Summary
The development of nucleoside analogues has had a major impact on cancer therapy. CS-682 is a novel, orally administered nucleoside analogue with a unique mechanism of action. CS-682 undergoes conversion to the active metabolite, CNDAC, which then leads to the inhibition of DNA polymerase and a novel “DNA self-strand breaking mechanism.” We conducted a Phase I study of CS-682, administered orally five days per week in patients with refractory solid tumor malignancies. Forty-eight patients were enrolled on study. The recommended phase II dose of 30 mg/m2 given orally once daily for 5 days a week for 4 weeks followed by 2 weeks off drug, was well tolerated. The most common dose limiting toxicity was neutropenia, which occurred at the highest dose levels of CS-682. This was correlated with higher CNDAC Cmax and AUC values. No tumor responses were noted in this heavily pretreated population. However, given the ease of administration and tolerability, further investigation of this agent is warranted.
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References
Grant S (1990) Biochemical modulation of cytosine arabinoside. Pharmac Ther 48:29–44
Fadl TL, Hasegawa T, Youssef AF, Farag HH, Omar FA, Kawaguchi T (1995) Synthesis and investigation of N4 –substituted cytarabine derivatives as prodrugs. Pharmazie 50:382–387
Noble S, Goa K (1997) Gemcitabine: A review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer. Drugs 54:447–472
Ruiz, van Haperen VW, Veerman G, Vermorken JB, Peters GJ (1993) 2′,2-difluoro-deoxycytidine (gemcitabine)incorporation into RNA and DNA of tumor cell lines. Biochem Pharmacol 46:762–766
Hanaoka K, Suzuki M, Kobayashi T, Tanzawa F, Tanaka K, Shibayama T, Miura S, Ikelda T, Iwabuchi H, Nakagawa A, Mitsuhashi Y, Hisaoka M, Kaneko M, Tomida A, Wataya Y, Nomura T, Sasaki T, Matsuda A, Tsuruo T, Kurakata S (1999) Antitumor activity and novel DNA self-strand breaking mechanism of CNDAC (1(2-c-cyano-2-deoxy-β-D-arabino-pentofuranosyl) cytosine) and its N4 –Palmitoyl Derivative (CS-682). Int J Cancer 82:226–236
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Gilbert, J., Carducci, M.A., Baker, S.D. et al. A Phase I study of the oral antimetabolite, CS-682, administered once daily 5 days per week in patients with refractory solid tumor malignancies. Invest New Drugs 24, 499–508 (2006). https://doi.org/10.1007/s10637-006-8219-0
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DOI: https://doi.org/10.1007/s10637-006-8219-0