1) For an exponentially-growing, asynchronous population of cells maintained under normal physiological conditions, which of the following statements concerning the effect of X-rays on clonogenic cell survival is INCORRECT? Cell killing is reduced if:
A. the cells are synchronized in S-phase at the time of irradiation
B. the cells are irradiated under hypoxic conditions
C. the cells are irradiated with the dose split into two fractions with a 24 hour interval between fractions rather than an acute exposure to the same total dose
D. the cells had incorporated bromodeoxyuridine into their DNA prior to irradiation
E. cysteine was added to the cellular growth medium before irradiation
2) For irradiation with X-rays, the increased cell survival observed when a given total dose is delivered at a low dose-rate (~1 Gy/hr) versus high dose-rate (~1 Gy/min) is due primarily to:
A. repair of DNA double-strand breaks
B. decreased production of DNA double-strand breaks
C. induction of free radical scavengers
D. activation of cell cycle checkpoints
E. down-regulation of apoptosis
3) Relative to the surviving fraction of cells maintained in a non-cycling state for several hours after irradiation, the decreased cell survival observed in cells forced to re-enter the cell cycle immediately after irradiation is evidence for:
A. rejoining of chromosome breaks
B. sublethal damage recovery
C. cell cycle reassortment
D. translesion DNA synthesis
E. expression of potentially lethal damage
4) Which of the following statements is TRUE concerning the effect on cell survival when a total dose of 5 Gy is delivered at a high (1 Gy/min) versus low (1 Gy/hr) dose rate?
A. The surviving fraction would change the least for a cell line with a radiation survival curve characterized by a low α/β ratio.
B. Treatment of cells during the course of irradiation with an agent capable of inhibiting DNA repair would likely have a greater impact on the surviving fraction for cells irradiated at the high dose rate.
C. More cell killing occurs for irradiation at the high dose rate.
D. A change in the surviving fraction results primarily from repopulation.
E. The total number of ionizations produced decreases.
5) A split dose experiment was performed using exponentially growing cells maintained at 37oC in 95% air/5% CO2, and irradiated with either a single dose of 8 Gy of X-rays or two 4 Gy fractions separated by either 2 hours or 8 hours. The surviving fractions for the three treatments were 0.02, 0.15 and 0.08, respectively. The two processes that best account for these experimental findings are:
A. reassortment and repopulation
B. repair and reassortment
C. reoxygenation and repair
D. repopulation and reassortment
E. repair and reoxygenation
6) Which of the following pairs of radiobiological process and corresponding assay method is CORRECT?
A. Reoxygenation – HIF-1α (HIF1A) phosphorylation by ATM
B. Potentially lethal damage recovery - tritiated thymidine uptake
C. Cell cycle “age response” – paired survival curve method
D. Sublethal damage recovery – split dose experiment
E. Repopulation - mitotic shakeoff procedure
7) Which of the following endpoints would NOT be useful to quantify the response of a tumor to irradiation?
A. lung colony assay
B. increase in number of tumors per animal
C. time to reach a certain size
D. growth delay
E. colony forming ability of cells explanted from the tumor
8) The TCD50 assay:
A. measures radiation-induced tumor growth delay
B. can be conducted using mouse tumors but not human tumor xenografts
C. gives a measure of the number of cells required to produce a tumor in a mouse
D. yields results independent of the immune competence of the host animal
E. measures tumor cure, making it a relevant endpoint for extrapolation to the clinic
9) Which of the following statements is TRUE concerning tumor hypoxia?
A. Hypoxic regions in tumors may be detected using labeled bortezomib.
B. Generally, as tumors increase in size, the hypoxic fraction decreases.
C. Regions of chronic hypoxia may develop in tumors due to the intermittent opening and closing of blood vessels.
D. In the absence of reoxygenation, it is unlikely that all hypoxic cells would be eliminated from a tumor following a typical course of radiotherapy.
E. Acutely hypoxic tumor cells usually exhibit slow reoxygenation while chronically hypoxic tumor cells reoxygenate rapidly.
10) Avastin is a monoclonal antibody that targets:
A. bFGF (FGF2)
B. HIF-1α (HIF1A)
C. VHL protein
D. RAS
E. VEGF (VEGFA)
11) Which of the following statements concerning tumor hypoxia is INCORRECT?
A. Exposure to hypoxia can induce the expression of angiogenesis-promoting genes.
B. Anti-angiogenic therapy can improve tumor oxygenation.
C. Exposure to hypoxia can enhance the metastatic potential of tumor cells.
D. Hypoxia generally inhibits apoptosis in tumor cells.
E. Loss of the apoptotic response may be one reason why hypoxic tumor cells develop a more metastatic phenotype.
12) Many human tumors contain regions of hypoxia and, for some, a high pre-treatment hypoxic fraction is associated with poor treatment outcome. For which one of the following types of tumors has the most extensive evidence been obtained consistent with this observation?
A. colon carcinoma
B. chronic myelogenous leukemia
C. non-small cell lung cancer
D. breast cancer
E. cervical carcinoma
13) Which of the following statements concerning chronically hypoxic cells in tumors is TRUE? Chronically hypoxic cells:
A. can be selectively targeted for killing by administering a bioreductive drug
B. are resistant to hyperthermia
C. are located within 10 μm of capillaries
D. exist in a high pH microenvironment
E. are a consequence of intermittent blood flow
14) Which of the following statements is CORRECT concerning tumor angiogenesis?
A. In the absence of angiogenesis, tumors could not grow beyond a diameter of about 2 cm.
B. For most tumor types, a high microvessel density, a measure of angiogenesis, has been negatively correlated with metastatic spread.
C. Vascular endothelial growth factor is induced under hypoxic conditions.
D. Angiostatin and endostatin are stimulators of angiogenesis.
E. Basic fibroblast growth factor is a negative regulator of angiogenesis.
15) Which of the following genes is NOT transcriptionally-regulated by hypoxia?
A. HSP70 (HSPA4)
B. CHK2 (CHEK2)
C. BRCA1
D. VEGF (VEGFA)
E. RAD51 36
16) The regulation of hypoxia-inducible factor-1α (HIF-1α) (HIF1A) by oxygen concentration is best described by which of the following statements?
A. Under hypoxic conditions, HIF-1α transcription and translation are up-regulated, causing the protein to translocate from the cytosol to the nucleus.
B. Under aerobic conditions, the HIF-1α heme moiety becomes oxygenated. This drives a conformational change in the protein limiting DNA binding and thereby preventing up-regulation of target genes.
C. Under hypoxic conditions, HIF-1α is activated by bioreduction, thereby promoting the up-regulation of target genes.
D. Under hypoxic conditions, the HIF-1α heme moiety becomes deoxygenated. This causes a conformational change in the protein, enhancing DNA binding and thereby promoting up-regulation of target genes.
E. Under aerobic conditions, HIF-1α is hydroxylated by HIF prolyl hydroxylases. This targets the protein for ubiquitination and subsequent proteosomal degradation, thereby preventing the up-regulation of target genes.
17) Which of the following statements best describes the “normalization hypothesis” proposed to explain the survival benefit associated with combining anti-angiogenics with traditional chemotherapy agents?
A. Anti-angiogenic therapy stimulates the formation of leaky blood vessels thereby enhancing access of chemotherapy agents to the tumor parenchyma.
B. Anti-angiogenic therapy transiently reduces pericyte coverage of tumor blood vessels, which would otherwise form a significant mechanical and biochemical barrier to the delivery of chemotherapy to the tumor.
C. Tumor cell-derived, pro-angiogenic factors, render endothelial cells resistant to chemotherapy-induced apoptosis. Anti-angiogenic therapy removes this protection and restores endothelial cell sensitivity to chemotherapy.
D. Anti-angiogenic therapy reduces the secretion of anti-apoptotic factors by vascular endothelial cells that would otherwise render nearby cancer cells relatively resistant to chemotherapeutic agents.
E. Anti-angiogenic therapy transiently restores the normal balance of pro- and anti-angiogenic factors in tumor tissue, causing reductions in tumor vessel leakiness, dilation and tortuosity, and increasing pericyte coverage. These morphological changes are accompanied by functional changes that permit improved penetration of drugs into tumor parenchyma.
18) At a distance of 150 μm into a tumor, one might expect all of the following microenvironmental conditions, EXCEPT:
A. increased hypoxia
B. decreased pH
C. decreased interstitial fluid pressure
D. decreased glucose
E. decrease in functional lymphatics
19) Paclitaxel appears to be effective in radiosensitizing tumors in vivo for all the following reasons, EXCEPT:
A. inducing apoptosis
B. upregulating HIF-1
C. oxygenating radioresistant hypoxic cells
D. arresting cells in the radiosensitive G2/M phase
E. decreasing interstitial fluid pressure
