Hypoxia-activated prodrugs in the treatment of advanced pancreatic adenocarcinoma.
Pancreatic cancer is an aggressive malignancy with poor survival and high mortality rate with 250 000 deaths per year worldwide. The unique pancreatic cancer microenvironment serves as a major obstacle in the effective treatment of this malignancy. The microenvironment consists not only of pancreatic ductal adenocarcinoma cells but also comprises cells of pancreatic cancer stellate, vascular, and immune origin combined with a dense extracellular matrix containing collagen. The aforementioned pathology leads to an increased intratumor pressure combined with an erratic vascular proliferation within the tumor causing hypoxia and decreased drug delivery. This has led both scientists and clinicians to develop and study drugs with unique mechanisms of action to target the pancreatic cancer microenvironment. Herein, we discuss the pancreatic cancer hypoxic microenvironment, development of hypoxia-activated prodrugs, and results of trials utilizing those drugs to target pancreatic cancer.
aVirginia G Piper Cancer Center Clinical Trials, HonorHealth Research Institute bDepartment of Internal Medicine, Division of Hematology-Oncology, Mayo Clinic Cancer Center, Scottsdale cClinical Translational Research Division, Translational Genomics Research Institute (TGen), Phoenix dDepartment of Internal Medicine, Division of Hematology Oncology, University of Arizona Cancer Center eDepartment of Internal Medicine, University of Arizona, Tucson, Arizona fDepartment of Molecular Medicine, Centre for Individualized Medicine, Rochester, Minnesota, USA gDepartment of Medicine, Dow University of Health Sciences, Karachi, Pakistan.
Hani M
HM
Babiker
Irbaz B
IB
Riaz
Syed R
SR
Shah
Daniel D
DD
Von Hoff
Mitesh J
MJ
Borad
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism*; D015687:Cell Hypoxia; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011355:Prodrugs / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D011355:Prodrugs