Biological activity of gemcitabine against canine osteosarcoma cell lines in vitro

McMahon, Melanie B.; Bear, Misty D.; Kulp, Samuel K.; Pennell, Michael L.; London, Cheryl A.

doi:10.2460/ajvr.71.7.799

Cited by 16 publications

(16 citation statements)

References 29 publications

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“…15 In this study, the IC50 for gemcitabine alone ranged from 5.7 to 15.3 μM for all OSA cell lines tested and the combination index indicated strong synergism at 1 μM gemcitabine/100 μM carboplatin. Based on the previous study evaluating the administration of carboplatin/gemcitabine to dogs, the recommended dosage of gemcitabine to be used with carboplatin was 2 mg/kg.…”

mentioning

confidence: 61%

“…28 In our preclinical work, we demonstrated that that addition of gemcitabine to carboplatin resulted in synergistic inhibition of OSA cell viability in vitro and found that growth inhibition was greater in 3/4 canine OSA cell lines when they were treated with carboplatin 4 hours before gemcitabine rather than with gemcitabine 4 hours before carboplatin. 15 …”

Section: Discussionmentioning

confidence: 99%

“…Based on in vitro studies the combination index indicated strong synergism (combination index <0.3) at concentrations equal to 1/100 μM of gemcitabine/carboplatin in all OSA cell lines tested. 15 This was achieved with exposures to gemcitabine and carboplatin of only 2 hours each. Therefore, our goal was to provide at least 2 hours of plasma drug concentration close to 1 μM (0.264 μg/mL).…”

Section: Methodsmentioning

confidence: 99%

“…For example, gemcitabine and carboplatin were found to induce synergistic killing of canine OSA cells in vitro. 15 The combination of gemcitabine and carboplatin demonstrated enhanced cytotoxicity in human nonsmall cell lung cancer lines and human endometrial carcinoma cell lines when coadministered in vitro. 16,17 In human patients with platinum-resistant ovarian cancer receiving carboplatin followed by gemcitabine, a significant reduction in the repair of carboplatin-induced DNA cross-links was observed.…”

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confidence: 99%

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Adjuvant Carboplatin and Gemcitabine Combination Chemotherapy Postamputation in Canine Appendicular Osteosarcoma

McMahon

Mathie

Stingle

et al. 2011

Veterinary Internal Medicne

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Background Appendicular osteosarcoma (OSA), the most common bone tumor in dogs, is typically treated by amputation and adjuvant chemotherapy. Despite numerous efforts, the median survival time (MST) for dogs receiving a platinum compound, doxorubicin, or a combination of these remains at 8–12 months. Evidence from studies in mice suggests that gemcitabine has activity against OSA in vivo. Our preliminary work demonstrated that the addition of low-dosage (10mM) gemcitabine to carboplatin resulted in synergistic inhibition of OSA cell viability in vitro. Objective The purpose of the following study was to determine whether the addition of low-dosage (2 mg/kg) gemcitabine to carboplatin chemotherapy in dogs with OSA after amputation would improve MST over carboplatin monotherapy. Animals Fifty dogs with histologically confirmed appendicular OSA. Methods Dogs were treated prospectively with amputation and up to 4 dosages of carboplatin and gemcitabine in combination every 3 weeks. Results The chemotherapeutic regimen was well tolerated with only 5 episodes of grade 3 or 4 hematologic toxicity. The median disease-free interval (DFI) was 203 days and the MST was 279 for all dogs in this study. The 1- and 2-year survival rates were 29.5 and 11.3%, respectively. Dogs with proximal humeral OSA had a shorter median DFI (P = .04) compared with dogs with OSA in other locations. Conclusions and Clinical Importance These results are comparable to those reported for carboplatin monotherapy indicating that the addition of gemcitabine to carboplatin in dogs with appendicular OSA does not appear to improve outcome.

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confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Adjuvant Carboplatin and Gemcitabine Combination Chemotherapy Postamputation in Canine Appendicular Osteosarcoma

McMahon

Mathie

Stingle

et al. 2011

Veterinary Internal Medicne

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“…All cells were maintained at 37°C in a humidified 5% CO 2 atmosphere. The following additional canine tumor cell lines were used to evaluate response to SINE compounds: C2, mast cell tumor line provided by Dr. George Caughey, UCSF, San Francisco, CA [33]; OSA16, osteosarcoma cell line, provided by Dr. Jaime Modiano, UM, Minneapolis, MN [34]; and 323610-3, malignant melanoma cell line, provided by Dr. Michael Kent, UCD, Davis, CA [35]. All cell lines were cultured in complete RPMI media containing 10% FBS, antibiotic/antimycotic, HEPES, sodium pyruvate, nonessential amino acids and Glutamax (media supplements from Gibco).…”

Section: Methodsmentioning

confidence: 99%

Preclinical Evaluation of the Novel, Orally Bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in Spontaneous Canine Cancer: Results of a Phase I Study

et al. 2014

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BackgroundThe purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE) compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1) against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability.Methods and FindingsCanine tumor cell lines derived from non-Hodgkin lymphoma (NHL), mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2–42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed), mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday) although biologic activity was observed at 1 mg/kg. Clinical benefit (CB) including partial response to therapy (PR, n = 2) and stable disease (SD, n = 7) was observed in 9/14 dogs with NHL with a median time to progression (TTP) for responders of 66 days (range 35–256 days). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35–354 days). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities.ConclusionsThis study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer.

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The Histone Deacetylase Inhibitor Entinostat/Syndax 275 in Osteosarcoma

Kiany

Harrison

Gordon

2020

Advances in Experimental Medicine and Biology

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Biological activity of gemcitabine against canine osteosarcoma cell lines in vitro

Cited by 16 publications

References 29 publications

Adjuvant Carboplatin and Gemcitabine Combination Chemotherapy Postamputation in Canine Appendicular Osteosarcoma

Adjuvant Carboplatin and Gemcitabine Combination Chemotherapy Postamputation in Canine Appendicular Osteosarcoma

Preclinical Evaluation of the Novel, Orally Bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in Spontaneous Canine Cancer: Results of a Phase I Study

The Histone Deacetylase Inhibitor Entinostat/Syndax 275 in Osteosarcoma

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