Journal article
Preclinical Evaluation of Promitil, a Radiation-Responsive Liposomal Formulation of Mitomycin C Prodrug, in Chemoradiotherapy
International journal of radiation oncology, biology, physics, Vol.96(3), pp.547-555
11/01/2016
DOI: 10.1016/j.ijrobp.2016.06.2457
PMID: 27681751
Abstract
To examine the effect of radiation on in vitro drug activation and release of Promitil, a pegylated liposomal formulation of a mitomycin C (MMC) lipid-based prodrug; and examine the efficacy and toxicity of Promitil with concurrent radiation in colorectal cancer models.
Promitil was obtained from Lipomedix Pharmaceuticals (Jerusalem, Israel). We tested the effects of radiation on release of active MMC from Promitil in vitro. We next examined the radiosensitization effect of Promitil in vitro. We further evaluated the toxicity of a single injection of free MMC or Promitil when combined with radiation by assessing the effects on blood counts and in-field skin and hair toxicity. Finally, we compared the efficacy of MMC and Promitil in chemoradiotherapy using mouse xenograft models.
Mitomycin C was activated and released from Promitil in a controlled-release profile, and the rate of release was significantly increased in medium from previously irradiated cells. Both Promitil and MMC potently radiosensitized HT-29 cells in vitro. Toxicity of MMC (8.4 mg/kg) was substantially greater than with equivalent doses of Promitil (30 mg/kg). Mice treated with human-equivalent doses of MMC (3.3 mg/kg) experienced comparable levels of toxicity as Promitil-treated mice at 30 mg/kg. Promitil improved the antitumor efficacy of 5-fluorouracil-based chemoradiotherapy in mouse xenograft models of colorectal cancer, while equitoxic doses of MMC did not.
We demonstrated that Promitil is an attractive agent for chemoradiotherapy because it demonstrates a radiation-triggered release of active drug. We further demonstrated that Promitil is a well-tolerated and potent radiosensitizer at doses not achievable with free MMC. These results support clinical investigations using Promitil in chemoradiotherapy.
Details
- Title: Subtitle
- Preclinical Evaluation of Promitil, a Radiation-Responsive Liposomal Formulation of Mitomycin C Prodrug, in Chemoradiotherapy
- Creators
- Xi Tian - University of North Carolina at Chapel HillSamuel B Warner - University of North Carolina at Chapel HillKyle T Wagner - University of North Carolina at Chapel HillJoseph M Caster - University of North Carolina at Chapel HillTian Zhang - Duke Medical CenterPatricia Ohana - Lipomedix Pharmaceuticals, Jerusalem, Israel.Alberto A Gabizon - Shaare Zedek Medical CenterAndrew Z Wang - University of North Carolina at Chapel Hill
- Resource Type
- Journal article
- Publication Details
- International journal of radiation oncology, biology, physics, Vol.96(3), pp.547-555
- DOI
- 10.1016/j.ijrobp.2016.06.2457
- PMID
- 27681751
- ISSN
- 0360-3016
- eISSN
- 1879-355X
- Grant note
- U54 CA198999 / NCI NIH HHS R21 CA182322 / NCI NIH HHS U54 CA151652 / NCI NIH HHS R01 CA178748 / NCI NIH HHS
- Language
- English
- Date published
- 11/01/2016
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984312975502771
Metrics
15 Record Views