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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Targeting tumors that lack methylthioadenosine phosphorylase (MTAP) activity
TLDR
The frequency of MTAP-deficiency is presented and past and recent strategies to target such deficient cells are discussed, including one in which MTA is administered, followed by very high doses of a toxic purine or pyrimidine analog.
Increased Sensitivity to Thiopurines in Methylthioadenosine Phosphorylase–Deleted Cancers
TLDR
Measurement of thiopurine metabolites support the hypothesis that DNPS inhibition is a major cause of cell death with 6-MP, whereas dGs incorporation is the main cause of cytotoxicity with 5-TG, and suggest thatThiopurines, particularly 6- MP, may be more effective in patients with deleted MTAP.
Increasing the therapeutic index of 5-fluorouracil and 6-thioguanine by targeting loss of MTAP in tumor cells
TLDR
The data suggest that the addition of MTA to anti-purine-based chemotherapy may greatly increase the therapeutic index of this class of drugs if used specifically to treat MTAP- tumors.
Specific Targeting of MTAP-Deleted Tumors with a Combination of 2'-Fluoroadenine and 5'-Methylthioadenosine.
TLDR
The results suggest that 2FA+MTA may be a promising combination for treating MTAP-deleted tumors and the MTAP protection strategy presented in this study could be very effective in treating these cancers.
6-thioguanine: a drug with unrealized potential for cancer therapy.
TLDR
The combination of MTA/6-TG has produced substantial shrinkage or slowing of growth in two different xenograft human tumor models: lymphoblastic leukemia and metastatic prostate carcinoma with neuroendocrine features.
Design, synthesis, and evaluation of potential carbamate prodrugs of 5′-methylthioadenosine (MTA)
TLDR
A series of carbamate prodrugs, namely the N-(alkyloxy)carbonyl-MTA derivatives 2a-f, was designed, synthesized, and evaluated as potential pro drugs of MTA and activation was shown to be mediated by carboxyesterases present in mouse liver microsomes.
Therapeutic targeting of methylthioadenosine phosphorylase
TLDR
A deep understanding of the clinical role and the metabolic reprogramming regulated by MTAP in cancer is provided as the guide to found out and solve the problems of MTAP based cancer therapy.
Next Generation Sequencing of Prostate Cancer from a Patient Identifies a Deficiency of Methylthioadenosine Phosphorylase, an Exploitable Tumor Target
TLDR
It is shown for the first time that treatment with methylthioadenosine and high dose 6-thioguanine causes marked inhibition of a patient-derived neuroendocrine xenograft growth while protecting the host from 6-thanguanine toxicity.
Characterization and Prognostic Significance of Methylthioadenosine Phosphorylase Deficiency in Nasopharyngeal Carcinoma
TLDR
MTAP deficiency was correlated with an aggressive phenotype and independently predictive of worse DSS and DMFS, suggesting its role in disease progression and as an independent prognostic biomarker of NPC, which potentially offers new strategy of targeted treatment for patients lacking MTAP expression.
Methylthioadenosine (MTA) inhibits melanoma cell proliferation and in vivo tumor growth
TLDR
MTA inhibits melanoma cell proliferation and in vivo tumor growth particularly in BRAF mutant melanoma cells, revealing a naturally occurring drug potentially useful for melanoma treatment.
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