John W. Harris

Initial report of the phase I trial of the hypoxic cell radiosensitizer SR-2508

From March 15, through August 31, 1983, 37 patients have been entered on the RTOG Phase I trial of SR-2508. The drug was given intravenously three times weekly for three weeks. The starting total dose was 11.7 g/m2 and the highest total dose given was 32 g/m2. The lower lipophilicity of SR-2508 has produced the expected decrease in terminal half-life (5.4 hrs) of drug excretion and increase in total drug excreted unchanged in the urine (71%) compared to misonidazole or desmethylmisonidazole. The maximum single dose (3.7 g/m2) administered was well tolerated. With multiple doses peripheral neuropathy is the dose-limiting toxicity. The lowest cumulative dose producing toxicity was 21.6 g/m2, the highest non-toxic dose was 29.7 g/m2. The use of an individual patients drug exposure as measured by the area under the curve of drug concentration vs time may be an excellent predictor of toxicity. This may eventually permit individualization of dose and prevention of serious toxicity. A single dose of 2 g/m2 will produce a tumor concentration of drug (approx. 100 micrograms/ml) that will yield a sensitizer enhancement ratio of 1.5 to 1.7. Using a starting dose of 2 g/m2 three times weekly, patients are now being studied on a five week drug schedule to further evaluate predictability of drug toxicity in preparation for clinical trials of drug efficacy.

Radiation Therapy for Thyroid Eye Diseases

Sixty-two patients (28 men and 34 women, 26 to 84 years old) with thyroid ophthalmopathy were treated with approximately 20 Gy of fractionated photon irradiation. Eight of 14 patients with motility problems improved after treatment. Ten of 14 with thyroid optic neuropathy improved or stabilized, but four had recurrences within five months after completion of irradiation. Generally, patients who had disease durations of less than six months responded better than those with more long-term ocular changes.

Response of extremely hypoxic cells to hyperthermia: survival and oxygen enhancement ratios.

Chinese hamster V79 cells and mouse EMT6 cells were made extremely hypoxic with a chamber technique that relies upon gas exchange rather than respiration-assisted oxygen depletion. Cells in these chambers were treated with heat (43degrees C) or heat plus x-irradiation, and colony-forming ability was determined. Hyperthermia: (a) kills exponentially growing V79 cells more efficiently than plateau-phase cells; (b) kills euoxic and extremely hypoxic cells equally; and (c) radiosensitizes euoxic and extremely hypoxic cells to the same degree, leaving the oxygen enhancement ratio unchanged.

The Effect of Extreme Hypoxia and Glucose on the Repair of Potentially Lethal and Sublethal Radiation Damage by Mammalian Cells

Confluent monolayers of Chinese hamster overy cells repaired potentially lethal X-ray damage under aerobic conditions but did not repair such damage under extremely hypoxic conditions. However, add...

Mammalian cell studies with diamide.

Abstract Diamide , diazenedicarboxylic acid bis (N,N′-dimethylamide), is a glutathione oxidant that has several advantages over classical sulfhydryl reagents , including reversibility. It is used widely to study glutathiones role in cellular function and radioresistance. It is also an effective radiosensitizer of hypoxic cells and acts by a unique mechanismm increasing the slope of the survival curve of irradiated hypoxic mammalian cells at high concentrations and decreasing the shoulder at low concentrations. Increased yields of radiation-induced chromosome aberrations and DNA strand breaks suggest that diamide sensitizes by mechanisms involving DNA. These mechanisms may include direct interactions with DNA and removal of cellular reducing species that normally repair radiation damage. Diamide sensitizes hypoxic cells synergistically with nitrofuran or nitroimidazole sensitizers, is effective against ascites tumors in vitro , and is useful for elucidating the mechanisms of aminothiol radioprotection. If used carefully, and with due regard for its limitations, it provides a useful tool with which to expand our knowledge of the mechanisms that govern cellular radiosensitivity and to hasten development of effective radiosensitizers for clinical use.

The in Vitro Sensitivity of Chronically Hypoxic EMT6/SF Cells to X-radiation and Hypoxic Cell Radiosensitizers

We have investigated the effect of extreme, prolonged hypoxia on the radiosensitivity of EMT6/SF cells in vitro. As cells were kept hypoxic for 1-24 h, their radiosensitivity increased, but no further change was noted for hypoxic incubation beyond 24 h. Chronically hypoxic (45 h) cells were more radiosensitive than acutely hypoxic (1 h) cells by a factor of 1.43. When chronically hypoxic cells were re-aerated, the increased radiosensitivity persisted, although it was reduced. Misonidazole (MISO) radiosensitization was equally effective under conditions of acute and chronic hypoxia. In contrast, MISO, SR2555 and SR2508 were more cytotoxic in chronically hypoxic cultures than in acutely hypoxic cells. Measurements suggested that intracellular thiols may play an important role in the effects observed.

Effects of adriamycin and x-rays on euoxic and hypoxic EMT-6 cells in vitro

Abstract EMT-6 mouse tumor cells were grown in vitro and exposed to Adriamycin (and six other drugs) under conditions of euoxia, acute hypoxia or chronic hypoxia. Although the sensitivity of these cells (assayed as colony formation) was somewhat different than other EMT-6 cell lines and varied considerably from drug to drug, there was no difference between euoxic and hypoxic conditions. Moreover, Adriamycin did not consistently affect the radiation survival of these EMT-6 cells and specifically did not modify the shoulder region of the X-ray survival curve.

Radiosensitization of hypoxic mammalian cells by diamide. I. Effects of experimental conditions on survival.

Diamide sensitizes hypoxic mammalian cells to x radiation in a complex manner. It sensitizes CHO cells more effectively than V79-S171 cells and is far more efficient at 0

Effects of glutathione depletion by buthionine sulfoximine on the sensitivity of EMT6/SF cells to chemotherapy agents or X radiation dennis

sup 0

Radiosensitization of hypoxic mammalian cells by diamide. II. Studies of mechanism.

C than at 18