Cisplatin is a widely used cytotoxic agent with therapeutic activity against various tumors, but also with substantial side effects, including nephrotoxicity, hepatotoxicity and myelosuppression. Therefore, a chemoprotective agent which reduces the side effects of cisplatin without affecting it efficacy would have significant clinical benefit. Currently, amifostine is the only FDA approved chemoprotective drug for cisplatin therapy. Amifostine is a sulfur-containing agent that reduces side effects resulted from both chemotherapy (including cisplatin) and radiotherapy regimens. Unfortunately, there are significant limitations associated with amifostine including (1) both amifostine and its active metabolite have very short half-lives in vivo requiring amifostine to be administered by a 15 minute infusion 30 minutes before cisplatin injection, and (2) amifostine is associated with side-effects including nausea and vomiting, as well as transient hypotension. Therefore, amifostine is not an ideal chemoprotector. An ideal chemoprotector should be orally administratable, with a longer half-life as compared to amifostine, and with little or no toxicity by itself. As such, we are proposing to investigate several novel small-molecule modulators of tumor necrosis factor alpha (TNF?), specifically UTL-5b, -5d, and -5g, as improved chemoprotective agents. UTL-5g will be the leading candidate for this Phase I study due to its promising biological effects and extremely low acute toxicity while UTL-5b and -5d will be backup compounds. UTL-5g is the subject compound in our recently completed SBIR Phase I grant for liver radioprotection (# 1 R43 CA117033-01A1). As a result, we have obtained promising results which are supportive of this proposal. The specific aims of this Phase I study are: (1) to conduct an animal study to show the chemoprotective effect of UTL-5g for cisplatin-induced side effects; the dose of UTL-5g with maximal protection will also be determined, (2) to conduct an animal study to show that UTL-5g does not decrease cancer killing during cisplatin therapy, and (3) to conduct a pharmacokinetic study to determine the half life of UTL-5g, and any metabolite(s). Once this phase I study is completed, we will know (1) whether UTL-5g reduces nephrotoxicity, hepatotoxicity, and/or myelosuppression induced by cisplatin in mice, (2) the optimal dose of UTL-5g for chemoprotection against cisplatin treatment in mice, (3) whether UTL-5g compromises cisplatin's anti-tumor activity in mice, and (4) the half-life of UTL-5g in mice and any metabolite(s).
Public Health Relevance: This phase I study will focus on the feasibility of using a small-molecule TNF- modulator, UTL-5g, as a chemoprotector to prevent/reduce side effects induced by cisplatin.
Public Health Relevance Statement: This phase I study will focus on the feasibility of using a small-molecule TNF- modulator, UTL-5g, as a chemoprotector to prevent/reduce side effects induced by cisplatin.
NIH Spending Category: Cancer; Digestive Diseases; Liver Disease.
Project Terms:(SP-4-2)-Diamminedichloroplatinum; (SP-4-2)-diammine[1,1-cyclobutanedicarboxylato(2--)-O,O']platinum; 1,1-cyclobutanedicarboxylic acid platinum complex; 1,2-diaminocyclohexane platinum oxalate; 1,2-diamminocyclohexane(trans-1)oxolatoplatinum(II); 1-OHP; AAT1; ALT1; APAETP; Acids; Acute; Adverse effects; Affect; Alanine Aminotransferase; Alanine Transaminase; Alanine-2-Oxoglutarate Aminotransferase; Alza Brand of Amifostine; Amifostine; Aminopropylaminoethylthiophosphoric Acid; Animals; Aspartate Aminotransferases; Aspartate Apoaminotransferase; Aspartate Transaminase; Bioavailability; Biologic Availability; Biological; Biological Availability; Blood Pressure, Low; CBDCA; CDDP; Cachectin; Cachectin-Tumor Necrosis Factor; Cancer Radiotherapy; Cancers; Carboplatin; Carboplatino; Chemoprotectants; Chemoprotection; Chemoprotective; Chemoprotective Agent; Chemoprotective Drugs; Cis-Diammine(cyclobutane-1,1-dicarboxylato)platinum; Cis-diammine-dichloroplatinum; Cis-diamminedichloridoplatinum; Cis-diamminedichloro Platinum (II); Cis-dichloroammine Platinum (II); Cis-platinous Diamine Dichloride; Cis-platinum II; Cis-platinum II Diamine Dichloride; Cisplatin; Cisplatina; Cisplatinum; Clinical; Clinical Trials, Phase I; Clinical Trials, Phase II; Cysplatyna; Cytotoxic agent; Cytotoxic drug; DDP; DIF; Development; Diaminocyclohexane Oxalatoplatinum; Dichlorodiammineplatinum; Dosage Forms; Dose; Drug Kinetics; Early-Stage Clinical Trials; Essex Brand of Amifostine; Ethanethiol, 2-((3-aminopropyl)amino)-, dihydrogen phosphate (ester); Ethiofos; Ethyol; FDA approved; Foundations; GPT; GPT1; Gammaphos; Glutamate-Aspartate Transaminase; Glutamic-Alanine Transaminase; Glutamic-Oxaloacetic Transaminase; Glutamic-Pyruvate Transaminase; Glutamic-Pyruvic Transaminase; Goals; Grant; Half-Life; Half-Lifes; Hepatotoxic effect; Hepatotoxicity; Hypotension; Infusion; Infusion procedures; Injection of therapeutic agent; Injections; Killings; L-Alanine[{..}]2-oxoglutarate aminotransferase; L-Aspartate-2-Oxoglutarate Aminotransferase; L-Aspartate[{..}]2-oxoglutarate aminotransaminase; L-OHP cpd; Licensing; Lilly Brand of Amifostine; Liver; Liver Toxicity; Malignant Cell; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; Mice; Murine; Mus; Myelosuppression; Nausea and Vomiting; Oral; Oxalatoplatin; Oxalatoplatinum; Peyrone's Chloride; Peyrone's Salt; Pharmaceutical Agent; Pharmaceuticals; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Phase; Phase 1 Clinical Trials; Phase 2 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phase II Clinical Trials; Physiologic Availability; Platinum; Platinum Black; Platinum Diamminodichloride; Platinum, Diaminedichloro-, cis- (8CI); Platinum, diamminedichloro-, (SP-4-2)-; Production; Protective Agents; Protective Drugs; Protocols, Treatment; Pt element; RGM; Radiation; Radiation therapy; Radioprotection; Radiotherapeutics; Radiotherapy; Reducing Agents; Reductants; Regimen; Research; Research Contracts; S element; S-(N-(3-Aminopropyl)-2-aminoethyl)thiophosphoric Acid; SBIR; SBIRS (R43/44); Schering-Plough Brand of Amifostine; Small Business Innovation Research; Small Business Innovation Research Grant; Solid; Sulfur; TNF; TNF A; TNF gene; TNF-alpha; TNFSF2; Technology; Therapeutic; Therapeutic Effect; Toxic effect; Toxic effect on liver cells; Toxicities; Treatment Protocols; Treatment Regimen; Treatment Schedule; Treatment Side Effects; Tumor Necrosis Factor; Tumor Necrosis Factor Gene; Tumor Necrosis Factor-alpha; US Bioscience Brand of Amifostine; Up-Regulation; Up-Regulation (Physiology); Upregulation; Vascular Hypotensive Disorder; Work; [(1R,-2R)-1,2-cyclohexanediamine-N,N'][oxalato (2--)-O,O']platinum; bioavailability of drug; body system, hepatic; cancer cell; cell killing; chemotherapy; cis dichlorodiammineplatinum; cis platinum compound; cis-Diaminedichloroplatinum; cis-Diammine(cyclobutanedicarboxylato)platinum II; cis-Diamminedichloroplatinum; cis-Diamminedichloroplatinum(II); cis-Dichlorodiammineplatinum(II); cis-Platinum; cis-diammine(1,1-cyclobutanedicarboxylato) platinum(II); glutamic aspartic transaminase; hepatoxicity; improved; in vivo; irradiation; malignancy; neoplasm/cancer; nephrotoxicity; novel; organ system, hepatic; oxalato (1R,2R-cyclohexanediamine)platinum(II); oxalato (trans-l-1,2-diaminocyclohexane)platinum(II); oxalato-(1,2-cyclohexanediamine)platinum II; oxaliplatin; oxaliplatine; phase 1 study; phase 1 trial; phase 2 study; phase 2 trial; phase I trial; phase II trial; platinum(II)-1,2-cyclohexanediamine oxalate; platinum, diammine(1,1-cyclobutanedicarboxylato(2-))-, (SP-4-2); pre-clinical; preclinical; preclinical study; prevent; preventing; protocol, phase I; protocol, phase II; public health relevance; ray (radiation); side effect; small molecule; study, phase II; therapy adverse effect; trans-l DACH oxalatoplatinum; trans-l diaminocyclohexane oxalatoplatinum; transaminase A; treatment adverse effect; tumor
