Phase I trial of oral 2'-deoxy-2'-methylidenecytidine: on a daily x 14-day schedule

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...

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Bibliographic Details
Published in:Clinical cancer research 2000-06, Vol.6 (6), p.2288
Main Authors: Masuda, N, Matsui, K, Yamamoto, N, Nogami, T, Nakagawa, K, Negoro, S, Takeda, K, Takifuji, N, Yamada, M, Kudoh, S, Okuda, T, Nemoto, S, Ogawa, K, Myobudani, H, Nihira, S, Fukuoka, M
Format: Article
Language:English
Subjects:
Adenocarcinoma - drug therapy
Aged
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - therapeutic use
Antineoplastic Agents - toxicity
Carcinoma, Squamous Cell - drug therapy
Chromatography, High Pressure Liquid
Colorectal Neoplasms - drug therapy
Deoxycytidine - analogs & derivatives
Deoxycytidine - chemistry
Deoxycytidine - pharmacokinetics
Deoxycytidine - therapeutic use
Deoxycytidine - toxicity
Deoxyuridine - analogs & derivatives
Deoxyuridine - chemistry
Deoxyuridine - pharmacokinetics
Dose-Response Relationship, Drug
Female
Humans
Lung Neoplasms - drug therapy
Male
Maximum Tolerated Dose
Middle Aged
Time Factors
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Summary: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.
ISSN:1078-0432