1-arabinofuranosylcytosine-5--stearylphosphate and Lung-Neoplasms

Since there have been relatively high incidence of cancer of the digestive organs in Japan, many 5-fluorouracil analogues have been studied as the drugs to treat such cancers. Beside these fluoropyrimine compounds, cytosine arabinoside (ara-C) analogues have also been studied, and some of them have shown appreciable clinical activities against human malignancies. In this paper, as such analogues, experimental and clinical studies of gemcitabine (dFdC). DMDC and cytarabine ocfosfate were reviewed. Among these drugs, gemcitabine (Eli Lilly, Japan) showed more than 20% response rate against non-small cell lung cancer in the late phase II study in Japan. Unfortunately, clinical study of DMDC (Yoshitomi) is currently suspended because of the lack of the hint of clinical activity, but the author believes that this might show some clinical activities by changing the treatment regimens in the future. Cytarabine ocfosfate (Nippon Kayaku) has already put on market as the first drug to be active against ANLL and MDS by giving orally.

Topics: Animals; Antimetabolites, Antineoplastic; Arabinonucleotides; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cytarabine; Cytidine Monophosphate; Deoxycytidine; Gemcitabine; Humans; Lung Neoplasms; Mice; Neoplasm Transplantation

Phase I study of YNK01 (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate), a derivative of cytosine arabinoside (Ara-C), was conducted by cooperative study groups between January 1986 and June 1987. The dosage for the single and 5-day oral administration ranged 50 to 1,200 and 100 to 900 mg/body/day, respectively. The main adverse effects were myelo-suppression and gastrointestinal toxicities such as nausea, vomiting, anorexia and diarrhea. In the single administration, the maximum tolerated dose (MTD) could not be determined, however, in the 5-day schedule MTD was considered to be 700 to 900 mg/body/day, and the dose limiting factor to be thrombocytopenia. After the single administration (800 mg/body/day) of YNK01, the plasma concentration of Ara-C, an active metabolite of YNK01, was 3.43 ng/ml (Cmax) at 24 hrs. and 0.82 ng/ml at 72 hrs. During the 5-day administration for 300 mg/body/day and 500 mg/body/day, the Ara-C concentration changed from 2.3 to 4.1 ng/ml, and from 1.5 to 11.9 ng/ml respectively, and sustained almost the same concentration as to during the administration period until the 2nd day after the completion of the administration.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anorexia; Antineoplastic Agents; Arabinonucleotides; Cytidine Monophosphate; Diarrhea; Drug Administration Schedule; Drug Evaluation; Female; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Male; Middle Aged; Myelodysplastic Syndromes; Nausea; Vomiting

The antitumor activity of cytarabine ocfosfate (SPAC) was tested against human colorectal, gastric and lung adenocarcinoma xenografts in nude mice in comparison with the activities of various antitumor drugs used clinically. SPAC showed higher therapeutic efficacy against human colorectal adenocarcinoma xenografts than against human gastric and lung adenocarcinoma xenografts. SPAC was effective against three of four human colorectal adenocarcinoma xenografts, with efficacy higher than that of 1-beta-D-arabinofuranosylcytosine, fluorouracil, cisplatin, doxorubicin, pirarubicin and vindesine sulfate, but lower than that of mitomycin C and cyclophosphamide. These results indicate that SPAC may be useful for induction and/or postoperative chemotherapy against colorectal adenocarcinomas.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Arabinonucleotides; Colorectal Neoplasms; Cytidine Monophosphate; Drug Administration Schedule; Drug Evaluation, Preclinical; Humans; Lung Neoplasms; Mice; Mice, Nude; Stomach Neoplasms; Transplantation, Heterologous