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Biomedical subjects

G E Adams

Publications and source records attributed to G E Adams.

At least 127 records · Page 7Linked to original sources
PubMed1980

The interaction of misonidazole with radiation, chemotherapeutic agents, or heat: a preliminary report.

Survival of hypoxic cells exposed to misonidazole at 37 degrees C show an initial lag period after which survival decreases exponentially with time. Hypoxic cells incubated with misonidazole for a time equivalent to that of the lag period on the survival curve show increased sensitivity when subsequently given x-irradiation. This is consistent with previously published observations. In addition, preincubation of hypoxic cells with misonidazole ata 37 degrees C also renders cells more sensitive to subsequent treatments by heat or melphalan, mustine and cis-Pt(II). Preincubation must be in hypoxia for cells to become sensitive to a second insult; preincubation in air does not change cellular sensitivity even when this preexposure is 5 mM misonidazole for 3 days. The potential of exploiting a physiological property of most solid tumors, viz., hypoxia, in order to increase sensitivity of tumor cells to cytotoxic agents is discussed.

Animals↗
PubMed1980

The development of some nitroimidazoles as hypoxic cell sensitizers.

The most promising hypoxic cell sensitizer for use in radiotherapy is, at present, the 2-nitroimidazole, misonidazole, although neurotoxicity prevents its use at dosages necessary for optimum results. In the search for agents with better therapeutic ratios, we have investigated several classes of substituted 2-, 4-, and 5-nitroimidazoles. In general, 2-nitro derivatives are the most efficient in line with electron affinity considerations. However, notable exceptions include some 4-nitroimidazoles substituted in the 5-position by various sulphonamide or sulphonate groups. Some of these compounds are as efficient as oxygen on a concentration basis and display activity greater than predicted from their electron affinities. Cellular studies with these compounds will be described. Further, in the 2-nitroimidazole series the effect of the chain length of the N1 side chain terminated with a morpholine, piperidine, and pyrrolidine group has been studied. Notwithstanding the fairly constant electron affinities in these compounds, results show that systematic changes in sensitizing efficiency and cytotoxicity can occur with varying chain length, which indicates possible potential for increasing therapeutic ratio. These and other studies will be used as examples of the methods used in the search for better hypoxic cell sensitizers.

Cells, Cultured↗
PubMed1980

Respiratory effects and ascorbate reactions with misonidazole and other recently developed drugs.

A number of nitro compounds behave as electron acceptors with ascorbate in a non-enzyme-catalyzed reaction and with NADPH as electron donor in an enzyme-catalyzed reaction with liver homogenate. In both systems, the oxygen consumption is conveniently monitored by a Clark-type oxygen electrode. The oxygen consumption by S9 homogenate was found to be influenced by the electron affinity of the nitro compound. Detailed studies with misonidazole as the electron acceptor demonstrated that the oxygen consumption was influenced by protein and drug concentrations. Various inhibitors of electron transfer reactions, such as rotenone, antimycin A, and sodium azide, had no effect on misonidazole-stimulated oxygen utilization. However, cyanide was found to be stimulating in this system and this may be due to the inhibition of enzymes such as catalase and superoxide dismutase known to be present in S9. The oxygen consumption by S9 did not appear to be due to a hydroxylating reaction because metyrapone, a known inhibitor of this reactions, had no effect. Methional, a hydroxyl radical scavenger, was inhibitory as was glutathione. Clelands reagent had no effect. Additional studies with thiol-reactive agents suggest that a protein thiol may be important for the enzyme-catalyzed reaction between NADPH, misonidazole, and oxygen.

Animals↗
PubMed1979

Structure-activity relationships in the development of hypoxic cell radiosensitizers. I. Sensitization efficiency.

The efficiency of 35 nitroaromatic and nitroheterocyclic compounds in radiosensitizing hypoxic Chinese Hamster cells in vitro was determined. The concentration C of the compound required to achieve an enhancement ratio of 1.6 was measured, and the redox and partition properties were quantified as the one-electron reduction potential at pH 7, E, and the octanol: water partition coefficient, P, respectively. Most of the compounds studied were 2-nitroimidazoles, but some 4- and 5-nitromidazoles, 5-nitrofurans and nitrobenzenes were investigated for comparison. Together with data for nine nitroimidazoles previously reported, the results were fitted to a structure-activity relationship of the form -log C = b0 + b1E + b2 log P + b3 (log P)2 using multiple linear regression analysis. Statistical tests showed that the coefficients b2 and b3 were not significantly different from zero and the simpler equation, obtained by omitting the terms in log P, explained 85 per cent of the variance in log C. Earlier reports that the radiosensitization efficiency of nitro compounds in vitro largely depends on the reduction potential were confirmed. The conclusive demonstration that P is unimportant in vitro is valuable in interpreting the results of experiments in vivo, where P is expected to have a much greater influence on biological response.

Animals↗
PubMed1979

Structure-activity relationships in the development of hypoxic cell radiosensitizers. II. Cytotoxicity and therapeutic ratio.

This paper describes measurements of the aerobic cytotoxicity of 42 nitroaromatic and nitroheterocyclic compounds towards Chinese Hamster cells in vitro. The results of acute and chronic exposure were quantified, and the concentration C required to achieve a standard response estimated. Fitting the data to an equation of the form - log C = b0 + b1E, where E is the one-electron reduction potential, explained 47 and 71 per cent of the variance in the acute and chronic aerobic cytotoxicity respectively. The addition of further terms to the equation, quantifying partition properties, was not statistically significant. The coefficient b1 was similar for both acute and chronic exposure; the dependence of both cytotoxicity and radiosensitization efficiency on reduction potential was also similar. A therapeutic ratio derived from these in vitro measurements showed no dependence on redox or partition properties. The insensitivity of cytotoxicity and radiosensitization properties to variations in molecular structure, other than those which influence redox behaviour, offers exceptional flexibility in developing compounds of improved therapeutic ratio.

Animals↗
PubMed1979

Free radical reactions with proteins and enzymes: the inactivation of pepsin.

The reactions of free radicals produced by ionizing radiation with pepsin have been studied by steady-state inactivation measurements and by pulse radiolysis. In de-aerated solutions thehydroxyl radical has been found to be the most efficient of the primary free radicals generated from water in causing inactivation. The reactions of the more selective oxidizing inorganic radical anions Br2-. and (SCN)2-., with pepsin have also beenexamined. In the case of the thiocyanate radical anion (SCN)2-., the inactivation efficiency is found to depend on SCN- concentration, an effect shown to arise from a reversible redox reaction involving the tryptophan and (SCN)2-. radicals. The results demonstrate that tryptophan residue plays an essential role in the enzyme activity of pepsin.

Argon↗
PubMed1978

Sensitization of ultraviolet radiation damage in bacteria and mammalian cells.

Bacteria (Serratia marcescens) and mammalian cell (Chinese hamster V79-379A) were irradiated in monolayers with ultraviolet light at 254 nm or 365 nm in the presence or absence of radiosensitizing drugs. At 254 nm, killing is very efficient (D37 approximately 1 J m-2 exposure, or approximately 6 x 10(4) photons absorbed by DNA per bacterium), and sensitizers have no effect. At 365 nm, cells are not killed in buffer, but are inactivated in the presence of nifurpipone or misonidazole. Lethal exposures (approximately 5 x 10(3) J m-2 at 10micrometer misonidazole) correspond to about 10 (7) photons absorbed by sensitizer molecules per bacterium. Toxicity of stabel photoproducts of the drugs is not involved, nor is oxygen required. Hence the transient species formed by photo-excitation of radiosensitizer molecules are capable of killing cells in the absence of other types of radiation damage.

Cell Survival↗
PubMed1977

Effect of hyperthermia on differential cytotoxicity of a hypoxic cell radiosensitizer, Ro-07-0582, on mammalian cells in vitro.

There is now evidence that several classes of nitro compounds which have been used as radiosensitizers also function as cytotoxic agents specific for hypoxic cells. The 2-nitroimidazole, Ro-07-0582, (1-(2-nitroimidazol-1-yl)-3-methoxy-2-propanol) is a compound of this type, and its effectiveness as a cytotoxic agent is dependent on drug concentration, contact time and temperature. In vitro, Ro-07-0582 in air at 37 degrees C does not cause loss of cell viability at concentrations up to 2 mM, even when in contact for several days. In contrast, hypoxic cells do not tolerate much lower concentrations of drugs, even if the contact time is only a few hours. When the temperature is raised above 37 degrees C, there is a pronounced increase in the slope of the survival curves; for example, at 41 degrees C (for 1 mM Ro-07-0582, (200 microng/ml), the slope changes by a factor of 2-0 relative to that for 37 degrees C. For cells in air at 41 degrees C, as at 37 degrees C, there is no toxic effect at the concentration of drug tested. In the absence of drug, there is no cytotoxic effect of hyperthermia alone under these conditions. These results are discussed in terms of Arrhenius parameters.

Anaerobiosis↗
PubMed1977

Clinical testing of the radiosensitizer Ro 07-0582: experience with multiple doses.

The hypoxic cell radiosensitizer, Ro 07-0582, has now been given in multiple doses to 16 patients. They have received a total of 15-51 g in 3-20 doses. Immediate tolerance was good, and satisfactory plasma levels of the drug were consistently obtained. Neurotoxicity was, however, troublesome: convulsions occurred in the patient given the highest dose, and there was peripheral neuropathy in 11 cases. Tumour concentrations similar to those in plasma were obtained in human tumours, in contrast to the findings in mouse tumours where concentrations are usually below 40% of plasma levels. In the treatment of human tumours, a lower dose of Ro 07-0582 should give useful hypoxic cell sensitization. Although the total dose of Ro 07-0582 must be limited, there is a real prospect that it will give benefit in clinical radiotherapy.

Adult↗
PubMed1977

Critical residues in D-amino acid oxidase. A pulse-radiolysis and inactivation study.

The enzyme D-amino acid oxidase and its apoenzyme have been irradiated at pH 5.5--10 under conditions designed to assess the inactivating effect of OH radicals and the selective free radicals Br2- and (SCN)2-. Near neutral pH, removal of the coenzyme FAD from the enzyme results in greater inactivation by selective free-radical attack. From pulse-radiolysis spectra, this increase is associated with attack on tyrosine and tryptophan residues in the protein. A large increase in inactivation of both the haloenzyme and apoenzyme by selective free-radical attack is seen with increasing alkalinity. This is consistent with attack on tyrosine being of major importance.

Amino Acids↗
PubMed1976

Hypoxic cell sensitisers in radiotherapy.

Solid tumours contain poorly oxygenated cells, and these are disproportionately resistant to therapeutic radiation. Several methods of overcoming this problem have been used clinically, including the administration of hyperbaric oxygen during irradiation, radiotherapy with heavy nuclear particles such as neutrons from cyclotrons, optimum size and spacing of multiple doses of conventional radiation, and, most recently, chemical radiosensitisers. These radiosensitisers mimic the sensitising effect of oxygen and are active only against hypoxic cells. They do not, therefore, increase radiation response in well-oxygenated normal tissues. They are not rapidly metabollised and so can penetrate further than oxygen from the vascular capillaries and effectively reach the hypoxic cells in the tumour. Some of these drugs are of considerable clinical promise. The results of in vitro and in vivo studies with radiosensitisers are summarised and preliminary clinical work is described.

Animals↗
PubMed1976

Clinical testing of the radiosensitiser Ro-07-0582. I. Dose tolerance, serum and tumour concentrations.

Patients have been given single oral doses of the radiosensitiser Ro-07-0582 and serum concentrations have been attained in the range expected to be of value in radiosensitisation. Immediate gastrointestinal side effects appear to limit the dose to below 140 mg/kg but radiosensitising serum levels of approximately 200 mug/ml can be attained. Tolerance may be improved by giving anti-emetics and a more palatable preparation. Estimates of the concentration of Ro-07-0582 in tumour have ranged from 12 to 92% of the serum concentration at the time of determination.

Adult↗