Preclinical combination therapy of the investigational drug NAMI-A(+) with doxorubicin for mammary cancer.

Abstract

AIM OF THE STUDY:

The tumor metastases targeting ruthenium complex NAMI-A synergistically improves the activity of gemcitabine in combination therapies. High-throughput screening was used to identify other potential drug combinations from a library of FDA approved drugs. Doxorubicin was identified as a hit compound and was therefore evaluated in combination with NAMI-A in vitro and in a preclinical in vivo model.

RESULTS:

High-throughput screening identified eight structurally diverse compounds that synergize with NAMI-A including doxorubicin. The combination index on MCF-7 cells showed synergism as the concentration of NAMI-A increases independent of the doxorubicin concentration. In MCa mammary carcinoma of CBA mice, NAMI-A (35 mg/kg/day i.p. on days 7-12) followed by doxorubicin (10 mg/kg i.p. on day 16), significantly increased the effects of the individual drugs on metastases with 70 % animals resulting free of macroscopically detectable tumor nodules in the lungs at sacrifice. NAMI-A, unlike doxorubicin, cured 60 % of the treated mice but the combination therapy was toxic to the animals.

CONCLUSIONS:

The combined therapy of NAMI-A with doxorubicin synergizes on lung metastasis in a preclinical mouse model. The combination therapy at the maximum tolerated doses of the two drugs is toxic. Hence, this combination is not suitable for clinical studies using maximum tolerated doses.

• Authors: Alberta Bergamo, Tina Riedel, Paul J Dyson, Gianni Sava
• Journal: Investigational new drugs (Invest New Drugs) Vol. 33 Issue 1 Pg. 53-63 (Feb 2015) ISSN: 1573-0646 [Electronic] United States
• PMID: 25338748 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Organometallic Compounds
• Ruthenium Compounds
• imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III)
• Ruthenium
• Doxorubicin
• Dimethyl Sulfoxide

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacokinetics, pharmacology, therapeutic use)
• Cell Survival (drug effects)
• Dimethyl Sulfoxide (administration & dosage, analogs & derivatives, pharmacokinetics)
• Doxorubicin (administration & dosage)
• Humans
• Kidney (metabolism)
• Liver (metabolism)
• Lung (metabolism)
• Lung Neoplasms (drug therapy, secondary)
• MCF-7 Cells
• Mammary Neoplasms, Animal (drug therapy, metabolism, pathology)
• Mice, Inbred CBA
• Organometallic Compounds (administration & dosage, pharmacokinetics)
• Ruthenium (metabolism)
• Ruthenium Compounds