ABSTRACT
Anthracycline anti-cancer drugs have been widely used in the treatment of several cancers; however, their use is limited by adverse effects (AEs). Alopecia is a common AE that is minimally invasive, but adversely affects mental health and reduces quality of life (QoL). Hand-foot syndrome (HFS) is a dose-limiting AE of DOXIL, a liposomal formulation of doxorubicin (DOX). Although it is not a life-threatening condition, HFS affects function and reduces QoL. TXB-001 is a new candidate polymer-conjugated anthracycline anti-cancer drug, and modified and optimized polymerized pirarubicin (THP), known as P-THP, is expected to have low toxicity and high efficacy. The anti-cancer effects of TXB-001 were examined using the 4T1 mouse model. An alopecia mouse model and HFS rat model were used to evaluate the alopecia- and HFS-inducing effects of TXB-001 and compare their severity with existing anthracycline anti-cancer drugs. A pharmacokinetic analysis of plasma as well as chest, palmar, and plantar skin samples after the single intravenous administration of DOXIL and TXB-001 to rats was also performed. The results obtained revealed that TXB-001 exerted similar anti-cancer effects to those of DOXIL in mice, weaker alopecia-inducing effects than DOX, DOXIL, and THP in mice, and no or markedly weaker HFS-like changes than DOXIL, which induced significant histopathological changes. The results of the pharmacokinetic analysis showed the accumulation of DOXIL, but not TXB-001, in skin, particularly palmar and plantar skin samples, and these differences were considered to contribute to their HFS-inducing effects.
Subject(s)
Alopecia , Disease Models, Animal , Doxorubicin , Doxorubicin/analogs & derivatives , Hand-Foot Syndrome , Mice, Inbred BALB C , Animals , Alopecia/chemically induced , Alopecia/drug therapy , Hand-Foot Syndrome/etiology , Hand-Foot Syndrome/drug therapy , Doxorubicin/toxicity , Female , Mice , Rats , Polymers/chemistry , Polymers/toxicity , Antibiotics, Antineoplastic/toxicity , Rats, Sprague-Dawley , Anthracyclines/toxicity , Anthracyclines/adverse effects , Cell Line, Tumor , Male , Antineoplastic Agents/toxicity , Polyethylene GlycolsABSTRACT
Spontaneous nonneoplastic proliferative lesions of the cardiac hemangioendothelium are extremely rare in humans and animals. Here, we describe a spontaneous hemangioendothelial cell hyperplasia in the heart of a 9-week-old male ICR mouse. The lesion was observed focally in the interventricular septum, with no compression of the surrounding tissues. In the lesion, a single layer of hemangioendothelial cells that had a polygonal shape with enlarged nuclei and plump cytoplasm closely lined surrounding widened capillary vascular spaces and cardiac muscles. There was little cellular atypia, and there were no multilayered endothelial cells. Immunohistochemical staining revealed that these cells were partly positive for factor VIII and CD31, hemangioendothelial cell markers, and negative for Ki-67. These features were consistent with those in aged female B6C3F1 mice in the only report in mice of spontaneous cardiac hemangioendothelial cell hyperplasia. Therefore, this is the first report of spontaneous hemangioendothelial cell hyperplasia in the heart of a young mouse.
ABSTRACT
Experimental autoimmune neuritis (EAN) is an animal model for Guillain-Barré syndrome (GBS), which results in neurological symptoms and histopathological changes in peripheral nerves. In this model, the correlation between the progression of the disease and the histopathological changes is not clear. To further examine histopathological changes in peripheral nerves in EAN rats, sciatic nerves were sampled at onset (day 10), peak (day 16), and recovery (days 22 and 25) of neurological symptoms in P2(57-81)-peptide-administered rats. Axon and myelin degeneration was observed by light microscopy at onset, degeneration became severe at peak, and persisted at recovery. Densities of myelinated nerve fibers and myelin areas decreased from day 10 to a minimum on day 22. Slight axon and myelin degeneration, such as accumulation of vesicles in axons and focal myelin splitting and folding, was observed by transmission electron microscopy at onset; severe degeneration, such as axonal loss, myelin ovoid, and demyelination, increased at peak; and regenerative changes, such as remyelination and enlargement of Schwann cell cytoplasm, occurred at recovery. These results suggest that EAN rats have histopathological similarities to some types of GBS patients and that EAN rats are a useful model to understand the pathogenesis of GBS.
