ABSTRACT
Trastuzumab is indicated for the treatment of patients with breast cancer overexpressing human epidermal growth factor 2 (HER2). Women with HER2-positive tumors have an increased risk of brain metastases. The blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier may prevent trastuzumab from reaching appropriate concentrations in the brain and CSF following standard intravenous administration. To evaluate the potential of effects on the central nervous system, a 4-week toxicology study with weekly intrathecal administration of trastuzumab was performed in cynomolgus monkeys at doses of 0, 3, or 15 mg. No trastuzumab-related effects on body weight, clinical signs, neurological function, clinical pathology, or anatomic pathology were noted. The applied doses and CSF concentrations achieved in the current study exceeded those reported in patients after intrathecal administration. The results support future studies for further evaluation of intrathecal application of trastuzumab in patients with brain metastases in HER2-positive breast cancer.
Subject(s)
Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal/toxicity , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/toxicity , Animals , Antibodies, Monoclonal/blood , Antibodies, Monoclonal/cerebrospinal fluid , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/blood , Antineoplastic Agents/cerebrospinal fluid , Body Weight/drug effects , Brain/drug effects , Brain/pathology , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Brain Neoplasms/secondary , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Catheters, Indwelling , Central Nervous System/drug effects , Central Nervous System/physiology , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Infusions, Parenteral , Macaca fascicularis , Male , Neurons/drug effects , Neurons/physiology , Receptor, ErbB-2/biosynthesis , Spine/drug effects , Spine/pathology , TrastuzumabABSTRACT
Tg.AC mice develop epidermal papillomas in response to treatment with dermally applied nongenotoxic and complete carcinogens. The persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a multi-site rodent carcinogen and tumor promoter that induces the formation of papillomas in Tg.AC mice. To examine the dose-response relationship and compare dermal and oral routes of exposure for TCDD-induced skin papillomas, female Tg.AC mice were exposed dermally to average daily doses of 0, 2.1, 7.3, 15, 33, 52, 71, 152, and 326 ng TCDD/kg/day or 0, 75, 321, and 893 ng TCDD/kg body weight by gavage for 26 weeks. The incidence of cutaneous papillomas was increased in a dose-dependent manner, and tumors developed earlier with higher exposure to TCDD regardless of route of administration. Increased incidences of cutaneous squamous cell carcinomas were observed in mice exposed to dermal (> or =52 ng/kg) and oral (893 ng/kg) TCDD. Higher gavage doses than dermal exposure doses were required to induce papillomas and squamous cell carcinomas. Despite a linear correlation between administered dose and terminal skin concentrations, the incidence of tumor formation was lower in the gavage study than in the dermal study with respect to mean terminal skin TCDD concentrations. These studies demonstrate that, although Tg.AC mice are less responsive to TCDD by gavage than by dermal exposure, the induction of skin neoplasms is a response to systemic exposure and not solely a local response at the site of dermal application. Differences in response between the routes of exposure may reflect pharmacokinetic differences in the delivery of TCDD to the skin over the duration of the study.
