Missing Enzyme Key to New Cancer Treatment

A two-drug treatment protocol takes advantage of the activity of an enzyme that is present in normal cells but missing in 35%-70% of many types of cancer.

The gene that encodes the enzyme methylthioadenosine phosphorylase (MTAP) is closely linked to the gene CDKN2A that encodes the tumor suppressor proteins p16 and p14ARF. MTAP and CDKN2A are homozygously codeleted, 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, the enzyme cleaves the natural substrate, 5′-deoxy-5′-methylthioadenosine (MTA), to adenine and 5-methylthioribose-1-phosphate (MTR-1-P), which are then converted to adenine nucleotides and methionine. Recognizing the possibility for exploiting the lack of MTAP in cancer cells, investigators at Dartmouth Medical School (Hanover, NH, USA; www.dms.dartmouth.edu) developed a two-drug approach for treating MTAP-minus tumors.

The treatment regimen comprises both MTA and a toxic adenine analog, such as 2,6-diaminopurine (DAP), 6-methylpurine (MeP), or 2-fluoroadenine (F-Ade). In MTAP-positive cells, abundant adenine, generated from the supplied MTA, competitively blocks the conversion of the toxic adenine analog, by adenine phosphoribosyltransferase (APRT), to its active nucleotide form. In MTAP-negative tumor cells, the supplied MTA is not metabolized to adenine; hence, conversion of the toxic analog is not blocked, and the tumor cells die.

Results published in the May 29, 2009, online edition of the journal PLoS ONE revealed that this combination treatment – adenine analog plus MTA – killed MTAP-negative A549 lung tumor cells, while MTAP-positive human fibroblasts (HF) were protected. In cocultures of the breast tumor cell line, MCF-7, and HF cells, MCF-7 was inhibited or killed, while HF cells proliferated robustly.

The authors summarized by stating, "Our strategy consists of two agents. One drug is given that is toxic both to cancer cells and to normal host tissues. A second, but non-toxic, drug is also given, which protects normal tissues from the toxic action of the first agent. This two-drug combination therapy kills tumor cells while normal tissues are well protected. Among the drugs used to kill the tumor cells, two - thioguanine and fluorouracil (or its prodrug Xeloda) - are already in clinical use. In general, the dose of these drugs is limited by toxic side effects. However, with our strategy, greatly increased doses might be used and tumors not susceptible to low doses could be attacked successfully at higher doses, without harm to host tissues.”

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