Abstract | PURPOSE: METHODS: The cytotoxicity of voreloxin in vitro was examined by MTT assay in 15 cell lines, including 4 drug-resistant lines. Activation of caspase in cell lines and tumors was evaluated by immunohistochemistry. Anti- tumor activity was assessed in 16 xenograft and 3 syngeneic tumor models in mice. Tumors were allowed to grow to approximately 150 mm(3) prior to treatment with voreloxin or comparator drugs. Activity of the anti- cancer agents was determined by calculating the inhibition rate (IR = [1 - (average tumor weight treated/average tumor weight control)] x 100%) and survival ratio (number surviving mice/number of mice per group at start of study) for each agent and dose and schedule tested. RESULTS: In vitro studies demonstrated voreloxin has broad anti-proliferative activity in 11 tumor cell lines, with IC(50) values ranging from 0.04 to 0.97 muM. Similar activity was observed in vitro in drug-resistant cell lines, including those that overexpress P-glycoprotein and have reduced topoisomerase levels. After a single intravenous dose, voreloxin concentrations in tumor were correlated with induction of the apoptosis marker caspase-3. The optimal dose and schedule was established using a KB nasopharyngeal carcinoma xenograft model. Administration of voreloxin at 20 mg/kg weekly for five doses effectively inhibited tumor growth (86%). Voreloxin demonstrated strong dose-dependent tumor growth inhibition (63-88%) in 10 of 11 solid tumor (breast, ovarian, colon, lung, gastric, and melanoma) xenograft models, 2 hematologic tumor xenograft models, 3 multidrug resistant tumor models and 3 murine syngeneic tumor models (Colon 26, Lewis Lung carcinoma, M5076 Ovarian Sarcoma). CONCLUSIONS: These data demonstrate that voreloxin is a broadly active anti- tumor agent in vitro and in vivo, with potent activity in aggressive and drug-resistant tumor models.
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Authors | Ute Hoch, Jennifer Lynch, Yuji Sato, Shigeki Kashimoto, Fumie Kajikawa, Yasuji Furutani, Jeffrey A Silverman |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 64
Issue 1
Pg. 53-65
(Jun 2009)
ISSN: 1432-0843 [Electronic] Germany |
PMID | 18931998
(Publication Type: Journal Article)
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Chemical References |
- Antineoplastic Agents
- Naphthyridines
- Thiazoles
- Caspase 3
- vosaroxin
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Topics |
- Animals
- Antineoplastic Agents
(administration & dosage, pharmacology)
- Apoptosis
(drug effects)
- Caspase 3
(drug effects, metabolism)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drug Resistance, Neoplasm
- Drug Screening Assays, Antitumor
- Female
- Humans
- Immunohistochemistry
- Inhibitory Concentration 50
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Naphthyridines
(administration & dosage, pharmacology)
- Neoplasms
(drug therapy, pathology)
- Thiazoles
(administration & dosage, pharmacology)
- Xenograft Model Antitumor Assays
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