Tezacitabine Hoechst Marion Roussel.
Tezacitabine (MDL-101731, KW-2331, FMdC), an antimetabolite deoxycytidine analog, is an irreversible ribonucleotide reductase inhibitor and DNA chain terminator discovered by Hoechst Marion Roussel, now Aventis Pharma, and under development by Matrix and Kyowa as a potential treatment for solid tumors [117987,153697]. It is in phase II trials for colorectal and hematological cancer [333949,343071,353481] and was evaluated in a phase II trial for non-small cell lung cancer, for which enrollment was reported to have stopped [342009]; however, tezacitabine continues to be explored for this indication [378351]. In February 1999, the first phase II trial patient was treated with tezacitabine. A total of 30 patients with non-small cell lung cancer were expected to be enrolled by Matrix [316463]; however, in October 1999, Matrix closed enrollment in this trial (after 28 patients were enrolled); preliminary analysis of the evaluable patients did not show meaningful clinical activity with tezacitabine as a stand-alone therapy in this indication at the dose and regimen tested [342009]. In May 1999, Matrix announced it would enroll up to 30 colorectal cancer patients for treatment in a phase II study [326017]. Despite closing enrollment for the NSCLC trial, as of October 1999, the phase II trial of tezacitabine in colorectal cancer was continuing to accrue patients [342009]. In March 2000, a clinical trial was initiated at the University of Pennsylvania to study tezacitabine administered intravenously in combination with cisplatin; a phase I trial studying the drug in combination with 5-FU at the Dana Farber Cancer Institute also commenced at that time [360590]. In May 1999, the results of four phase I trials were presented at the 35th Annual Meeting of the American Society of Clinical Oncology (ASCO). The studies enrolled 70 patients, 97% of whom had had previous chemotherapy and 46% of whom had failed three or more prior regimens. Groups of patients were given i.v. infusions of tezacitabine in schedules ranging from once every 3 weeks to twice a week for 3 weeks at doses ranging from 16 to 630 mg/m2. The dose-escalation studies showed the compound to be well tolerated and indications of efficacy were observed in patients with various advanced solid tumors [325070,327102]. In September 1998, Matrix Pharmaceutical acquired worldwide rights to tezacitabine except in Japan [299373]. Kyowa Hakko Kogyo has a license from HMR to develop tezacitabine in Japan [195494]; in 1995, the company began phase I clinical trials in Japan for tezacitabine administered orally [195494]. In 1996, this product was designated one of HMR's nine top priority products, serving an unmet medical need and addressing a potential market in excess of US $500 million per year [221118].
Georgia Institute of Technology, School of Chemistry and Biochemistry, Boggs Building, Atlanta, GA 30332-0400, USA. seley@chem-mail.chemistry.gatech.edu
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D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D000075202:Contraindications; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015507:Drugs, Investigational / Q000009:adverse effects / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D003841:Deoxycytidine; C086432:tezacitabine