Fig 1.
Oxidative stress in cancer cells under cycling hypoxic conditions.
Oxidative stress is a state of redox imbalance caused by the increased production of reactive oxygen species (ROS), which are mostly generated by the leakage of excessive levels of electrons relative to O2 in impaired mitochondrial respiratory chains. ROS damage proteins and DNA/RNA and also act as signaling molecules to drive cancer cell motility/invasion and tumor progression. ROS (superoxide anion: O2-, hydrogen radical: HO., hydrogen peroxide: H2O2)
Fig 2.
Cu(II)-ATSM and fluorinated nitroimidazole (FR-NO2) retention mechanisms in cancer cells.
During the course of tracer retention in cancer cells, key factors are shown in red for both Cu(II)-ATSM and fluorinated nitroimidazole (FR-NO2). Cu(II)-ATSM is a neutral lipophilic molecule that easily penetrates cell membranes. In cancer cells over-reduced due to mitochondrial dysfunction and hypoxia, Cu(II)-ATSM may be converted to [Cu(I)-ATSM]- with electrons (e-) supplied from abnormally reduced mitochondria in a number of forms including NADH and NADPH, and retained in cells because of its negative charge. Cu(I) is subsequently dissociated by reactive chemical species (RS) generated in the reduced condition and is irreversibly trapped as Cu(I)-RS in cells. FR-NO2 pass through cell membranes by slow diffusion and may be converted to a reduced form, FR-NO2-, by xanthine oxidoreductase. Under hypoxic conditions (low pO2), FR-NO2- may be reduced further by intracellular reductases in a low oxygen concentration-dependent manner to R-NH2, which binds covalently to macromolecules in cancer cells.
Table 1.
Patient Characteristics.
Fig 3.
Kaplan-Meier curves of progression-free survival (PFS) for 62Cu-ATSM PET (a) and 18F-FDG PET (b) in patients with HNC.
Two groups of high (dotted lines) and low (solid lines) tracer accumulation were determined by each cut-off value of the tumor-to-muscle ratios (TMRATSM and TMRFDG). TMRATSM, one of the intensity-based redox parameters, showed a significant difference in PFS between two groups (p = 0.03), whereas TMRFDG, one of the intensity-based metabolic parameters, did not (p = 0.15). The three-year PFS rate was 74% for patients with lower accumulation tumors (TMRATSM ≤ 3.2) and 29% for those with over-reductive tumors (TMRATSM > 3.2).
Fig 4.
Kaplan-Meier curves of progression-free survival (PFS) (a) and cause-specific survival (CSS) (b) in patients with HNC.
Two groups with the accumulation of large (> 14.0, dotted lines) and small (≤ 14.0, solid lines) amounts of 62Cu-ATSM were determined by total-lesion-reduction (TLR), one of the volume-based redox parameters. The two groups showed significant differences in PFS (p = 0.02) and CSS (p = 0.02). Three-year PFS and CSS rates were 61% and 67% for patients with a smaller reductive tumor burden (TLR ≤ 14.0), and 14% and 20% for those with a greater reductive tumor burden (TLR > 14.0), respectively.
Fig 5.
Kaplan-Meier curves of progression-free survival (PFS) (a) and cause-specific survival (CSS) (b) in patients with HNC.
Two groups with the accumulation of large (> 8.1, dotted lines) and small (≤ 8.1, solid lines) volumes of 18F-FDG were determined by metabolic-tumor-volume (MTV), one of the volume-based metabolic parameters. The two groups showed significant differences in PFS (p = 0.03) and CSS (p = 0.03). Three-year PFS and CSS rates were 70% and 73% for patients with a smaller metabolic volume (MTV ≤ 8.1), and 30% and 37% for those with a larger metabolic volume (MTV > 8.1), respectively.
Fig 6.
PET images of 62Cu-ATSM (a) and 18F-FDG (b) of a 62-year-old man with tongue cancer.
Tumor contours were delineated to include voxels presenting SUV values greater than 70% SUVATSM of 4.6 for 62Cu-ATSM PET and 40% SUVFDG of 10.1 for 18F-FDG PET. Volume-based parameters were calculated as follows; RTV = 3.6, MTV = 19.3, TLR = 12.8, and TLG = 115.9. He is still alive without any recurrence or metastasis after being treated (CRT + SO). The volume-based redox parameter, TLR, which was smaller than the cut-off value of 14.0, correctly predicted his outcome. On the other hand, volume-based metabolic indices were greater than each cut-off value.
Fig 7.
PET images of 62Cu-ATSM (a) and 18F-FDG (b) of a 64-year-old man with right parotid cancer.
Tumor contours were delineated to include voxels presenting SUV values greater than 70% SUVATSM of 6.9 for 62Cu-ATSM PET and 40% SUVFDG of 8.8 for 18F-FDG PET. Volume-based parameters were calculated as follows; RTV = 5.9, MTV = 6.3, TLR = 32.0, and TLG = 30.0. He developed iliac bone metastasis 15 months after being treated (CRT + SO). The volume-based redox parameters, RTV and TLR, which were greater than each cut-off value (RTV: 2.9 and TLR: 14.0, respectively), correctly predicted his outcome. On the other hand, volume-based metabolic indices were smaller than each cut-off value.
Fig 8.
Hypothetical relationships between excess ROS production levels, cancer cell states, and treatment options.
The arrow indicates the direction of the level of excess ROS from the normal to lethal range. The black deformed quadrangle represents excess ROS concentrations. SO: surgical operation, RT: radiation therapy, CT: chemotherapy, CR: complete response.