Abstract
Abstract Many potential chemopreventive drugs have adverse effects on human subjects when given daily. One strategy to alleviate these adverse events is to give the drugs on an intermittent dosing schedule. Such intermittent dosing has proven effective in other settings to reduce toxicity with limited effect on efficacy. Two animal models were used: the rat methylnitrosourea (MNU) - induced mammary cancer model and the rat hydroxy-butyl(butyl)-nitrosamine (OH-BBN) -induced urinary bladder cancer model. For the mammary study female Sprague-Dawley rats were given 75 mg of MNU/kg body weight at 50 days of age and five days later the EGFR inhibitors, Erlotinib, Gefitinib or Lapatinib were administered either daily or once a week at two dose levels. Multiplicity of ER-positive mammary cancers was followed weekly for four months. For the urinary bladder study female Fischer 344 rats were given 150 mg OH-BBN/gavage twice weekly beginning at 56 days of age and continuing for 8 weeks. Two weeks after the last OH-BBN treatment the rats were given naproxen either daily, one week on/one week off, or 3 weeks on/3 weeks off. Bladders were excised after 8 months of naproxen treatment and bladders with tumors were excised and weighed. EGFR inhibitors and the NSAID, Naproxen, have similar efficacy when given intermittently compared to daily. The EGFR antagonists, Erlotinib and Lapatinib, decreased mammary cancer multiplicity by 90% given daily and 75 % given weekly. The NSAID, naproxen, decreased large bladder cancers by about 65-80% given either daily, one week on/one week off or 3 weeks on/3 weeks off. Therefore intermittent dosing can be used for agents in two different mechanistic classes in animal mammary and bladder cancer models to lower toxicity, yet show little reduction in chemoprevention efficacy compared to daily dosing. Intermittent dosing schedules in the clinic should reduce EGFR mediated rash and NSAID induced gastric toxicity clinically while retaining efficacy. Citation Format: Vernon E. Steele, Clinton J. Grubbs, Ronald A. Lubet. Intermittent dosing regimens maintain efficacy of several cancer preventing drugs. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PR09.
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