title: Phase I trial of oral 2'-deoxy-2'-methylidenecytidine: on a daily x 14-day schedule.
abstract: 2'-deoxy-2'-methylidenecytidine (DMDC) is a potent deoxycytidine analogue. Preclinical studies of DMDC demonstrated activity against a variety of murine and human tumors in cell cultures and murine models and indicate enhanced antitumor activity of DMDC when it was administered in a manner that provided prolonged systemic exposure. In view of this observation, this study was designed to determine the toxicities, maximum-tolerated dose, and pharmacokinetic profile of DMDC. DMDC was given p.o. under fasting conditions for 14 consecutive days every 4 weeks in patients with advanced solid tumors. The starting dose was 12 mg/m2/day. Pharmacokinetic studies were carried out on days 1 and 14 of the first cycle. Fourteen patients received 22 courses of DMDC. The dose-limiting toxicities were anorexia, leukopenia, thrombocytopenia, and anemia. General fatigue was the common nonhematological toxicity. The maximum-tolerated dose was 18 mg/m2/day, at which two of six patients developed grade 3 toxicities. This dose level could also be considered for Phase II testing with this schedule. At the 18-mg/m2/day dose level, the mean terminal half-life, maximum plasma concentration (Cmax), the area under the plasma drug concentration-time curve (AUC(0-infinity)) on day 1 were 1.7496 h, 112.9 ng/ml, and 399.8 ng x h/ml, respectively. Forty to 50% of the administered dose was recovered in the urine, indicating a good bioavailability and resulting significant systemic exposure to the drug, which may enable chronic oral treatment.
authors.affiliation: Department of Internal Medicine, Osaka Prefectural Habikino Hospital, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Masuda
authors.forename: K
authors.initials: K
authors.lastname: Matsui
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.forename: T
authors.initials: T
authors.lastname: Nogami
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
authors.forename: S
authors.initials: S
authors.lastname: Negoro
authors.forename: K
authors.initials: K
authors.lastname: Takeda
authors.forename: N
authors.initials: N
authors.lastname: Takifuji
authors.forename: M
authors.initials: M
authors.lastname: Yamada
authors.forename: S
authors.initials: S
authors.lastname: Kudoh
authors.forename: T
authors.initials: T
authors.lastname: Okuda
authors.forename: S
authors.initials: S
authors.lastname: Nemoto
authors.forename: K
authors.initials: K
authors.lastname: Ogawa
authors.forename: H
authors.initials: H
authors.lastname: Myobudani
authors.forename: S
authors.initials: S
authors.lastname: Nihira
authors.forename: M
authors.initials: M
authors.lastname: Fukuoka
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000368:Aged; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; C416375:Ro 09-3431; D003841:Deoxycytidine; C056034:2'-deoxy-2'-methylenecytidine; D003857:Deoxyuridine