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Oncotarget Nov 2014Myxofibrosarcomas are genetically complex and involve recurrently deleted chromosome 9p, for which we characterized the pathogenically relevant target(s) using genomic...
Myxofibrosarcomas are genetically complex and involve recurrently deleted chromosome 9p, for which we characterized the pathogenically relevant target(s) using genomic profiling. In 12 of the 15 samples, we detected complete or partial losses of 9p. The only aggressiveness-associated, differentially lost region was 9p21.3, spanning the potential inactivated methylthioadenosine phosphorylase (MTAP) that exhibited homozygous (4/15) or hemizygous (3/15) deletions. In independent samples, MTAP gene status was assessed using quantitative- and methylation-specific PCR assays, and immunoexpression was evaluated. We applied MTAP reexpression or knockdown to elucidate the functional roles of MTAP and the therapeutic potential of L-alanosine in MTAP-preserved and MTAP-deficient myxofibrosarcoma cell lines and xenografts. MTAP protein deficiency (37%) was associated with MTAP gene inactivation (P < 0.001) by homozygous deletion or promoter methylation, and independently portended unfavorable metastasis-free survival (P = 0.0318) and disease-specific survival (P = 0.014). Among the MTAP-deficient cases, the homozygous deletion of MTAP predicted adverse outcome. In MTAP-deficient cells, MTAP reexpression inhibited cell migration and invasion, proliferation, and anchorage-independent colony formation and downregulated cyclin D1. This approach also attenuated the tube-forming abilities of human umbilical venous endothelial cells, attributable to the transcriptional repression of MMP-9, and abrogated the susceptibility to L-alanosine. The inhibiting effects of MTAP expression on tumor growth, angiogenesis, and the induction of apoptosis by L-alanosine were validated using MTAP-reexpressing xenografts and reverted using RNA interference in MTAP-preserved cells. In conclusion, homozygous deletion primarily accounts for the adverse prognostic impact of MTAP deficiency and confers the biological aggressiveness and susceptibility to L-alanosine in myxofibrosarcomas.
Topics: Alanine; Animals; Apoptosis; Cell Growth Processes; Cell Line, Tumor; Cyclin D1; Down-Regulation; Female; Fibrosarcoma; Heterografts; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, SCID; Middle Aged; Molecular Targeted Therapy; Purine-Nucleoside Phosphorylase; Survival Analysis
PubMed: 25426549
DOI: 10.18632/oncotarget.2552 -
Leukemia Sep 2002Methylthioadenosine phosphorylase (MTAP) is an important enzyme used for the salvage of adenine and methionine. Cells lacking this enzyme are expected to be sensitive to...
Methylthioadenosine phosphorylase (MTAP) is an important enzyme used for the salvage of adenine and methionine. Cells lacking this enzyme are expected to be sensitive to purine synthesis inhibitors and/or methionine starvation. We reported previously that the MTAP gene is deleted in adult T cell leukemia (ATL) cells. In the present study, we expanded our series and used a real-time quantitative PCR assay for accurate diagnosis of the deletion and nine of 65 primary ATL samples (13.8%) were MTAP negative. In spite of this low incidence, ATL cells showed significantly higher sensitivity to L-alanosine, an inhibitor of de novo adenosine monophosphate (AMP) synthesis, than normal lymphocytes, suggesting that the MTAP gene is inactivated not only by deletion but also by other mechanisms. Indeed, a real-time quantitative RT-PCR assay disclosed that primary ATL cells had significantly lower MTAP mRNA expression than normal lymphocytes. Since MTAP-negative ATL cell lines also showed much higher sensitivity to L-alanosine than MTAP-positive ATL cell lines, we used these cell lines to investigate whether it is possible to develop selective therapy targeting MTAP deficiency. A substrate of MTAP, methylthioadenosine (MTA) or its substitutes rescued concanavalin A (Con A)-activated normal lymphocyte proliferation from L-alanosine toxicity. All the compounds except 5'-deoxyadenosine, however, also caused the undesirable rescue of MTAP-negative ATL cell lines. 5'-Deoxyadenosine had the desired ability to rescue hematopoietic progenitor cells without rescuing ATL cell lines. These results support the rationale for a chemotherapy regimen of L-alanosine combined with 5'-deoxyadenosine rescue in MTAP-deficient ATL.
Topics: Adenosine Monophosphate; Antibiotics, Antineoplastic; Blotting, Southern; Cell Division; Colony-Forming Units Assay; DNA Primers; Drug Resistance, Neoplasm; Gene Deletion; Humans; Leukemia-Lymphoma, Adult T-Cell; Lymphocyte Activation; Purine-Nucleoside Phosphorylase; RNA, Messenger; RNA, Neoplasm; Reverse Transcriptase Polymerase Chain Reaction; Thymidine
PubMed: 12200696
DOI: 10.1038/sj.leu.2402570 -
Il Farmaco; Edizione Scientifica Feb 1969
Topics: Amino Acids; Anti-Bacterial Agents; Antimetabolites
PubMed: 5768828
DOI: No ID Found -
Investigational New Drugs 1983L-Alanosine, an antitumor antibiotic was administered by members of the Southwest Oncology Group (SWOG) to 22 patients with resistant acute non-lymphocytic leukemia. The...
L-Alanosine, an antitumor antibiotic was administered by members of the Southwest Oncology Group (SWOG) to 22 patients with resistant acute non-lymphocytic leukemia. The drug was administered by continuous infusion for five days at a starting dose of 125 mg/m2/day. Mucositis was dose-limiting in 15 patients and no marrow aplasia was attained. As administered, L-Alanosine is not an effective single agent in acute leukemia.
Topics: Acute Disease; Adolescent; Adult; Aged; Alanine; Antibiotics, Antineoplastic; Drug Evaluation; Female; Humans; Infusions, Parenteral; Leukemia; Male; Middle Aged
PubMed: 6678874
DOI: 10.1007/BF00208898 -
Cancer Chemotherapy and Pharmacology 1985L-Alanosine [L-2-amino-3(N-hydroxy-N-nitrosamino)propionic acid], a tumor-inhibiting agent, induces pregnancy arrest after single or multiple SC or PO administration to...
L-Alanosine [L-2-amino-3(N-hydroxy-N-nitrosamino)propionic acid], a tumor-inhibiting agent, induces pregnancy arrest after single or multiple SC or PO administration to rats and hamsters. Its contragestational effects are dose- and route-dependent, with no important differences in species-sensitivity or administration schedules. L-Alanosine is maximally effective shortly (3-4 days) after implantation. Both placenta and fetus appear to be target tissues. Consistent with previous in vitro findings, adenine but not aspartic acid counteracts the contragestational action of L-alanosine. The 'contragestational test', i.e., the effect on conceptus growth, appears to be an interesting approach for learning more about the antiproliferative activity of an antineoplastic agent.
Topics: Adenine; Alanine; Animals; Antibiotics, Antineoplastic; Aspartic Acid; Cell Division; Cricetinae; Dose-Response Relationship, Drug; Female; Fertility; Mesocricetus; Pregnancy; Rats; Rats, Inbred Strains; Time Factors
PubMed: 3965163
DOI: 10.1007/BF00552730 -
Cancer Treatment Reports Nov 1983
Topics: Alanine; Carcinoma, Squamous Cell; Drug Evaluation; Female; Head and Neck Neoplasms; Humans; Leukopenia; Male; Stomatitis; Thrombocytopenia
PubMed: 6640554
DOI: No ID Found -
Journal of Economic Entomology Oct 1975
Topics: Alanine; Animals; Diptera; Female; Fertility; Insect Control; Nitroso Compounds; Ovum
PubMed: 1184818
DOI: 10.1093/jee/68.5.581 -
Proceedings of the Society For... Dec 1968
Topics: Animals; Bacteria; Brain; Carboxy-Lyases; Methods; Plants, Edible; Pyridoxal Phosphate; Rats; Vegetables
PubMed: 5725103
DOI: 10.3181/00379727-129-33438 -
Experimental Cell Biology 1978
Topics: Adenine; Alanine; Animals; Mice; Mice, Inbred BALB C; Mitosis; Molar; Morphogenesis; Nitrosamines; Odontogenesis; Organ Culture Techniques; Tooth Germ
PubMed: 627296
DOI: 10.1159/000162891 -
Pharmacology 1970
Topics: Agglutination; Animals; Anti-Bacterial Agents; Antibodies; Antibody Formation; Female; Immunosuppressive Agents; Male; Rabbits; Salmonella typhi; Streptomyces
PubMed: 5445906
DOI: 10.1159/000136069