pirarubicin and Necrosis

Pirarubicin is a derivative of doxorubicin with improved intracellular uptake and reduced cardiotoxicity. We have prepared a micellar formulation of pirarubicin using styrene-maleic acid copolymer (SMA) of mean molecular weight of 1.2 kDa, which exhibits a mean diameter of 248 nm in solution. Being a macromolecule, SMA-pirarubicin micelles exhibit excellent tumor targeting capacity due to the enhanced permeability and retention (EPR) effect. Here we report the antitumor activity of SMA-pirarubicin micelles on human colon and breast cancer cell lines in vitro, and a murine liver metastasis model in vivo. Metastatic tumor microvasculature, necrosis, apoptosis, proliferation, and survival were also investigated using immunohistochemistry for Ki-67, active caspase-3, and CD34, respectively. Drug cytotoxicity in vitro was assessed using MTT (3-[4,5-dimethyl-2-thiazolyl]-2, 5-diphenyl-2H-tetrazolium bromide) assay. In vivo, SMA-pirarubicin was administered at 100, 150, or 200 mg/kg (pirarubicin equivalent). Tumor microvasculature was also assessed using scanning electron microscopy. Styrene-maleic acid copolymer (SMA)-pirarubicin micelles were toxic against human colorectal and breast cancer cells in vitro. IC(50) was at or below 1 muM, free pirarubicin equivalent. In vivo, SMA-pirarubicin at 100 mg/kg reduced tumor volume by 80% and achieved a survival rate of 93% at 40 days after tumor inoculation. Styrene-maleic acid copolymer (SMA)-pirarubicin micelles demonstrated potent antitumor activity in this liver metastases model, contributing to prolonged survival. Histological examination of tumor nodules showed significant reduction and proliferation of tumor cells (>90%). The present results suggest that investigation of the effect of multiple dosing at later time points to further improve survival is warranted.

Topics: Animals; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Humans; Liver Neoplasms, Experimental; Male; Maleates; Mice; Mice, Inbred CBA; Micelles; Necrosis; Neoplasms, Experimental; Polystyrenes

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

A patient with liver metastasis of pancreatic cancer received chemotherapy using mitomycin C and degradable starch microspheres. The patient was a 52-year-old woman who had undergone surgery for cancer of the head of the pancreas in October 1996. She had stage III disease and was followed up as an outpatient on oral therapy with a combined uracil and tegafur preparation. In October 2000, abdominal computed tomography (CT) scans detected multiple liver metastases. Three courses of intra-arterial infusion of mitomycin C and microspheres (1000 mg) resulted in regression of her tumor and a decrease of tumor marker levels. After three more courses of this therapy, the patient developed bile duct necrosis and died of disseminated intravascular coagulation. As her metastases were controlled for about 7 months, hepatic arterial infusion of mitomycin C and degradable starch microspheres appears to be useful for treating liver metastasis of pancreatic cancer, but careful attention should be paid to the risk of severe complications such as bile duct necrosis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bile Duct Diseases; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Chemotherapy, Adjuvant; Combined Modality Therapy; Doxorubicin; Fatal Outcome; Female; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Middle Aged; Mitomycin; Necrosis; Neoplasm Staging; Pancreatic Neoplasms; Pancreaticoduodenectomy; Risk Assessment; Starch; Tomography, X-Ray Computed