Therapeutic efficacy of aldoxorubicin in an intracranial xenograft mouse model of human glioblastoma.
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.
Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA.
Luis
L
Marrero
Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA.
Dorota
D
Wyczechowska
Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
Alberto E
AE
Musto
Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA.
Anna
A
Wilk
Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA.
Himanshu
H
Vashistha
Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA.
Adriana
A
Zapata
Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA.
Chelsey
C
Walker
School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA.
Cruz
C
Velasco-Gonzalez
Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA.
Christopher
C
Parsons
CytRx Corporation, Los Angeles, CA.
Scott
S
Wieland
CytRx Corporation, Los Angeles, CA.
Daniel
D
Levitt
Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA.
Krzysztof
K
Reiss
Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA.
Om
O
Prakash
D061605:Administration, Intravenous; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D006835:Hydrazones / Q000493:pharmacokinetics / Q000494:pharmacology*; D020714:Maximum Tolerated Dose; D008819:Mice, Nude; D013997:Time Factors; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D006835:Hydrazones; D004317:Doxorubicin; C575867:DOXO-EMCH
Aldoxo, Aldoxorubicin; BBB, Blood-brain barrier; Doxo, Doxorubicin; GBM, Glioblastoma multiforme; HPLC, High-performance liquid chromatography; MTD, Maximum tolerated dose; TMZ, Temozolomide