Albert Einstein Cancer Center

Growth and metastases of human lung cancer are inhibited in mouse xenografts by a transition state analogue of 5'-methylthioadenosine phosphorylase

The S-adenosylmethionine (AdoMet) salvage enzyme 5'-methylthioadenosine phosphorylase (MTAP) has been implicated as both a cancer target and a tumor suppressor. AECC investigators Schramm, Guha, Belbin, Locker and colleagues 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. MTDIA treatment inhibited A549 (human non-small cell lung carcinoma (NSCLC)) and H358 (human bronchioloalveolar NSCLC cells) xenograft tumor growth in immunodeficient Rag2-/-gammaC-/- and NCr-nu mice. Systemic MTA accumulation was implicated as the tumor-suppressive metabolite since MTDIA was 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). The potent antitumor activity of MTDIA in xenografts supports MTAP as a target for lung cancer therapy. 

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