency of excision-related strand breaks in human mononuclear cells. Addition of ribonucleosides to the medium did not enhance excision-break rejoining. The survival of fibroblasts, of cycling T-lymphocytes and of unstimulated xeroderma pigmentosum T-lymphocytes was not enhanced by deoxyribonucleosides. This suggests that the hypersensitivity is due to reduced rejoining of excision breaks as a consequence of low intracellular deoxyribonucleotide pools and that it can be redressed by supplementation of the medium with deoxyribonucleosides or upregulation of ribonucleotide reductase following mitogen stimulation. We suggest that UV-B forms an additional DNA lesion which is not a pyrimidine dimer or 6-4 photoproduct, which is relatively common, and at which incision is particularly efficient. In fibroblasts, repair of this lesion is completed with high efficiency, whereas in normal unstimulated T-lymphocytes, rapid incision exacerbates the effects of the reduced rate of strand rejoining and leads to cell death.
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PMID:Effect of deoxyribonucleosides on the hypersensitivity of human peripheral blood lymphocytes to UV-B and UV-C irradiation. 751 7

Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and cisplatin are commonly used in the treatment of many solid tumors, although the impact of chemotherapy is limited in metastatic non-small cell lung cancer. However, in clinical practice, there is a minority of patients who can attain long-term survival. Upregulation of mRNA transcripts has been linked to chemoresistance, and in some instances, mRNA expression has been correlated with polymorphisms. Cisplatin resistance is directly linked to the nucleotide excision repair system, specifically to the transcription-coupled nucleotide excision repair pathway that involves genes that are deficient in rare inborn disorders such as Cockayne syndrome and xeroderma pigmentosum. Overexpression of ERCC1 correlates with poor survival in gemcitabine/cisplatin-treated non-small cell lung cancer patients. At the preclinical level, ERCC1 and XPD mRNA expression correlate with each other, and overexpression of XPD causes selective cisplatin resistance in human tumor cell lines. XPD polymorphisms have been associated with lower DNA repair capacity. In our experience, time to progression is significantly higher in gemcitabine/cisplatin-treated patients with the Lys751Gln genotype (9.6 months) than in those with the Lys751Lys genotype (4.2 months; P =.03). Other polymorphisms involved in parallel DNA repair systems may well provide the same information, indicating a high degree of biologic redundancy. The overexpression of the subunit M1 of ribonucleotide reductase (RRM1) has been linked to gemcitabine resistance in our retrospective assessment. Preliminary findings that a subset of gemcitabine/cisplatin-treated patients with low ERCC1 and RRM1 mRNA levels show a significantly longer survival and highlight the possibilities of individually tailored chemotherapy.
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PMID:Targeted therapy in combination with gemcitabine in non-small cell lung cancer. 1291 17

Cisplatin or carboplatin is commonly used with gemcitabine, docetaxel, paclitaxel or vinorelbine as chemotherapy doublets in the treatment of advanced non-small cell lung cancer. Several randomized trials have failed to identify major differences in survival between any of these doublets. This lack of evidence for improvement in survival with any chemotherapy regimen has created a tabula rasa in which no more large randomized trials should be conducted with out including a genetic analysis. Patients see survival as their major concern, and other considerations, such as cost of treatment and qualify of life, are relegated to lower positions. Genetic alterations related to the transcription-coupled repair pathway of the nucleotide excision repair system (TC-NER) have revealed the subset of patients who are resistant to cisplatin. TC-NER involves genes that are deficient in rare inborn disorders such as Cockayne syndrome and xeroderma pigmentosum. For a long time, ERCC1 mRNA levels have been known to correlate with DNA repair capacity in various tissues. Levels of DNA cisplatin adducts in peripheral blood and buccal mucosa cells predict chemotherapy response, and high ERCC1 mRNA levels have been related to chemoresistance in ovarian cancer and in malignant lymphocytes from chronic lymphocytic leukemia. Moreover , in some instances, mRNA expression has been correlated with polymorphisms. Overexpression of ERCC1 correlates with poor survival gemcitabine/cisplatin-treated non-small cell lung cancer patients. An ongoing customized ERCC1-based chemotherapy trial has been established on this knowledge. Patients are randomized to the control arm of cisplatin/docetaxel is combined with cisplatin or gemcitabine according to ERCC1 levels. To date, 80 patients have been included. At the preclinical level, ERCC1 and XPD mRNA expression correlate with each other, and overexpression of XPD causes selective cisplatin resistance in human tumor cell lines. Some XPD polymorphisms have been associated with lower DNA repair capacity. In our experience, time to disease progression is significantly higher in gemcitabine/cisplatin-treated patients with the Lys751Gln genotype (9.6 months) than in those with the Lys751Lys genotype (4.2 months; p = 0.03). Other polymorphisms involved in parallel DNA repair systems may well provide the same information, indicating a high degree of biological redundancy. The overexpression of the subunit M1 of ribonucleotide reductase (RRM1) has been linked to gemcitabine resistance in our retrospective assessment. Preliminary findings indicate that a subset of gemcitabine/cisplatin-treated patients with low ERCC1 and RRM1 mRNA levels show a significantly longer survival. This highlights the possibilities of individually tailored chemotherapy. However, in patients treated with cisplatin/vinorelbine, the opposite effect has been observed. Patients with Lys751Lys had a longer time to progression. When docetaxel was added to gemcitabine/cisplatin, patients with Lys751Lys also had better survival. Our findings indicate that TC-NER status can help to decide between cisplatin/gemcitabine and docetaxel/ cisplatin. TC-NER-dependent activity is similar to other anticancer agents that cause DNA-binding enzymes to kill cells (topoisomerase inhibitors). At least 50% of non-small cell lung cancer patients harbor Lys751Lys and can benefit from docetaxel/ cisplatin treatment. Genes involved in spindle formation, centrosome functions and mRNA transport along the microtubule tracks should provide further information on potential markers of docetaxel resistance.
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PMID:Influence of genetic markers on survival in non-small cell lung cancer. 1466 33