maleic-acid and Necrosis

Doxorubicin is a commonly used chemotherapy limited by cardiotoxicity. Pirarubicin, derived from doxorubicin, selectively targets tumors when encapsulated in styrene maleic acid (SMA), forming the macromolecular SMA pirarubicin. Selective targeting is achieved because of the enhanced permeability and retention (EPR) effect. SMA-pirarubicin inhibits the growth of colorectal liver metastases, but tumor destruction is incomplete. The role played by the tumor microcirculation is uncertain. This study investigates the pattern of microcirculatory changes following SMA-pirarubicin treatment.. Liver metastases were induced in CBA mice using a murine-derived colon cancer line. SMA-pirarubicin (100 mg/kg total dose) was administered intravenously in 3 separate doses. Twenty-four hours after chemotherapy, the tumor microvasculature was examined using CD34 immunohistochemistry and scanning electron microscopy. Tumor perfusion and permeability were assessed using confocal in vivo microscopy and the Evans blue method.. SMA-pirarubicin reduced the microvascular index by 40%. Vascular occlusion and necrosis were extensive following treatment. Viable cells were arranged around tumor vessels. Tumor permeability was also increased.. SMA-pirarubicin damages tumor cells and the tumor microvasculature and enhances tumor vessel permeability. However, tumor necrosis is incomplete, and the growth of residual cells is sustained by a microvascular network. Combined therapy with a vascular targeting agent may affect residual cells, allowing more extensive destruction of tumors.

Topics: Animals; Antigens, CD34; Antineoplastic Agents; Colorectal Neoplasms; Doxorubicin; Drug Delivery Systems; Immunohistochemistry; Liver Neoplasms, Experimental; Male; Maleates; Mice; Mice, Inbred CBA; Microcirculation; Microscopy, Confocal; Necrosis; Permeability; Styrene

Administration of maleic acid to the rat is used as an experimental model of Fanconi's syndrome. To determine the site and extent of morphologic injury within the kidney after maleic acid administration, we systematically examined renal tissue using light, transmission electron, and scanning electron microscopy. Tissue was studied either immediately or 24 hours after rats received maleic acid, 200 mg. or 400 mg. per kg. of body weight, and was compared with tissue from controls. In kidneys of maleic acid-treated rats, evidence of injury was observed only in cells of the late pars convoluta and the pars recta in the medullary rays of the cortex and in the outer stripe of the medulla. Injured cells were characterized by an increase in cytoplasmic density, accumulation of numerous small vesicles in the apical region of the cells, abnormal-appearing mitochondria with compressed cristal membranes and flocculent densities, and focal loss of microvilli. Injury was apparent immediately after maleic acid administration and progressed to extensive necrosis by 24 hours after either the 200- or 400-mg. per kg. dose. Except for the presence of granular and hyaline casts in the lumena, the loops of Henle and distal convoluted tubules were normal. Collecting ducts in the outer medulla, but not in the cortex, medullary rays, or inner medulla, had significantly increased numbers of dark cells per total cell population when compared with controls (p less than 0.005). This increase in dark cells may represent an adaptive response of the medullary collecting duct to the functional abnormalities of maleic acid-induced Fanconi's syndrome. Collecting ducts showed no evidence of cell injury or necrosis. These observations provide evidence that maleic acid, like many other renal toxins, produces tubular injury and necrosis only in the proximal tubules, primarily in the medullary rays, and outer stripe of the medulla, and not in the distal tubules.

Topics: Animals; Disease Models, Animal; Fanconi Syndrome; Kidney Tubules, Proximal; Male; Maleates; Microscopy, Electron; Microscopy, Electron, Scanning; Necrosis; Rats; Rats, Inbred Strains