Therapeutic efficacy of aldoxorubicin in an intracranial xenograft mouse model of human glioblastoma.

Abstract

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a median survival of 12 to 15 months after diagnosis. Acquired chemoresistance, high systemic toxicity, and low penetration of the blood brain barrier by many anticancer drugs contribute to the failure of anti-GBM therapies. To circumvent some of these obstacles, we tested a novel prodrug approach to evaluate anti-GBM efficacy by utilizing serum albumin-binding doxorubicin (Doxo), aldoxorubicin (Aldoxo), which is less toxic, is released from albumin in an acidic environment and accumulates in tumor tissues. A human GBM cell line that expresses a luciferase reporter (U87-luc) was stereotactically injected into the left striatum of the brain of immunodeficient mice. Following initial tumor growth for 12 days, mice were injected once a week in the tail-vein with Aldoxo [24 mg/kg or 18 mg/kg of doxorubicin equivalents-3/4 maximum tolerated dose (MTD)], Doxo [6 mg/kg (3/4 MTD)], or vehicle. Aldoxo-treated mice demonstrated significantly slower growth of the tumor when compared to vehicle-treated or Doxo-treated mice. Five out of eight Aldoxo-treated mice remained alive more than 60 days with a median survival of 62 days, while the median survival of vehicle- and Doxo-treated mice was only 26 days. Importantly, Aldoxo-treated mice exhibited high levels of Doxo within the tumor tissue, accompanied by low tumor cell proliferation (Ki67) and abundant intratumoral programmed cell death (cleaved caspase-3). Effective accumulation of Aldoxo in brain tumor tissues but not normal brain, its anti-tumor efficacy, and low toxicity, provide a strong rationale for evaluating this novel drug conjugate as a treatment for patients afflicted with GBM.

• Authors: Luis Marrero, Dorota Wyczechowska, Alberto E Musto, Anna Wilk, Himanshu Vashistha, Adriana Zapata, Chelsey Walker, Cruz Velasco-Gonzalez, Christopher Parsons, Scott Wieland, Daniel Levitt, Krzysztof Reiss, Om Prakash
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 16 Issue 10 Pg. 874-82 (Oct 2014) ISSN: 1476-5586 [Electronic] United States
• PMID: 25379024 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Hydrazones
• Doxorubicin
• DOXO-EMCH

Topics

• Administration, Intravenous
• Animals
• Antibiotics, Antineoplastic (pharmacokinetics, pharmacology)
• Apoptosis (drug effects)
• Brain Neoplasms (drug therapy, mortality, pathology)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Doxorubicin (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)
• Female
• Glioblastoma (drug therapy, mortality, pathology)
• Humans
• Hydrazones (pharmacokinetics, pharmacology)
• Maximum Tolerated Dose
• Mice, Nude
• Time Factors
• Treatment Outcome
• Xenograft Model Antitumor Assays