Effects of erlotinib on lung injury induced by intratracheal administration of bleomycin (BLM) in rats.

Interstitial lung disease has been reported in cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors, erlotinib and gefitinib. Preclinical safety studies with erlotinib did not show any evidence for an induction of injury on intact lungs in rats and dogs. In the present study, we investigated the effects of erlotinib on lung injury induced by intratracheal administration of bleomycin (BLM) in rats. In Experiment 1, we examined the effects of short-term (7- and 21-day) administration of erlotinib (10 mg/kg/day, p.o.; subtoxic dose) on the BLM (0.1 or 0.6 mg/rat)-induced lung injury of slight and moderate severity. In Experiment 2, we examined the effects of long term (up to 63-day) administration of higher-dose (up to 20 mg/kg/day; toxic dose; accompanied with decreased body weight gain and severe skin lesions) erlotinib on the BLM-induced lung injury. In rats receiving erlotinib alone, no lung lesions were noted. In rats receiving BLM alone, diffuse alveolar damage (DAD) and, subsequently, pulmonary fibrosis of slight or moderate severity was observed. The administration of erlotinib to BLM-treated rats showed no exacerbation of lung injuries in indices such as macroscopic findings, lung weights, histopathological scores (lung lesion density and lung fibrosis score), and pulmonary hydroxyproline (HyP) level. These results suggest that erlotinib does not have any exacerbating effects on lung injuries induced by BLM in rats.

Collaborative work on evaluation of ovarian toxicity. 10) Two- or four-week repeated dose studies and fertility study of di-(2-ethylhexyl) phthalate (DEHP) in female rats.

The main purpose of this collaborative work is to determine the optimal administration period required to detect toxic effects in evaluation of ovarian morphological changes in repeated-dose toxicity studies. To assess the morphological and functional changes induced in the ovaries by di-(2-ethylhexyl) phthalate (DEHP), two repeated-dose toxicity studies (repeated dose for 2 or 4 weeks) of DEHP administrated to female rats at dose levels of 0, 300, 1,000 and 3,000 mg/kg were conducted in collaboration with a female fertility study at the same dosages from 2 weeks prior to mating to Day 7 of pregnancy. Histopathology of the ovaries in both repeated-dose toxicity studies showed vacuolation of stromal cells in the groups receiving 300 mg/kg or more and an increase of large atretic follicles in groups at 1,000 mg/kg or more. In the 4-week study, a decrease in new corpora lutea was observed in the 3,000 mg/kg group. In the female fertility study, the 3,000 mg/kg group showed prolongation of the mean estrous cycle and irregular estrous cycles. Cesarean section revealed a decrease of pregnancy rate in the 3,000 mg/kg group. No effects on fertility or early embryonic development were found in groups at 1,000 mg/kg or less. These findings indicate that histopathological changes in the ovary are important endpoints for the evaluation of drugs which induce ovarian damage. In conclusion, for a repeated-dose toxicity study, a 2-week administration period is sufficient to detect ovarian toxicity caused by DEHP.

IL-6R distribution in normal human and cynomolgus monkey tissues.

Interleukin-6 (IL-6) is a pleiotropic cytokine and a contributing factor in many diseases such as rheumatoid arthritis, Castleman's disease, Crohn's disease, and multiple myeloma. Since the blockade of the signaling pathway of the IL-6/interleukin-6 receptor (IL-6R)/gp130 complex is considered to have therapeutic value in such diseases, we developed an IL-6R humanized antibody (tocilizumab). In the current report, distribution of IL-6R in both normal human and cynomolgus monkey tissues was assessed as fundamental data to support preclinical and clinical studies of tocilizumab. Human and cynomolgus monkey tissue panels were stained with commercially available anti-human IL-6R and a species- and isotype-matched negative antibody, as well as assay control slides. The detection system applied used an Envision immunoperoxidase staining procedure with DAB reaction. Positive reactions were observed in the tissue elements of lymphatic, hematopoietic, digestive, reproductive, exocrine, endocrine, neural, muscular, epidermal, respiratory, and urinary systems of the human and cynomolgus monkey tissue panels. The current report is inclusive of a wide variety of tissues and shows the distribution of IL-6R to be similar for both human and monkey tissues. We consider this information fundamental for the support and interpretation of preclinical and clinical studies of anti-IL-6R antibody therapy.