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Biomedical subjects

J D Chapman

Publications and source records attributed to J D Chapman.

At least 109 records · Page 6Linked to original sources
PubMed1977

The application in radiation therapy of substances which modify cellular radiation response.

Compounds to be considered as potential adjuvants in radiotherapy should indicate a strong mechanistic rationale for a differential response between tumor and normal tissues. Drugs which selectively radiosensitize hypoxic cells might be exploited in radiotherapy to increase the sterilization of resistant hypoxic areas of solid tumors which have outgrown their vascular supply. Several compounds have been shown to selectively radiosensitize hypoxic mammalian cells in vitro but their application in clinical studies in presently limited by their toxicity at the high drug dosages required to effect the sensitization. Phase I and Phase II clinical studies have now been completed with the sensitizer, metronidazole. This drug was tolerated by patients at dosages of 6 g/m2 three times a week for 3 weeks with a minimum of side effects, and survival of patients with glioblastoma multiforme treated with fractionated radiotherapy was significantly increased when the sensitizer was used in combination with the radiation. Drugs which selectively radioprotect oxygenated cells might also be exploited in therapy be permitting the use of higher radiation doses and thereby incurring more damage to the resistant hypoxic cells in tumours. Again, drug toxicity appears to be a limiting factor with this approach. If toxicities are not additive, combinations of radiosensitizers and radioprotectors might prove more effective than either individual approach.

Amifostine↗
PubMed1977

The time-scale of radioprotection in mammalian cells.

The chain of reactions, resulting in mutation and cell death, initiated when ionizing radiation interacts with mammalian cells is complex and traverses a time-scale from a fraction of a picosecond to a few hours. Recently, progress has been made in identifying some of the more important pathways and potentially damaging free radical intermediates. Protection can, in principle, result from modification at several steps in these reaction chains, each with its distinctive time-scale. To date we have demonstrated that radio-protection can be effected in mammalian cells by the modification of processes at three quite different times. In this paper, the temporal sequence of radiation-initiated events are reviewed and the potential for or measurement of radioprotection of each is discussed. Such an understanding of cellualr radioprotection has become possible by our improved understanding of cellular radiation mechanisms derived from recent studies of its chemistry [1-4].

Catalase↗
PubMed1977

Clinical phase I study of the hypoxic cell radiosensitizer RO-07-0582, a 2-nitroimidazole derivative.

RO-07-0582 toxicity studies were performed in 12 patients for a total of 16 assays. Single and multifraction dose schedules were used, and drug concentrations in solid tumor tissue, cerebrospinal fluid, and blood (at 14 to 24 hr.) were established. A severe peripheral neuropathy occurred in 1 patient on the multifraction regimen when the total dosage reached 24 g. Drug absorption and concentration in the blood do not significantly differ from that of metronidazole. Maximum blood levels were reached at from 2 to 4 hr., and several days subsequent to administration had stabilized to levels only slightly above control levels.

Chondrosarcoma↗
PubMed1976

Radiation and high-dose metronidazole in supratentorial glioblastomas.

We used "high-dose" metronidazole, an "in vitro" and "in vivo" specific radiosensitizer of hypoxic cells, in a controlled trial to evaluate possible enhancement of radiation effect in patients with supratentorial glioblastomas. Thirty-six patients were stratified according to functional level and randomly allocated within two weeks of operation to one of two therapeutic groups: Group 1, radiation alone; and Group 2, radiation as in Group 1 but with high-dose metronidazole. We examined survival with the Kaplan-Meier probability plot and non-parametric tests. Patients in Group 2 had a 4 1/2-month delay between relapse and subsequent death (P = 0.02). This shift of the survival curves suggests a delay in the time of tumor regrowth consistent with the ability of metronidazole to make the hypoxic tumor cells less radioresistant. Nitroimidazole derivatives may be useful radiosensitizers in human solid tumors.

Administration, Oral↗
PubMed1976

DNA strand breaks, repair, and survival in x-irradiated mammalian cells.

The yields of unrepairable single-and double-strand breaks in the DNA of x-irradiated Chinese hamster cells were measured by low-speed neutral and alkaline sucrose density gradient sedimentation in order to investigate the relation between these lesions and reproductive death. After maximal single-strand remoining, at all doses, the number of residual single-strand breaks was twice the number of residual double-strand breaks. Both double-strand and unrepairable single-strand breaks were proportional to the square of absorbed dose, in the range 10-50 krad. No rejoining of double-strand breaks was observed. These observations suggest that, in mammalian cells, most double-strand breaks are not repairable, while all single-strand breaks are repaired except those that are sufficiently close on complementary strands to constitute double-strand breaks. Comparison with cell survival measurements at much lower doses suggests that loss of reproductive capacity corresponds to induction of approximately one double-strand break.

Cell Line↗
PubMed1975

Some properties of a protease (subtilisin BPN') immobilized to porous glass.

Subtilisin BPN' was immobilized to porous glass via isothiocyanate coupling. The pH optimum of the enzyme was shifted to the alkaline side on binding. This effect was more pronounced with ethyl lactate than with N-tosyl arginine methyl ester (TAME). Presumably, the shift is a reflection of the negative charge on the surface of the glass. The Michaelis constant and Vmax of soluble subtilisin BPN' with TAME were two and one orders of magnitude, respectively, lower than with ethyl lactate. Vmax, calculated per g of active enzyme, with TAME as the substrate was not affected by immobilization, while Vmax with ethyl lactate decreased greater than tenfold. The apparent KM decreased on immobilization with ethyl lactate as substrate and increased with TAME. Results are explained in terms of diffusional resistance and a possible attraction of ethyl lactate to the glass surface. Active site titration indicated that about 25% of the immobilized enzyme was active.

Glass↗
PubMed1975

Phase 1 study of high-dose metronidazole: a specific in vivo and in vitro radiosensitizer of hypoxic cells.

Metronidazole was administered orally to 25 patients and its maximum concentration in blood and tumor tissues, its ability to cross the blood/brain barrier and concentrate in the cerebrospinal fluid and brain tumor tissue, its immediate and long-term toxicity, and its enhancement of irradiation in normal tissue were studied. Maximum blood concentrations of 700-1,200 muM (120-220 mug/ml) were obtained at four hours with doses of 6 g/m2. Moderate and transient nausea and vomiting were the only immediate signs of toxicity. No long-term toxicity was found up to 18 months after administration of the drug. These data indicate that metronidazole can feasibly be adminstered in clinical trials of fractionated radiotherapy using dosages ranging from 9.5 to 11 g three times a week for three to four weeks.

Brain Neoplasms↗