Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The DNA repair protein, O6-alkylguanine DNA alkyltransferase, is a major contributor to the resistance to the nitrosourea, triazine, and tetrazine class of alkylating agents. Many tumor cells and primary tumor samples contain high levels of this protein, although a great deal of heterogeneity exists between and within tumors. Inhibition of the alkyl-transferase by O6-benzylguanine results in significant potentiation of the cytotoxic effects of these chemotherapeutic agents, generating responses in human tumor xenografts that are completely resistant to nitrosoureas alone. These studies may rekindle the interest in the nitrosourea class of alkylating agents and stimulate the search for inhibitors of other mechanisms of chemotherapy resistance.
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PMID:O6-alkylguanine-DNA alkyltransferase. A target for the modulation of drug resistance. 764 72

Genomic instability is characteristic of malignant cells, and a strong correlation exists between abnormal karyotype and tumorigenicity. Increased expression of the homologous recombination and DNA repair protein Rad51 has been reported in immortalized cell lines and multiple primary tumor cell types which could alter recombination pathways to contribute to the chromosomal rearrangements found in these cells. In addition, Rad51 participates in a complex network of interactions that includes DNA damage sensors, tumor suppressors, and cell cycle and apoptotic regulators, and mutation of many of these proteins have also been associated with tumor initiation or progression. Insights into the connection between disregulated Rad51 and malignant phenotype indicate that Rad51 is a potential target for new anti-cancer regimens including those that use siRNA technology.
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PMID:RAD51, genomic stability, and tumorigenesis. 1567 Aug 90

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) plays a pivotal role in alkylating drug resistance. Here, we determined MGMT activity in primary and recurrent glioblastomas (GBM, WHO grade IV) of patients who received radiation therapy (RT) or RT plus chemotherapy with alkylating agents (temozolomide, chloroethylnitrosoureas). The mean MGMT activity of untreated GBM was 37 +/- 45 (range 0-205) fmol/mg proteins. In the 1st, 2nd and 3rd recurrences, MGMT activity increased from 66 +/- 50 (13-194) to 68 +/- 44 (14-143) and 182 +/- 163 (64-423) fmol/mg protein, respectively. Comparing patients who received RT only with RT plus chemotherapy, a significant increase of MGMT in 1st recurrences was only found after treatment with RT plus chemotherapy, indicating either selection of MGMT expressing cells or induction of the MGMT gene by alkylating agents. The p53 status was not significantly related to the MGMT expression level, although a trend for lower MGMT activity in p53 positively stained tumors was observed. Patients expressing MGMT activity of <or=30 fmol/mg protein in the pretreatment tumor had a significant better therapeutic response than patients expressing MGMT above this level, which was shown by Kaplan-Meyer curves and the recurrence free interval after primary tumor resection. In patients who received RT only, this correlation was not found. The data revealed a threshold of MGMT expression (30 fmol/mg protein) below which patients respond better to alkylating agents. Therefore, determination of MGMT activity in the primary tumor appears to be useful in predicting the outcome of GBM therapy.
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PMID:MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome. 1800 Aug 22

Glioblastoma (GBM) is the most frequent and aggressive primary tumor in the central nervous system. Previously, the secretion of CXCL12 in the brain subventricular zones has been shown to attract GBM cells and protect against irradiation. However, the exact molecular mechanism behind this radioprotection is still unknown. Here, we demonstrate that CXCL12 modulates the phosphorylation of MAP kinases and their regulator, the nuclear MAP kinase phosphatase 1 (MKP1). We further show that MKP1 is able to decrease GBM cell death and promote DNA repair after irradiation by regulating major apoptotic players, such as Jun-N-terminal kinase, and by stabilizing the DNA repair protein RAD51. Increases in MKP1 levels caused by different corticoid treatments should be reexamined for GBM patients, particularly during their radiotherapy sessions, in order to prevent or to delay the relapses of this tumor.
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PMID:MKP1 phosphatase is recruited by CXCL12 in glioblastoma cells and plays a role in DNA strand breaks repair. 3150 51