Hypoxia-Activated Prodrugs in Cancer Therapy: Progress to the Clinic

Abstract

The hypoxic cells common in solid tumors (because of their inefficient blood supply) limit the effectiveness of radiotherapy and many cytotoxic drugs. Nontoxic prodrugs that generate active species in hypoxic tissue by selective bioreduction have long been explored, and the first examples, representing a variety of different chemistries, have now reached advanced clinical trials. In the process, a great deal has been learnt about the properties that such drugs require to be successful, notably, efficient extravascular diffusion, appropriate reduction chemistry and kinetics, and an effective biological profile of the activated species, including a good bystander effect. The critical importance of prodrug diffusion and techniques to quantify this have assisted the development of models to predict the killing of tumor cells, which promises to help accelerate new drug evaluation. A cell cycle-independent mechanism of killing by the released cytotoxin is also a potential advantage, although it is likely that much of the killing will be when out-of-cycle hypoxic cells reoxygenate and resume division.

Dual-effect laser handpiece for modification of tissue permeability

“…The dermal diffusion rate for MMC bound to albumin would be much lower than free MMC, due to its combined molecular size. 35 However, the calculations of steady state depths of penetration of MMC in dermis performed here, ignoring binding with albumin, are consistent with the experimental results from bladder studies. MMC rapidly washes out of the bladder wall after instillation in the bladder, 7 contrary to what may be expected if much of the drug is bound to albumin within tissue.…”

Role of the Hypoxia-inducible factor-1 alpha induced autophagy in the conversion of non-stem pancreatic cancer cells into CD133+ pancreatic cancer stem-like cells

“…Cancer stem cells are believed to rely on their special microenvironments termed niches to sustain the population. These niches (vascular proliferations, hypoxia/necrosis) represent the hallmarks of malignant tumors [21,22]. Pancreatic cancer is characterized by intratumoral hypovascularity.…”

Prodrugs—from Serendipity to Rational Design

“…Hypoxia, the deficiency of oxygen as a result of an insufficient vasculature, imposes an environmental stress on the cells, which contributes to tumor progression, invasion, and metastasis. Moreover, a low oxygen content increases the resistance to radiotherapy and chemotherapy (Denny, 2010). However, the hypoxic state of solid tumors can be turned to a therapeutic advantage by designing cytotoxic prodrugs, which are bioactivated to their active species selectively in the hypoxic environment of solid tumors by endogenous reductive enzymes.…”