Disease relevance of AI3-52867

• We demonstrate that MTAP- T-ALL cells obtained at relapse are as sensitive to L-alanosine toxicity as diagnosis samples [1].
• EFA (9-beta-D-erythrofuranosyladenine) is an effective salvage agent for methylthioadenosine phosphorylase-selective therapy of T-cell acute lymphoblastic leukemia with L-alanosine [1].
• Thus, the particularly high prevalence of MTAP codeletion in mesothelioma makes it an ideal candidate for trials of targeted therapy using inhibitors of de novo AMP synthesis (e.g., L-alanosine) [2].
• L-alanosine: a noncooperative substrate for Escherichia coli aspartate transcarbamylase [3].
• Phase II study of L-alanosine (NSC 153353) in patients with advanced breast cancer. A Southwest Oncology Group study [4].

High impact information on AI3-52867

• Collectively, these data indicate that EFA is an effective agent for salvaging MTAP+ cells from L-alanosine toxicity and is superior to MTA due to lower cytotoxicity [1].
• EFA at 20 microM or less rescued primary MTAP+ T-ALL cells and normal lymphocytes from L-alanosine toxicity [1].
• The deficiency of methylthioadenosine phosphorylase (MTAP) in T-cell acute lymphoblastic leukemia (T-ALL) and other cancers, while constitutively expressed in normal cells, allows for selective therapy using L-alanosine, an inhibitor of de novo AMP synthesis [1].
• The ability to salvage adenine declined substantially in the pseudorevertant cell lines when they were removed from selective media containing inhibitors of de novo 5'-AMP synthesis (alanosine and azaserine); for one pseudorevertant cell line this decline was accelerated by the addition of DAP to the medium [5].
• These results indicate that SLC7A11 mediates cellular uptake of L-alanosine but confers resistance to geldanamycin by supplying cystine for glutathione maintenance [6].

Chemical compound and disease context of AI3-52867

• However, the addition of methylthioadenosine, the substrate of MTAP, protected the MTAP(+) cells but not the MTAP(-) cells from alanosine toxicity [7].
• We also compared the effects of L-alanosine and 5'-deoxyadenosine on MTAP (+) and MTAP (-) T-ALL cell lines [8].
• In addition, a low specific activity of the enzyme, adenylosuccinate synthetase, appeared to predispose an organ to the toxicity of alanosine [9].
• Status of methylthioadenosine phosphorylase and its impact on cellular response to L-alanosine and methylmercaptopurine riboside in human soft tissue sarcoma cells [10].
• The antitumor action of L-alanosine (NSC 153553) was investigated in murine leukemia P388 (P388/S), P388 resistant to adriamycin (P388/ADR), P388 resistant to vincristine (P388/VCR) and leukemia L5178Y sensitive to L-asparaginase (L5178Y/S) [11].

Biological context of AI3-52867

• As measured by [3H]thymidine incorporation, DNA synthesis in all seven MTAP-primary T-ALL cells was inhibited by L-alanosine with a mean IC50 of 4.8+/-5.3 ILM (range, 0.3-11.3 microM) [12].
• In contrast, L-alanosine (adenine starvation) failed to affect DNA synthesis for at least 24 hr at a concentration that inhibits cell growth by 80% [13].
• The saturation curve of the native enzyme for L-alanosine indicates the lack of homotropic cooperative interactions between the catalytic sites for the utilization of this compound [3].
• In the presence of subinhibitory concentrations of alanosine, both CHO cells and the HDF show excessive sensitivity to exogenous guanine--a phenotype which closely resembles that seen with some of the mutants containing reduced enzymatic activity of ASS [14].
• A novel synergistic effect of the antitumor agent alanosine (2-amino-3-(hydroxynitrosoamino) propionic acid), which specifically inhibits the enzyme adenylosuccinate synthetase (ASS) and guanine on the growth of Chinese hamster ovary (CHO) cells and human diploid fibroblasts (HDF) has been observed [14].

Anatomical context of AI3-52867

• Oocytes from hormonally primed, immature mice were cultured overnight in Eagle's minimum essential medium containing dibutyryl cyclic AMP (dbcAMP) (to maintain meiotic arrest), plus either mycophenolic acid or alanosine (inhibitors of guanyl and adenyl nucleotide production, respectively) [15].
• Even though treatment of HL60 cells with alanosine resulted in the depletion of guanylates, this effect was secondary to the depletion of adenylates and developed only upon prolonged exposure [16].
• The LD50 of L-alanosine (given intraperitoneally) was approximately 2 g/kg; L-5178Y/AR tumor, small intestine, liver, and lung were the tissues more consistently or severely damaged by the drug [9].
• Inhibition of mouse molar tooth germ morphogenesis in organ culture by alanosine [17].

Associations of AI3-52867 with other chemical compounds

• Linking expression of SLC7A11 with potency of 1,400 candidate anticancer drugs identified 39 showing positive correlations, e.g., amino acid analogue, L-alanosine, and 296 with negative correlations, e.g., geldanamycin [6].
• Five MCL cell lines were analyzed for MTAP expression and for the in vitro sensitivity to L-alanosine, an inhibitor of adenylosuccinate synthetase, and hence de novo AMP synthesis [18].
• T-state active site of aspartate transcarbamylase: crystal structure of the carbamyl phosphate and L-alanosine ligated enzyme [19].
• This result strongly supports the kinetic results that alanosine did not inhibit the carbamylation of aspartate in the normal reaction of native ATCase plus CP and aspartate [Baillon, J., Tauc, P., and Hervé, G. (1985) Biochemistry 24, 7182-7187] [19].
• MTAP loss itself has therapeutic implications since it may confer selective sensitivity to inhibitors of de novo purine biosynthesis, such as L-alanosine [20].

Gene context of AI3-52867

• Alanosine, an inhibitor of AMP synthesis, inhibited the growth of both MTAP(+) (Molt-4 and Molt-16) and MTAP(-) (CEM and HSB2) cell lines [7].
• We found that p53 mutated cell lines were more resistant to L-alanosine than p53 wild type cell lines [21].
• To survive in the presence of alanosine, cells must have adenosine kinase in order to utilize exogenous adenosine as the sole source of AMP [22].
• Restoration of MTAP into HT-1080 MTAP-deficient cells also led to decreased sensitivity to L-alanosine and MMPR [10].
• The inhibition of purine and pyrimidine nucleotide biosynthesis in mycophenolic acid, acivicin and alanosine-treated cells resulted in an increase in the steady-state concentration of PRPP [16].

Analytical, diagnostic and therapeutic context of AI3-52867

• Thus, our results support the use of L-alanosine alone or in combination with a salvage agent as a MTAP-selective therapy and therefore lay the foundation for the initiation of clinical trials for the treatment of T-ALL and other MTAP-deficient malignancies with L-alanosine [12].
• L-Alanosine [3-(hydroxynitrosoamino)-L-alanine] is an antitumor antibiotic that at the present is undergoing phase II clinical trials [23].
• Determination of L-alanosine in plasma and urine by reversed-phase high-performance liquid chromatography of the Dns derivative [24].
• The authors conducted a phase II study of L-alanosine in 39 patients (19 without prior chemotherapy) in advanced malignant melanoma [25].
• Using a previously reported in vitro assay, they found a paradoxal increase in the mitotic index in the presence of L-alanosine in lymphocyte cultures of patients with 5p- who were on no medication [26].

References