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Combination of paclitaxel thermal gel depot with temozolomide and radiotherapy significantly prolongs survival in an experimental rodent glioma model

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Abstract

OncoGel™ incorporates paclitaxel, a mitotic inhibitor, into ReGel™, a thermosensitive gel depot system to provide local delivery, enhance efficacy and limit systemic toxicity. In previous studies the alkylating agent temozolomide (TMZ) incorporated into a polymer, pCPP:SA, also for local delivery, and OncoGel were individually shown to increase efficacy in a rat glioma model. We investigated the effects of OncoGel with oral TMZ or locally delivered TMZ polymer, with and without radiotherapy (XRT) in rats with intracranial gliosarcoma. Eighty-nine animals were intracranially implanted with a 9L gliosarcoma tumor and divided into 12 groups that received various combinations of 4 treatment options; OncoGel 6.3 mg/ml (Day 0), 20 Gy XRT (Day 5), 50 % TMZ–pCPP:SA (Day 5), or oral TMZ (50 mg/kg, qd, Days 5–9). Animals were followed for survival for 120 days. Median survival for untreated controls, XRT alone or oral TMZ alone was 15, 19 and 28 days, respectively. OncoGel 6.3 or TMZ polymer alone extended median survival to 33 and 35 days, respectively (p = 0.0005; p < 0.0001, vs. untreated controls) with 50 % living greater than 120 days (LTS) in both groups. Oral TMZ/XRT extended median survival to 36 days (p = 0.0002), with no LTS. The group that received OncoGel and Oral TMZ did not reach median survival with 57 % LTS (p = 0.0002). All other combination groups [OncoGel/XRT], [TMZ polymer/XRT], [OncoGel/TMZ polymer], [OncoGel/TMZ polymer/XRT], and [OncoGel/oral TMZ/XRT] yielded greater than 50 % LTS (p < 0.0001 for each combination as compared to controls), therefore median survival was not reached. OncoGel/TMZ polymer and OncoGel/oral TMZ/XRT had 100 % LTS (p < 0.0001 and p = 0.0001 vs. oral TMZ/XRT, respectively). These results indicate that OncoGel given locally with oral or locally delivered TMZ and/or XRT significantly increased the number of LTS and improved median survival compared to oral TMZ and XRT given alone or in combination in a rodent intracranial gliosarcoma model.

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Funding

This work was supported by the Research Scholar Grant 116293-RSG-08-119-01-CCE from the American Cancer Society.

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Authors and Affiliations

  1. Department of Neurosurgery, Johns Hopkins University School of Medicine, 1550 Orleans Street CRB2 2M41, Baltimore, MD, 21231, USA

    Ananth K. Vellimana, Violette Renard Recinos, Lee Hwang, Khan W. Li, Saint Okonma, Henry Brem & Betty M. Tyler

  2. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Charles G. Eberhart & Henry Brem

  3. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Henry Brem

  4. Radiation Oncology and Molecular Radiation Services, Baltimore, MD, 21231, USA

    Yonggang Zhang

  5. Protherics Salt Lake City Inc., Salt Lake City, UT, USA

    Kirk D. Fowers

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  1. Ananth K. Vellimana
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  2. Violette Renard Recinos
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Correspondence to Betty M. Tyler.

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Vellimana, A.K., Recinos, V.R., Hwang, L. et al. Combination of paclitaxel thermal gel depot with temozolomide and radiotherapy significantly prolongs survival in an experimental rodent glioma model. J Neurooncol 111, 229–236 (2013). https://doi.org/10.1007/s11060-012-1014-1

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  • DOI: https://doi.org/10.1007/s11060-012-1014-1

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