| Title | Growth and metastases of human lung cancer are inhibited in mouse xenografts by a transition state analogue of 5′-methylthioadenosine phosphorylase |
| Publication Type | Journal Article |
| Year of Publication | 2011 |
| Authors | Basu, I., Locker J., Cassera M. B., Belbin T. J., Merino E. F., Dong X., Hemeon I., Evans G. B., Guha C., and Schramm V. L. |
| IRL Team | Carbohydrate Chemistry |
| Journal | Journal of Biological Chemistry |
| Volume | 286 |
| Pagination | 4902-4911 |
| Keywords | adenine, Amino acids, animal, animal experiment, animal model, animal tissue, Anti-tumor activities, antimetastatic agent, antineoplastic agent, article, Biological organs, cancer inhibition, cancer transplantation, Carcinoma, cell line, controlled study, down regulation, drug accumulation, drug antagonism, drug metabolism, drug structure, drug tumor level, enzymology, gene expression, genetics, Heterologous, human, human cell, Human lung, immucillin A, in vivo study, lung alveolus cell carcinoma, Lung cancer therapy, Lung Neoplasms, lung non small cell cancer, lung tumor, metabolism, metastasis, methionine, methodology, methylthio-DADMe-immucillin-A, Methylthioadenosine phosphorylase, Mice, mouse, Mus, Neoplasm Metastasis, Non-small cell lung carcinomata, Non-Small-Cell Lung, nonhuman, nucleoside, nude mouse, phosphorylation, polyamine derivative, Polyamines, priority journal, purine nucleoside phosphorylase, Pyrrolidines, RAG2 protein, Salvage enzymes, Thionucleosides, Transition-state |
| Abstract | The S-adenosylmethionine (AdoMet) salvage enzyme 5′- methylthioadenosine phosphorylase (MTAP) has been implicated as both a cancer target and a tumor suppressor. We tested these hypotheses in mouse xenografts of human lung cancers. AdoMet recycling from 5′-methylthioadenosine (MTA) was blocked by inhibition of MTAP with methylthio-DADMe-Immucillin-A (MTDIA), an orally available, nontoxic, picomolar transition state analogue. Blood, urine, and tumor levels of MTA increased in response to MTDIA treatment. MTDIA treatment inhibited A549 (human non-small cell lung carcinoma) and H358 (human bronchioloalveolar non-small cell lung carcinoma cells) xenograft tumor growth in immunodeficient Rag2-/-γC-/- and NCr-nu mice. Systemic MTA accumulation is implicated as the tumor-suppressive metabolite because MTDIA is effective for in vivo treatment of A549 MTAP-/- and H358 MTAP+/+ tumors. Tumors from treated mice showed increased MTA and decreased polyamines but little alteration in AdoMet, methionine, or adenine levels. Gene expression profiles of A549 tumors from treated and untreated mice revealed only modest alterations with 62 up-regulated and 63 down-regulated mRNAs (≥3-fold). MTDIA antitumor activity in xenografts supports MTAP as a target for lung cancer therapy. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. |
| URL | http://www.scopus.com/inward/record.url?eid=2-s2.0-79953000186&partnerID=40&md5=73c26347d8fc201800ed59d92e16c14b |
| DOI | 10.1074/jbc.M110.198374 |
