Hall Book Ch 26 (The Biology and Exploitation of Tumor Hypoxia) Flashcards
What is hypoxia-inducible factors (HIFs)?
Transcription factors that facilitate both oxygen delivery and adaptation to oxygen deprivation by regulating the expression of genes that are involved in many cellular processes includ9ing glucose uptake and metabolism, angiogenesis, erythropoiesis, cell proliferation and apoptosis.
HIFs binds to DNA as
heterodimers composed of an oxygen-sensitive alpha-subunit known as the aryl hydrocarbon receptor nuclear translocator (ARNT).
Hypoxia-Inducible Factor
At both the molecular and cellular levels, in physiologic and pathologic settings, oxygen homeostasis is controlled primarily through the function of a ( ).
The HIF-α subunits are oxygen regulated through ( ), binding to ( ) and degradation in the ( ).
heterodimeric transcription factor, the HIF-1
hydroxylation
VHL (von Hippel-Lindau) tumor suppressor
proteasome
Loss of certain tumor suppressor genes such as ( ) can cause HIF to become active under ( ) conditions.
VHL and PTEN, normoxic
HIF plays various critical roles in tumors, regulating ( ).
HIF can also influence the response of tumors to radiotherapy by increasing the resistance of the vasculature through the increased expression of ( ) factors and by promoting vasculogenesis through the ( ).
metabolism, angiogenesis, and metastasis
proangiogenic
recruitment of BM-derived cells
Overall, HIF-1 stabilization promotes ( ) and HIF-1 deficient tumors are more sensitive to radiation compared to wild-type tumors.
radioresistance
The UPR (Unfold Protein Response) responds to an accumulation of misfolded proteins by stopping protein translation through the activation of ( ) and chaperone proteins that function in the ER to assist in folding, trafficking, and secretion of proteins.
Inhibition of ( ) activities result in decreased tumor growth.
PERK and through the induction of XBP-1
PERK (Protein Kinase-like Endoplasmic Reticulum Kinase) or XBP-1 (X-box binding protein 1)
Prolonged periods of hypoxia can activate non-HIF signaling pathway such as the (
).
unfolded protein response (UPR)
Radiosensitizing Hypoxic Cells
Hypoxic cell radiosensitizers increase the radiosensitivity of hypoxic cells but not ( ) cells. The differential effect on tumors is based on the presence of ( ) in tumors but not in normal tissues.
aerated, hypoxic cells
Sensitization is a ( ) process. The sensitizer mimics ( ) by “fixing” damage produced by free radicals.
free radical, oxygen
( ), the first compound used widely, sensitizes cells in culture as well as in both animal and human tumors.
Misonidazole
Doses of misonidazole that can be used clinically are limited to suboptimal levels by (
). Only 1 of 30 or so clinical trials showed an advantage for misonidazole.
peripheral neuropathy
( ) is less toxic than misonidazole, and 3 times larger doses are tolerated. However, clinical trials in Europe and the United States showed ( ) advantage of combined radiotherapy and etanidazole over radiotherapy alone.
Etanidazole, no
( ) is less active as a radiosensitizer but so much less toxic than either
( ) that much larger doses can be given.
Nimorazole, misonidazole or etanidazole
A benefit was shown for adding ( ) to conventional radiotherapy for head and neck cancer (Danish head and neck cancer trial).
nimorazole
