Abstract— The photoexcited chlorpromazine reacts with methanol to yield promazine and 2‐methoxypromazine by two different reaction pathways: hydrogen atom abstraction and nucleophilic attack. respectively. When the photoexcitation of chlorpromazine is performed in the presence of protein or nucleic acids, chlorpromazine binds to the biopolymer. This binding is drastically pH‐dependent and correlates to the phototoxic effect exhibited in chlorpromazine—photosensitization of E. coli. No photodynamic damage of E. coli attributed to CPZ‐sensitization of molecular oxygen could be detected.

The incorporation of thymidine, uridine and leucine into DNA, RNA and proteins, respectively, was measured in log‐phase Chinese hamster cells photosensitized by chloroaluminum phthalo‐cyanine tetrasulfonate (A1PCS). Post‐treatment synthesis of all macromolecules was inhibited. The inhibition became progressively more pronounced with time, reaching a maximum at ca. 3 h after treatment. The differences between relative sensitivity of protein, RNA and DNA syntheses to A1PCS photosensitization, were not statistically significant. Some of the observed inhibition was due to a reduced uptake of the labeled precursors from the growth medium. Energy metabolism, as reflected by glucose oxidation, was sensitive to A1PCS plus light. Inhibition of glucose oxidation was evident immediately after treatment, and became more pronounced with time. Following a sublethal light fluence, maximum inhibition was observed at 3 h and there was a gradual recovery at later times. Inhibition of glucose oxidation was about two fold higher in plateau‐phase compared to log‐phase cells. The former were also twice as sensitive with respect to cell killing. These results suggest that inhibition of glucose oxidation induced by mitochondrial damage as seen in human lymphocytes, may be a primary cause for AlPCS‐photosensitized cell killing.

We compared the effects of the radioprotective aminothiols WR-1065 and WR-255591 on the induction of DNA double-strand breaks (DSBs) and on the survival of aerated Chinese hamster ovary cells exposed to 60Co gamma radiation. DSBs were measured using the pH 9.6 neutral elution method. In agreement with earlier studies, protection factors for both drugs measured using the end point of clonogenic cell survival were significantly greater than the protection factors for DSB induction when DSBs were measured after gamma-ray doses ranging from 20 to 90 Gy. However, when DSBs and cell survival measurements were made on the same cell populations after low radiation doses (between 3 and 30 Gy) using the replicate plating method, there appeared to be a close correlation between the modification of DSB induction and the modification of cell survival produced by both drugs. The major influence accounting for the differences between these and previously obtained results appears to be the range of radiation doses used, suggesting that protection against DSB induction is radiation-dose dependent.

We examined the effect of manipulating the levels of two endogenous radioprotectors, glutathione (GSH) and polyamines, on the ability of exogenous aminothiols to protect Chinese hamster ovary cells from the lethal effects of gamma-radiation. Treatment with 0.5 mmol dm-3 buthionine sulfoximine (BSO) for 24 h depleted GSH levels to < 1% of control and significantly sensitized the cells to irradiation in air. Undepleted control cells were protected by WR-1065 (4 mmol dm-3; 30-min preirradiation treatment at 37 degrees C) by 2.09-fold (range 1.98-2.21) at the 10% survival level, whereas BSO-treated cells were protected by a factor of 1.98 (range 1.95-2.14) at this survival level. Thus, GSH depletion had no significant effect on the radioprotective capacity of WR-1065. Treating cells with 1 mmol dm-3 alpha-difluoromethyl ornithine (DFMO) for 48 h depleted the polyamines putrescine and spermidine to very low levels, while spermine was not significantly depleted. DFMO also sensitized cells to aerobic irradiation. WR-1065 protected DFMO-treated cells by 2.29-fold (range 2.08-2.53), whereas undepleted control cells were protected by 2.09-fold (range 1.98-2.21) at the 10% survival level. Thus, WR-1065 appeared to offset the radiosensitizing effect of the DFMO treatment. Cysteamine, on the other hand, protected control and DFMO-treated cells to the same extent. We also examined the effect of combinations of exogenous thiols on radiosensitivity. Cells were treated with WR-1065 (4 mmol dm-3) for 30 min and then with increasing concentrations of dithiothreitol for 5 min prior to irradiation. The protective effects of these two thiols were simply additive.

Exposure of Chinese hamster cells to polyamines at an elevated temperature (42 degrees C) results in synergistic cell killing. The effectiveness of polyamines in potentiating thermal killing decreases in the following order: spermine greater than spermidine greater than cadaverine greater than putrescine. The magnitude of the synergism increases with exposure time. The survival curves, when plotted as a function of polyamine concentration, display a shoulder during 1 h exposure at 42 degrees C, followed by exponential cell killing. Longer exposure times eliminate the shoulder and result in steeper slopes of the survival curves. The effect is maximal when exposure to polyamines and heat is simultaneous. Separation in time between the two treatments causes a rapid disappearance of the synergism. The order of application is of only minor importance in this regard. The results suggest that the intracellular level of spermine may be a major factor in determining heat sensitivity of Chinese hamster cells.