title: Tumor radiosensitization by monomethyl auristatin E: mechanism of action and targeted delivery.
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.
authors: Department of Radiation Medicine and Applied Sciences.
authors: Lisa
authors: L
authors: Buckel
authors: Department of Pharmacology.
authors: Elamprakash N
authors: EN
authors: Savariar
authors: Department of Pharmacology.
authors: Jessica L
authors: JL
authors: Crisp
authors: Department of Pathology Department of Surgery.
authors: Karra A
authors: KA
authors: Jones
authors: Department of Radiation Medicine and Applied Sciences.
authors: Angel M
authors: AM
authors: Hicks
authors: Department of Radiation Medicine and Applied Sciences.
authors: Daniel J
authors: DJ
authors: Scanderbeg
authors: Division of Head and Neck Surgery.
authors: Quyen T
authors: QT
authors: Nguyen
authors: Division of Surgical Oncology.
authors: Jason K
authors: JK
authors: Sicklick
authors: Division of Surgical Oncology.
authors: Andrew M
authors: AM
authors: Lowy
authors: Department of Pharmacology.|Howard Hughes Medical Institute.
authors: Roger Y
authors: RY
authors: Tsien
authors: Department of Radiation Medicine and Applied Sciences.|Center for Advanced Radiotherapy Technologies University of California San Diego.
authors: Sunil J
authors: SJ
authors: Advani
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage; D059248:Chemoradiotherapy; D015179:Colorectal Neoplasms / Q000473:pathology / Q000628:therapy; D053903:DNA Breaks, Double-Stranded; D016503:Drug Delivery Systems; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D009842:Oligopeptides; D011838:Radiation-Sensitizing Agents; C495575:monomethyl auristatin E