Hepatotoxicity with antibody maytansinoid conjugates: A review of preclinical and clinical findings.

Maytansinoids, the potent cytotoxic derivatives of the alkaloid maytansine are used as payloads in antibody maytansinoid conjugates. This article reviews clinical and preclinical hepatotoxicity observed with antibody maytansinoid conjugates used to treat cancer. Specific aspects of drug distribution, metabolism and excretion that may impact hepatotoxicity are reviewed vis-à-vis the kind of maytansinoid in the conjugate, cleavable or non-cleavable linkers, linker-payload combinations, drug to antibody ratio, metabolite formation, hepatic enzyme induction in relation to drug-drug interactions and species, age and gender differences. The article also sheds light on factors that may protect the liver from toxic insults.

Lens Capsule Perforation Without Inflammation in 4 Rabbits From Intravitreal Injection Studies.

Historically, it was thought that lens protein was sequestered, and injury to the lens capsule causing release of lens material into the eye would always result in ocular inflammation. Currently, it is believed that lens antigens are recognized as self, subject to normal T-cell tolerance. Three different single-dose intravitreal injection/implantation studies of 4 different test materials, ranging from 4 to 6 weeks in length, were performed in New Zealand White rabbits. The test materials included polymer microspheres, polymer rods, a solvent, and a hydrogel. Intravitreal injection/implantation procedures were performed on day 1, and indirect ophthalmoscopy and slit-lamp biomicroscopy examinations were performed by board-certified veterinary ophthalmologists periodically throughout the course of each study. None of the affected animals received corticosteroids or other immunomodulatory agents during the course of the studies. Four rabbits had perforation of the posterior lens capsule during the injection/implantation procedure on day 1, visible on clinical ophthalmic examination as lens capsule alterations described as "lens hits" and/or incipient posterior cataracts. Findings on slit-lamp biomicroscopy examination were limited to vitreous cells in 2 of the animals, although not centered on the area of lens capsule disturbance. Histologically, there was no evidence of inflammation in association with extruded lens protein material in any of the affected eyes. These results indicate that iatrogenic damage to the lens capsule during aseptically performed intravitreal injections/implantations does not appear to induce inflammation in rabbits.

Carboplatin chemotherapy in a cat with a recurrent anal sac apocrine gland adenocarcinoma.

An 8-year-old, castrated male, domestic shorthaired cat was presented for evaluation of a perianal mass. The mass was incompletely excised, and histological assessment resulted in a diagnosis of anal sac adenocarcinoma. The cat had a partial response to carboplatin therapy but a short overall duration of response. Necropsy confirmed the original diagnosis as well as metastasis to the regional lymph nodes and lungs.

What is your diagnosis? Lingual mass in a dog.

A 3.5-year-old female spayed Rat Terrier was presented for evaluation of a submucosal lingual mass. Fine-needle aspiration of the mass revealed a population of neoplastic cells composed predominantly of small, round cells and large, round to spindle-shaped cells, which occasionally had blunt cytoplasmic borders and multiple nuclei. The neoplastic cells had moderate to marked anisocytosis and anisokaryosis. The cytologic interpretation was malignant neoplasia, most likely sarcoma. Histopathologic examination of a biopsy specimen revealed an unencapsulated, poorly demarcated, moderately cellular neoplasm composed of individualized, infiltrative spindle cells. Elongate skeletal muscle cells with prominent, rectangular borders (strap cells) were observed. A morphologic diagnosis of rhabdomyosarcoma was made. Staining with phosphotungstic acid-hematoxylin revealed haphazardly arranged skeletal muscle cross-striations. Immunohistochemical staining results for vimentin, Myo D1, desmin, and myoglobin were positive, though staining intensity of tumor cells varied with the degree of differentiation. Using transmission electron microscopy, irregular, disorganized Z-bands were identified. Rhabdomyosarcomas are uncommon tumors in the dog, and rarely may involve the tongue or oral cavity. Cytologic evaluation of a rhabdomyosarcoma may reveal a pleomorphic population of cells and definitive diagnosis may require histologic examination, immunohistochemical staining, and electron microscopy.

Dystrophin-deficient muscular dystrophy in a Weimaraner.

A 2-year-old, male Weimaraner with muscular dystrophy was presented with generalized muscle atrophy of the limbs; hypertrophy of the neck, infraspinatus, and lingual muscles; dysphagia; and regurgitation. Unilateral cryptorchidism, unilateral renal agenesis, and hiatal hernia were also detected. Spontaneous muscle activity was identified on myography. Serum creatine kinase was markedly elevated. Immunohistochemical staining for dystrophin was restricted to suspected revertant (characteristics of immaturity) fibers. Histologically, skeletal myofiber degeneration, endomysial fibrosis, and mineralization were present. Following euthanasia, necropsy revealed hypertrophy of the diaphragm and cardiac muscle fibrosis. This case of muscular dystrophy represents a slowly progressive form with organ agenesis.

Lead-induced cell signaling cascades in GT1-7 cells.

The effects of lead on the signal transduction pathways that may be involved in the release of gonadotropin-releasing hormone (GnRH) from neurons in the hypothalamus have not been well defined. Using the GT1-7 cell line, an in vitro model for GnRH-secreting neurons, we examined signal transduction pathways directly affected by lead. We found that lead-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2), as well as p90RSK and cAMP response element-binding protein (CREB), but did not induce IkappaB degradation. MEK1/2 inhibitor (PD98059) suppressed lead-induced ERK and p90RSK activation. Neither PKC inhibitors (Go6983, Go6976) nor CaMKII inhibitor (KN-62) had a pronounced effect on lead-induced ERK1 and ERK2 phosphorylation. However, MEK1/2 inhibitor, CaMKII inhibitor, and PKC inhibitor significantly suppressed lead-induced CREB phosphorylation. These results indicate that lead-activated PKC, CaMKII and MEK/ERK/p90RSK pathways simultaneously, all of which contributed to CREB phosphorylation. Our results also indicate that lead-induced p90RSK and CREB activation does not alter expression of early response genes like c-fos. We conclude that lead activates PKC, CaMKII or MEK-ERK-p90RSK pathways in GT1-7 cells, leading to CREB phosphorylation and modulation of gene expression.