Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Contrary to bacterial DNA, mammalian DNA contains very little if any N(6)-methyldeoxyadenosine (MDA). The possible biological effect of this nucleoside on eukaryotic cells has been studied on different tumor cell lines. Addition of MDA to C6.9 glioma cells triggers a differentiation process and the expression of the oligodendroglial marker 2',3'-cyclic nucleotide 3'phosphorylase (CNP). The biological effects of N(6)-methyldeoxyadenosine were not restricted to C6.9 glioma cells since differentiation was also observed on pheochromocytoma and teratocarcinoma cell lines and on dysembryoplastic neuroepithelial tumor cells. The precise mechanism by which MDA induces cell differentiation remains unclear, but is related to cell cycle modifications. These data point out the potential interest of N(6)-methyldeoxyadenosine as a novel antitumoral and differentiation agent. They also raise the intriguing question of the loss of adenine methylation in mammalian DNA. Furthermore, the finding that a methylated nucleoside found in bacterial DNA induces a biological process might have implications in gene therapy approaches when plasmid DNAs are injected into humans.
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PMID:The bacterial nucleoside N(6)-methyldeoxyadenosine induces the differentiation of mammalian tumor cells. 1145 63

Researchers at the University of California at San Diego (UCSD) are developing alanosine as a potential treatment for cancer [227466], [408222]. The compound was originally under development in collaboration with Triangle, which initiated its development in 1996 [227466], but later discontinued development of the compound [406677]. As of May 2001, UCSD's ongoing clinical trials of alanosine included phase II trials for non-small cell lung cancer (NSCLC) and phase I trials for acute lymphoid leukemia (ALL), while a phase II trial for glioma at UCSD had been suspended [408222]. Alanosine is an amino acid analog originally derived from Streptomyces alanosinicus. It interferes with the de novo synthesis of adenosine in both malignant and normal cells. In cancer cells that lack methyladenosine phosphorylase (MTAP, required in the salvage pathway), alanosine should deprive such cells (but not normal cells) of de novo synthesized adenosine [277968]. In early 1997, patients were being recruited for a phase II pilot efficacy trial of alanosine as a treatment for glioma and NSCLC, since a significant number of these tumor types lack MTAP and, it was hoped, would therefore be sensitive to alanosine [239280], [248260]. Phase I and II trials were completed in the 1980s by the NCI before they were discontinued because alanosine caused toxicity typically associated with chemotherapy, and did not produce significant response rates in common tumors such as breast or colon cancers. Researchers at UCSD found that some types of cancer lack MTAP, which was responsible for alanosine's previous clinical failure [227466]; phase II trials were being carried out at the university in 1997 [269338]. Triangle obtained an option for a worldwide license from the Regents of the University of California that expired in September 1998 (but had an option to extend the period for a further one year) [277968].
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PMID:Alanosine (UCSD). 1176 67

Understanding the mechanistic basis for temozolomide (TMZ)-induced glioma resistance is an important obstacle in developing an effective form of chemotherapy for this type of tumor. Glycogenolysis is known to play an essential role in cellular proliferation and potassium homeostasis and involves the glycogen phosphorylase isoenzyme BB (GPBB). In this investigation, plasma GPBB was correlated with TMZ-resistance. Elevated plasma GPBB concentrations were found to be more frequent in a TMZ-resistant cohort of patients with poor survival rates. TMZ inhibits cell proliferation and induces TMZ resistance by upregulating the expression of O(6)-methylguanine-DNA methyltransferase (MGMT). This process requires glycogenolysis, which was confirmed herein by treatment with 1,4-dideoxy-1,4-imino-D-arabinitol hydrochloride, a glycogenolysis inhibitor and a special GPBB inhibitor. Acute TMZ treatment leads to upregulation of [Ca2+]i, extracellular-regulated kinase (ERK)1/2 phosphorylation, and chronic TMZ treatment leads to upregulation of the expression of Na,K-ATPase, ERK1/2, and MGMT protein. Upregulation was abolished for each of these by inhibitors of transient receptor potential channel 1 and the inositol trisphosphate receptor. L-channel [Ca2+]i inhibitors and RyR antagonists had no such effect. These results demonstrate that [Ca2+]i-dependent glycogenolysis participates in acquired glioma TMZ-resistance by upregulating MGMT via a Na,K-ATPase/ERK1/2 signaling pathway. GPBB and glycogenolysis may therefore represent novel therapeutic targets for overcoming TMZ-resistant gliomas.
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PMID:Glycogenolysis in Acquired Glioma Resistance to Temozolomide: A Role for the [Ca2+]i-dependent Activation of Na,K-ATPase/ERK1/2 Signaling. 3013