Selective Killing of Tumors Deficient in Methylthioadenosine Phosphorylase: A Novel Strategy

@article{Lubin2009SelectiveKO,
  title={Selective Killing of Tumors Deficient in Methylthioadenosine Phosphorylase: A Novel Strategy},
  author={Martin Lubin and Adam Lubin},
  journal={PLoS ONE},
  year={2009},
  volume={4}
}
Background The gene for methylthioadenosine phosphorylase (MTAP) lies on 9p21, close to the gene CDKN2A that encodes the tumor suppressor proteins p16 and p14ARF. MTAP and CDKN2A are homozygously co-deleted, with a frequency of 35 to 70%, in lung and pancreatic cancer, glioblastoma, osteosarcoma, soft-tissue sarcoma, mesothelioma, and T-cell acute lymphoblastic leukemia. In normal cells, but not in tumor cells lacking MTAP, MTAP cleaves the natural substrate, 5′-deoxy-5′-methylthioadenosine… 

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References

SHOWING 1-10 OF 57 REFERENCES
5'-Deoxy-5'-methylthioadenosine phosphorylase and p16INK4 deficiency in multiple tumor cell lines.
TLDR
It is demonstrated that the phosphorylase deficiency is distributed among almost all the most important human cancers and suggested that deletions at 9p21 (in humans) or at syntenic chromosomes (in other species) might represent a general mechanism of p16INK4 gene loss of function and possibly, in turn, of cancer development and/or progression.
A Transition State Analogue of 5′-Methylthioadenosine Phosphorylase Induces Apoptosis in Head and Neck Cancers*
TLDR
The selective action of MT-DADMe-ImmA on head and neck squamous cell carcinoma cells suggests potential as an agent for treatment of cancers sensitive to reduced CpG island methylation.
Homozygous deletions of methylthioadenosine phosphorylase in human biliary tract cancers
TLDR
In vitro analysis using a selective inhibitor of the de novo purine synthesis pathway, l-alanosine, shows robust growth inhibition in MTAP-negative biliary cancer cell lines CAK-1 and GBD-1 accompanied by striking depletion of intracellular ATP and failure to rescue this depletion via addition of exogenous methylthioadenosine, the principal substrate of the MTAP gene product.
Status of methylthioadenosine phosphorylase and its impact on cellular response to L-alanosine and methylmercaptopurine riboside in human soft tissue sarcoma cells.
TLDR
Results provide the basis for selective therapy using inhibitors of de novo purine nucleotide synthesis such as L-alanosine or MMPR to treat patients with STS lacking this enzyme.
Frequent deletion in the methylthioadenosine phosphorylase gene in T-cell acute lymphoblastic leukemia: strategies for enzyme-targeted therapy.
TLDR
Findings suggest the possibility of targeting MTAP for selective therapy of T-ALL and the addition of methylthioadenosine, the substrate of MTAP, protected theMTAP(+) cells but not the MTAP(-) cells from alanosine toxicity.
EFA (9-beta-D-erythrofuranosyladenine) is an effective salvage agent for methylthioadenosine phosphorylase-selective therapy of T-cell acute lymphoblastic leukemia with L-alanosine.
TLDR
Data indicate that EFA is an effective agent for salvaging MTAP+ cells from L-alanosine toxicity and is superior to MTA due to lower cytotoxicity.
Characterization of methylthioadenosin phosphorylase (MTAP) expression in malignant melanoma.
Methylthioadenosine phosphorylase deficiency in human non-small cell lung cancers.
TLDR
The data suggest that MeSAdo phosphorylase deficiency is frequently found in non-small cell lung cancers and can be exploited in designing enzyme-selective chemotherapy.
Selective killing of human malignant cell lines deficient in methylthioadenosine phosphorylase, a purine metabolic enzyme.
TLDR
Human malignant tumor cell lines naturally deficient in methylthioadenosine phosphorylase could be selectively killed when de novo purine synthesis was inhibited and methylthioloadenosine was the only exogenous source of purines.
Methylthioadenosine phosphorylase gene deletions are common in osteosarcoma.
TLDR
The MTAP gene is commonly deleted in osteosarcoma patient samples, leading to an absence of mRNA and protein expression; these results indicate that inhibitors of de novo purine synthesis or methionine depletion may be effective as treatments for patients whose tumors fail to express MTAP.
...
1
2
3
4
5
...