Journal article
Tumor radiosensitization by monomethyl auristatin E: mechanism of action and targeted delivery
Cancer research (Chicago, Ill.), Vol.75(7), pp.1376-1387
04/01/2015
DOI: 10.1158/0008-5472.CAN-14-1931
PMCID: PMC4458508
PMID: 25681274
Abstract
Intrinsic tumor resistance to radiotherapy limits the efficacy of ionizing radiation (IR). Sensitizing cancer cells specifically to IR would improve tumor control and decrease normal tissue toxicity. The development of tumor-targeting technologies allows for developing potent radiosensitizing drugs. We hypothesized that the anti-tubulin agent monomethyl auristatin E (MMAE), a component of a clinically approved antibody-directed conjugate, could function as a potent radiosensitizer and be selectively delivered to tumors using an activatable cell-penetrating peptide targeting matrix metalloproteinases and RGD-binding integrins (ACPP-cRGD-MMAE). We evaluated the ability of MMAE to radiosensitize both established cancer cells and a low-passage cultured human pancreatic tumor cell line using clonogenic and DNA damage assays. MMAE sensitized colorectal and pancreatic cancer cells to IR in a schedule- and dose-dependent manner, correlating with mitotic arrest. Radiosensitization was evidenced by decreased clonogenic survival and increased DNA double-strand breaks in irradiated cells treated with MMAE. MMAE in combination with IR resulted in increased DNA damage signaling and activation of CHK1. To test a therapeutic strategy of MMAE and IR, PANC-1 or HCT-116 murine tumor xenografts were treated with nontargeted free MMAE or tumor-targeted MMAE (ACPP-cRGD-MMAE). While free MMAE in combination with IR resulted in tumor growth delay, tumor-targeted ACPP-cRGD-MMAE with IR produced a more robust and significantly prolonged tumor regression in xenograft models. Our studies identify MMAE as a potent radiosensitizer. Importantly, MMAE radiosensitization can be localized to tumors by targeted activatable cell-penetrating peptides.
Details
- Title: Subtitle
- Tumor radiosensitization by monomethyl auristatin E: mechanism of action and targeted delivery
- Creators
- Lisa Buckel - Department of Radiation Medicine and Applied SciencesElamprakash N Savariar - Department of PharmacologyJessica L Crisp - Department of PharmacologyKarra A Jones - Department of Pathology Department of SurgeryAngel M Hicks - Department of Radiation Medicine and Applied SciencesDaniel J Scanderbeg - Department of Radiation Medicine and Applied SciencesQuyen T Nguyen - Division of Head and Neck SurgeryJason K Sicklick - Division of Surgical OncologyAndrew M Lowy - Division of Surgical OncologyRoger Y Tsien - Howard Hughes Medical InstituteSunil J Advani - Center for Advanced Radiotherapy Technologies University of California San Diego
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.75(7), pp.1376-1387
- Publisher
- United States
- DOI
- 10.1158/0008-5472.CAN-14-1931
- PMID
- 25681274
- PMCID
- PMC4458508
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Grant note
- 5R01CA158448 / NCI NIH HHS R01 EB014929 / NIBIB NIH HHS Howard Hughes Medical Institute K08 CA168999 / NCI NIH HHS R01 CA155620 / NCI NIH HHS CA155620 / NCI NIH HHS R01 CA158448 / NCI NIH HHS
- Language
- English
- Date published
- 04/01/2015
- Academic Unit
- Pathology
- Record Identifier
- 9984047612402771
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