alanosine and Neoplasms

Personalized cancer medicine aims to develop individualized treatment options adapted to factors relevant for the prognosis of each patient. Molecular biomarkers are required to predict the likelihood of an individual tumor's responsiveness or of toxicity in normal organs and to advise optimized treatments with improved efficacy at reduced side effects for each cancer patient. In the present review, we present a concept, which takes advantage of methods of molecular diagnostics to identify predictive markers at the DNA, mRNA, and protein levels. Markers with prognostic value concerning treatment response and patient survival can then be used as targets to develop optimized drugs. We focus on three examples to illustrate this strategy: (i) chemoselective treatment of tumors with 9p21 deletion by L-alanosine, (ii) treatment of multidrug-resistant P-glycoprotein-expressing tumor cells by non-cross-resistant natural products or by inhibitors of P-glycoprotein to overcome multidrug resistance, and (iii) natural products that inhibit the epidermal growth factor receptor (EGFR) in EGFR-overexpressing tumor cells.

Topics: Alanine; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Products; Biomarkers, Tumor; Cytogenetics; Drug Resistance, Neoplasm; ErbB Receptors; Genetic Variation; Humans; Neoplasms; Phytotherapy; Precision Medicine; RNA, Messenger

Methylthioadenosine phosphorylase (MTAP)-deficient tumors are dependent on the de novo purine synthesis pathway. These cancers are potential targets for selective chemotherapy with inhibitors of de novo adenine synthesis such as L-alanosine [L-2-amino-3-(N-hydroxy-N-nitrosamino) propionic acid]. This phase II study was designed to evaluate the efficacy and safety of L-alanosine in patients with MTAP-deficient solid tumors.. Patients with mesothelioma, non-small cell lung cancer (NSCLC), soft tissue sarcoma, osteosarcoma, or pancreatic cancer whose tumors were MTAP deficient by immunohistochemistry were eligible. Patients received L-alanosine at a starting dose of 80 mg/m(2) by continuous intravenous infusion daily for 5 days every 21 days. Computed tomography scans or magnetic resonance imaging were performed every 3 cycles.. 65 patients (16 mesothelioma, 13 NSCLC, 15 soft tissue sarcoma, 7 osteosarcoma, 14 pancreatic cancer) were enrolled at 19 centers; 55 were evaluable for response. There were no objective responses; 24% had s disease, including 2 patients with mesothelioma who had prolonged stable disease lasting 7.5 and 15.2 months, respectively. Grade 3/4 toxicities included mucositis 11%, fatigue 6%, nausea 3%, and renal failure 1.5%.. At this dose and schedule, L-alanosine was ineffective in patients with advanced MTAP-deficient tumors.

Topics: Adenine; Adolescent; Adult; Aged; Alanine; Antimetabolites, Antineoplastic; Drug Administration Schedule; Female; Humans; Male; Neoplasms; Purine-Nucleoside Phosphorylase

Topics: Adenosine Monophosphate; Alanine; Antibiotics, Antineoplastic; Clinical Trials as Topic; Drug Resistance, Neoplasm; Gene Deletion; Homozygote; Humans; Neoplasms; Purine-Nucleoside Phosphorylase

L-alanosine (NSC 15353) is a newly developed antitumor antibiotic which acts as an inhibitor of purine intermediary metabolism. Experimental antitumor activity was demonstrated in a variety of murine neoplasms. A Phase I trial was undertaken on a daily x 5 (d x 5) schedule in 22 evaluable patients. Dose limiting toxicity was an oral mucositis characterized by beefy red oral, lingual and pharyngeal erythema. The maximum tolerated dose is 320 mg/m2/d x 5 every three weeks. The recommended dose for Phase II evaluation is 160 mg/m2/d x 5 every three weeks.

Topics: Adult; Aged; Alanine; Antibiotics, Antineoplastic; Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Middle Aged; Neoplasms; Stomatitis

Topics: Alanine; Animals; Chelating Agents; Copper; Humans; Lethal Dose 50; Leukemia P388; Male; Mice; Neoplasms; Nitrosamines; Rabbits; Superoxide Dismutase; Zinc