Enhanced antitumor efficacy of clinical-grade vasculature-targeted liposomal doxorubicin.

Abstract

PURPOSE:

In vivo evaluation of good manufacturing practice-grade targeted liposomal doxorubicin (TVT-DOX), bound to a CD13 isoform expressed on the vasculature of solid tumors, in human tumor xenografts of neuroblastoma, ovarian cancer, and lung cancer.

EXPERIMENTAL DESIGN:

Mice were implanted with lung, ovarian, or neuroblastoma tumor cells via the pulmonary, peritoneal, or orthotopic (adrenal gland) routes, respectively, and treated, at different days post inoculation, with multiple doses of doxorubicin, administered either free or encapsulated in untargeted liposomes (Caelyx) or in TVT-DOX. The effect of TVT-DOX treatment on tumor cell proliferation, viability, apoptosis, and angiogenesis was studied by immunohistochemical analyses of neoplastic tissues and using the chick embryo chorioallantoic membrane assay.

RESULTS:

Compared with the three control groups (no doxorubicin, free doxorubicin, or Caelyx), statistically significant improvements in survival was seen in all three animal models following treatment with 5 mg/kg (maximum tolerated dose) of TVT-DOX, with long-term survivors occurring in the neuroblastoma group; increased survival was also seen at a dose of 1.7 mg/kg in mice bearing neuroblastoma or ovarian cancer. Minimal residual disease after surgical removal of neuroblastoma primary mass, and the enhanced response to TVT-DOX, was visualized and quantified by bioluminescence imaging and with magnetic resonance imaging. When treated with TVT-DOX, compared with Caelyx, all three tumor models, as assayed by immunohistochemistry and chorioallantoic membrane, showed statistically significant reductions in cell proliferation, blood vessel density, and microvessel area, showing increased cell apoptosis.

CONCLUSION:

TVT-DOX should be evaluated as a novel angiostatic strategy for adjuvant therapy of solid tumors.

• Authors: Fabio Pastorino, Daniela Di Paolo, Federica Piccardi, Beatrice Nico, Domenico Ribatti, Antonio Daga, Gabriella Baio, Carlo E Neumaier, Chiara Brignole, Monica Loi, Danilo Marimpietri, Gabriella Pagnan, Michele Cilli, Eugene A Lepekhin, Seema V Garde, Renato Longhi, Angelo Corti, Theresa M Allen, Jinzi J Wu, Mirco Ponzoni
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 22 Pg. 7320-9 (Nov 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 19010847 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Liposomes
• Doxorubicin
• CD13 Antigens

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage)
• CD13 Antigens (metabolism)
• Cell Line, Tumor
• Doxorubicin (administration & dosage)
• Drug Delivery Systems
• Female
• Humans
• Immunohistochemistry
• Liposomes
• Mice
• Mice, Nude
• Neoplasms, Experimental (drug therapy)
• Neovascularization, Pathologic (drug therapy)
• Xenograft Model Antitumor Assays