title: Effect of intermittent dosing regimens of erlotinib on methylnitrosourea-induced mammary carcinogenesis.
abstract: EGF receptor (EGFR) inhibitors are used in the therapy of lung and pancreatic cancers and effectively prevent cancers in multiple animal models. Although daily dosing with erlotinib is effective, weekly dosing may reduce toxicity and have advantages, particularly for prevention. We tested alternative dosing regimens for preventive/therapeutic efficacy in a rat mammary cancer model. For prevention, erlotinib was administered by gavage beginning 5 days after methylnitrosourea (MNU). For therapy and biomarker studies, rats with palpable mammary cancers were treated for six weeks or for six days, respectively. Experiment A, erlotinib (6 mg/kg body weight/day, intragastric): daily (7 times/week); one day on/one day off; and two days on/two days off. All regimens decreased tumor incidence, increased tumor latency, and decreased cancer multiplicity versus controls (P < 0.01). However, intermittent dosing was less effective than daily dosing (P < 0.05). Experiment B, erlotinib (6 mg/kg body weight/day) daily or two days on/two days off or one time per week at 42 mg/kg body weight. All regimens reduced cancer incidence and multiplicity versus controls (P < 0.01). Interestingly, daily and weekly dosing were equally effective (P > 0.5). Experiment C, erlotinib administered at 42 or 21 mg/kg body weight 1 time per week, decreased tumor incidence and multiplicity (P < 0.01). Erlotinib had a serum half-life of ≤ 8 hours and weekly treatment yielded effective serum levels for ≤ 48 hours. Daily or weekly treatment of cancer bearing rats reduced mammary tumor size 25% to 35%, whereas control cancers increased >250%. Levels of phosphorylated extracellular signal-regulated kinase (ERK) were strongly decreased in rats treated daily/weekly with erlotinib. Thus, altering the dose of erlotinib retained most of its preventive and therapeutic efficacy, and based on prior clinical studies, is likely to reduce its toxicity.
authors.affiliation: National Cancer Institute, Executive Plaza North, Suite 2110, 6130 Executive Boulevard, Bethesda, MD 20852, USA. lubetr@mail.nih.gov
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.forename: Eva
authors.initials: E
authors.lastname: Szabo
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Iwata
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Gill
authors.forename: Chris
authors.initials: C
authors.lastname: Tucker
authors.forename: Ann
authors.initials: A
authors.lastname: Bode
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.forename: M Margaret
authors.initials: MM
authors.lastname: Juliana
authors.forename: Holly L
authors.initials: HL
authors.lastname: Nicastro
authors.forename: Clinton J
authors.initials: CJ
authors.lastname: Grubbs
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D000069347:Erlotinib Hydrochloride; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008770:Methylnitrosourea / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D014018:Tissue Distribution
chemical_list: D000477:Alkylating Agents; D011799:Quinazolines; D008770:Methylnitrosourea; D000069347:Erlotinib Hydrochloride; D048049:Extracellular Signal-Regulated MAP Kinases