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M V Williams

Publications and source records attributed to M V Williams.

At least 109 records · Page 6Linked to original sources
PubMed1987

The cribriform plate: a sanctuary site for meningeal leukaemia.

Cranial irradiation is an effective prophylactic treatment for subclinical meningeal infiltration in lymphoblastic leukaemia. However, central nervous system (CNS) relapse still occurs in 6-10% of cases overall and in as many as 30% of cases with a poor prognosis in some series. These recurrences may be due in part to inadvertent underdosage of the cribriform plate, which is centrally situated between the orbits and is projected over their upper third in a lateral view. The dose to the adjacent meninges may thus be reduced by shielding of the radiosensitive lenses. This problem is exacerbated if conventional lateral fields centred on the mid-skull are used, because the eyes will not then project over one another. If the field centre is moved to the edge of the orbit, this problem of beam divergence can be overcome. Central axis beam blocking of both lenses is then possible, and in some patients the cribriform plate can be adequately irradiated. However, in most children the geometry of the orbit is such that it is necessary to add an anterior electron beam to ensure homogeneous dosage. These refinements in irradiation technique might prevent meningeal relapse with a lower whole-brain dose and, hence, fewer neuropsychological sequelae. This hypothesis could be tested in a clinical trial.

Child↗
PubMed1987

In vivo effects of mercury (II) on deoxyuridine triphosphate nucleotidohydrolase, DNA polymerase (alpha, beta), and uracil-DNA glycosylase activities in cultured human cells: relationship to DNA damage, DNA repair, and cytotoxicity.

The effect of mercuric acetate on the activities of deoxyuridine triphosphate nucleotidohydrolase (dUTPase), DNA polymerase (alpha, beta), and uracil-DNA glycosylase has been studied in cultured human KB cells. There was a dose- and time-dependent inactivation of both dUTPase and DNA polymerase alpha activities by mercuric acetate. In cells exposed to low concentrations (10 microM) of mercuric acetate, dUTPase was most sensitive to inhibition with 30% of the activity being inhibited after a 1-hr exposure. At higher concentrations or for longer exposure times, DNA polymerase alpha was most sensitive to inhibition with greater than 60% of the activity being inhibited by 25 microM mercuric acetate after a 15-min exposure. There was no inhibition of DNA polymerase beta or uracil-DNA glycosylase activities in cells exposed to 50 microM mercuric acetate for 90 min. In fact, there was a time- and dose-dependent activation of uracil-DNA glycosylase activity with maximum activation occurring in cells exposed to 50 microM mercuric acetate. The inhibition of dUTPase and DNA polymerase alpha activities and the activation of uracil-DNA glycosylase activity correlated with the induction of single-strand breaks in DNA by mercuric acetate and with the decrease in cell viability.

Cations, Divalent↗
PubMed1986

PPi-dependent phosphofructotransferase (phosphofructokinase) activity in the mollicutes (mycoplasma) Acholeplasma laidlawii.

A PPi-dependent phosphofructotransferase (PPi-fructose 6-phosphate 1-phosphotransferase, EC 2.7.1.90) which catalyzes the conversion of fructose 6 phosphate (F-6-P) to fructose 1,6-bisphosphate (F-1, 6-P2) was isolated from a cytoplasmic fraction of Acholeplasma laidlawii B-PG9 and partially purified (430-fold). PPi was required as the phosphate donor. ATP, dATP, CTP, dCTP, GTP, dGTP, UTP, dUTP, ITP, TTP, ADP, or Pi could not substitute for PPi. The PPi-dependent reaction (2.0 mM PPi) was not altered in the presence of any of these nucleotides (2.0 mM) or in the presence of smaller (less than or equal to 300 microM) amounts of fructose 2,6-bisphosphate, (NH4)2SO4, AMP, citrate, GDP, or phosphoenolpyruvate. Mg2+ and a pH of 7.4 were required for maximum activity. The partially purified enzyme in sucrose density gradient experiments had an approximate molecular weight of 74,000 and a sedimentation coefficient of 6.7. A second form of the enzyme (molecular weight, 37,000) was detected, although in relatively smaller amounts, by using Blue Sepharose matrix when performing electrophoresis experiments. The back reaction, F-1, 6-P2 to F-6-P, required Pi; arsenate could substitute for Pi, but not PPi or any other nucleotide tested. The computer-derived kinetic constants (+/- standard deviation) for the reaction in the PPi-driven direction of F-1, 6-P2 were as follows: v, 38.9 +/- 0.48 mM min-1; Ka(PPi), 0.11 +/- 0.04 mM; Kb(F-6-P), 0.65 +/- 0.15 mM; and Kia(PPi), 0.39 +/- 0.11 mM. A. laidlawii B-PG9 required PPi not only for the PPi-phosphofructotransferase reaction which we describe but also for purine nucleoside kinase activity. a dependency unknown in any other organism. In A. laidlawii B-PG9, the PPi requirement may be met by reactions in this organism already known to synthesize PPi (e.g., dUTPase and purine nucleobase phosphoribosyltransferases). In almost all other cells, the conversion of F-6-P to F-1,6-P2 is ATP dependent, and the reaction is generally considered to be the rate-limiting step of glycolysis. The ability of A. laidlawii B-PG9 and one other acholeplasma to use PPi instead of ATP as an energy source may offer these cytochrome-deficient organisms some metabolic advantage and may represent a conserved metabolic remnant of an earlier evolutionary process.

Acholeplasma laidlawii↗
PubMed1986

Length of follow-up in teratomas--results of a modification of Einhorn's regime in testicular teratomas.

A modification of Einhorn's original chemotherapy schedule was used to treat 40 patients with metastatic testicular teratomas. Each cycle of chemotherapy consisted of cisplatin (100 mg/m2), bleomycin (30 mg X 3) and vinblastine (5 mg/m2 X 2). Four patients failed to achieve a complete response and died with advanced disease. There was one treatment death. Only two of 14 patients who had residual masses resected still had active tumour. The 2-year actuarial disease free survival for patients in first remission was 85%, but this fell to 77% at 5 years as 3 patients relapsed (34, 36, 37 months). The results are comparable with other series but are associated with less toxicity. The need for continued follow-up is demonstrated in view of relapses occurring after 2 years.

Aged↗
PubMed1986

Effects of mercury (II) compounds on the activity of dUTPases from various sources.

The deoxyuridine triphosphate nucleotidohydrolases (dUTPases, EC 3.6.1.23) from Escherichia coli K-12-,Acholeplasma laidlawii B-PG9-, human KB cell-, and the herpes simplex virus (HSV) type 1- and 2-induced dUTPases were purified and used to determine the effect of various mercury (II) compounds on their activities. Mercuric acetate, 5-mercuri-dUTP (HgdUTP), and 5-mercuri-dCTP (HgdCTP) acted as irreversible active site-directed inhibitors of the dUTPases purified from eukaryotic organisms but not those from prokaryotic organisms. The inhibition constants (Ki) were estimated for the KB, HSV-1, and HSV-2 dUTPases to be 8 +/- 2, 12 +/- 3, and 9 +/- 2 microM for mercuric acetate, 204 +/- 25, 121 +/- 15, and 111 +/- 10 microM for HgdUTP, and 775 +/- 25 and 651 +/- 23 microM for HgdCTP, respectively. The conversion of HgdUTP to its mercurithio-derivative resulted in a decrease in the affinity of the derivative for the eukaryotic dUTPases. The 5-mercurithioethylene glycol derivative of dUTP did not act as a substrate for the KB dUTPase but it did act as a substrate for the HSV-1- and HSV-2-induced dUTPases with Ki values of 526 +/- 47 and 483 +/- 32 microM, respectively. These results demonstrate that the eukaryotic dUTPases can be distinguished based upon differences in their affinities for the mercurithio-derivatives of dUTP and suggest that there are differences in the steric binding properties of the nucleotide-binding site of these enzymes.

Acholeplasma laidlawii↗
PubMed1985

Induction of a deoxyuridine triphosphate nucleotidohydrolase activity in Epstein-Barr virus-infected cells.

Superinfection of Raji cells with Epstein-Barr virus (EBV) or chemical induction of HR-1 cells with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) results in the induction of a deoxyuridine triphosphate nucleotidohydrolase (dUTPase) which is not observed in mock-treated cells or TPA-treated EBV genome-negative BJAB cells. The EBV-induced dUTPase could be distinguished from the host dUTPase based upon differences in their migration in polyacrylamide gels and sensitivity to the 5-mercurithioguanosine derivitive of dUTP. The expression of the EBV-specified dUTPase is prevented by phosphonoacetic acid indicating that its expression is dependent upon EBV-DNA replication.

Antiviral Agents↗
PubMed1985

A review of alpha/beta ratios for experimental tumors: implications for clinical studies of altered fractionation.

Clinical interest in the use of more and smaller dose fractions in radical radiotherapy has been stimulated by recent reviews of experimental results with normal tissues. It has been found that if the dose per fraction is reduced (i.e., in hyperfractionation) there is sparing of late responding normal tissues relative to those which respond early. This phenomenon can be understood in terms of the shapes of the underlying dose effect relationships, which can be described using the linear quadratic equation. The ratio (alpha/beta) of the linear (alpha) and quadratic (beta) terms is a useful measure of the curviness of such dose effect curves. Low alpha/beta values (1.5 to 5 Gy) have been observed for late responding normal tissues and indicate that radiation damage should be greatly spared by the use of dose fractions smaller than the 2 Gy used in conventional radiotherapy. By contrast the high alpha/beta values (6-14 Gy) observed for acutely responding normal tissues indicate that the response is relatively linear over the dose range of clinical interest. Hence less extra sparing effect is to be expected if lower doses per fraction are administered. If tumors respond in the same way as acutely responding normal tissues then hyperfractionation might confer a therapeutic gain relative to late responding normal tissues. We have reviewed published results for experimental tumors irradiated in situ and either assayed in situ or after excision. The alpha/beta ratios were usually at least as high as those for acutely responding normal tissues, and 36/48 tumors gave values greater than 8 Gy. Low values of less than 5 Gy were obtained for only 4/48 tumors. There are considerable technical problems in interpreting these experiments, but the results do suggest that hyperfractionation might confer therapeutic gain relative to late responding normal tissues on the basis of differences in repair capability. In clinical practice more efficient reoxygenation, cell cycle redistribution and decreased overall treatment time might also confer therapeutic gain.

Animals↗
PubMed1985

The influence of overall treatment time on renal injury after multifraction irradiation.

The influence of overall treatment time on the radiation response of the mouse kidney was studied in an experiment in which 16 fractions were administered either evenly distributed over 20, 40 or 80 days, or as a split course (8 F/3 days; 74 days rest; 8 F/3 days). Urine output and an isotope assay of glomerular filtration were used to test the mice sequentially. The data were used both to obtain dose-response curves and also to determine the latent period before a chosen level of injury was expressed functionally. Prolonging the overall time from 20 to 80 days increased the isoeffect dose by 2-5 Gy (4-9%) for the isotope assay, and by 4-9 Gy (7-18%) for the urine output assay. This additional recovery as the interval between fractions was prolonged from 1 to 5 days is consistent with slow repair and can be expressed as a small "T" exponent of 0.02-0.12. (One analysis gave a result consistent with negative repair, but the errors on this result were unusually wide.) When the radiation was given as a split course, at the rate of 2 fractions per day, with a large gap of 10.5 weeks between courses, there was no additional sparing compared with 16 fractions over 20 days. This indicates that any sparing that might have resulted from slow repair or stimulated repopulation in the gap has been counterbalanced by having less time for repair of sublethal injury when intervals of 6-12 h are used instead of 24-48 h. Clearly no great increase in the tolerance dose for mouse kidney resulted from the split course.

Animals↗
PubMed1985

Pyrimidine deoxyribonucleotide metabolism in Acholeplasma laidlawii B-PG9.

Extracts of Acholeplasma laidlawii B-PG9 were examined for the enzymes associated with the interconversion of the pyrimidine deoxyribonucleotides and the biosynthesis of thymidine nucleotides. A. laidlawii B-PG9 possessed deaminases for deoxycytidine and dCMP, pyrophosphatases for dUTP, phosphorylases for thymidine and uridine, and a membrane-associated pyrimidine deoxyribonucleoside monophosphate phosphatase activity. The role these enzyme activities have in the generation of deoxyribose-1-phosphate during growth may explain the ability of A. laidlawii B-PG9 to utilize either thymine or thymidine for biosynthesis.

Acholeplasma laidlawii↗
PubMed1984

Deoxyuridine triphosphate nucleotidohydrolase induced by herpes simplex virus type 1. Purification and characterization of induced enzyme.

A deoxyuridine triphosphate nucleotidohydrolase (dUTPase) which is induced in KB cells infected with herpes simplex virus type 1 (HSV-1) was purified approximately 175-fold using affinity, hydrophobic, adsorption, and ion-exchange chromatography techniques. Of the nucleoside triphosphates commonly found in DNA and RNA, only dUTP acted as a substrate for the enzyme, and the apparent Km was 4 microM. While the HSV-1-induced dUTPase exhibited activity in the absence of added divalent cations, the activity was stimulated by Mg2+ and inhibited by EDTA. The inhibition caused by EDTA was reversed by Mg2+, Co2+, or Mn2+. The HSV-1-induced dUTPase was also inhibited by hydroxymercuribenzoate and to a lesser degree by pyrophosphate but not by orthophosphate. The molecular weight of the enzyme was estimated to be 53,000, and its isoelectric point was 5.8. The enzyme exhibited maximal activity over the pH range of 6.5-8.5. The enzyme was thermolabile at 45 degrees C, exhibiting a t1/2 of 35 min. The HSV-1-induced dUTPase was distinguishable from the KB dUTPase by its elution pattern on the various chromatography matrixes, isoelectric point, migration in polyacrylamide gels, thermostability, and response to divalent cations.

Carcinoma↗
PubMed1984

Resolution after radiotherapy of severe pulmonary damage due to paraquat poisoning.

A 29 year old man was admitted 36 hours after ingesting about 5 g paraquat. His arterial oxygen pressure fell progressively to 3.4 kPa (34 mm Hg), and pulmonary damage induced by paraquat was diagnosed. His condition did not improve after treatment with prednisolone and cyclophosphamide, but after irradiation both lungs cleared and arterial oxygen pressure started to improve. Irradiation of the lungs should be considered in patients who, after surviving the acute phase of poisoning with paraquat, show progressive deterioration of respiratory function.

Adult↗
PubMed1984

Radiation induced renal damage in mice: influence of fraction size.

Two functional assays (urine output and isotope clearance) have been used to assess the response of mouse kidneys to localized irradiation. The influence of the size of each X ray dose has been investigated by using single doses and two to 16 equal fractions. The X ray dose in each treatment ranged from 16 Gy as a single dose to 3.5 Gy (X 16 fractions). Three separate experiments were performed, one with and two without anesthetic for the irradiation. Sequential testing of the mice was used to determine the latent period before radiation damage became manifest. Latency was found to be dose dependent; functional defects appeared earlier after higher doses but there was a minimum period of 14-19 weeks before the onset of damage. The repair capacity of the kidney was assessed by comparing isoeffective doses from the dose-response curves. Within 24 hours a recovered dose of 5 Gy was obtained if 2 doses were used instead of one. The isoeffective dose increased with fractionation and a fraction number exponent of 0.42 was obtained. Analysis of the data using a linear quadratic model yielded a low alpha/beta ratio of 0-3.5 Gy. This is similar to values obtained for other late responding normal tissues and implies that the use of small dose fractions will spare the kidney relative to tumors and acutely reacting normal tissues. In conventional radiotherapy more effective sparing of the kidney should be achieved by using thin shielding with each fraction than by completely shielding the kidney for the latter part of the treatment course.

Animals↗
PubMed1984

Tumor sensitization and protection: influence of stromal injury on estimates of dose modification.

Tumor regrowth delay is an assay which reflects tumor cell kill but can be modified by growth rate changes resulting from damage to the stroma (tumor bed effects). If the stromal damage is modified by radiosensitizers and radioprotectors to a different degree from the tumor cells, the overall measurement of dose modifying factors may be influenced by the choice of a regrowth size for the growth delay analysis. We have studied the response of two mouse tumors; a fibrosarcoma which showed only a small TBE and a carcinoma which showed a very large TBE. Sensitizer enhancement ratios and protection factors have been obtained by assessing regrowth to a variety of endpoint sizes. The dose modifying effects on the stroma have then been determined by analyzing the regrowth rates of tumors after irradiation. The choice of endpoint size modified both the sensitizer enhancement ratio and the protection factor for both tumors. It appears that stromal damage may be the cause of the radioprotection observed in the carcinoma, whereas direct tumor cell radioprotection is indicated in the fibrosarcoma. Both direct tumor cell killing and cell death secondary to stromal damage will play an important role in determining the local control of irradiated tumors.

Amifostine↗
PubMed1984

Dose-response relationships for human tumors: implications for clinical trials of dose modifying agents.

Clinical benefit from dose modifying agents depends upon the effectiveness of the agents and the steepness of dose response curves for the local control of human tumors by radiotherapy. We have analyzed the two prospective trials and the many retrospective analyses of clinical data from the literature to determine what dose increment is needed to increase local control from 40 to 60%. This increment ranges from 3 to greater than 35%. Thus a dose modifying factor of at least 1.03 (to greater than 1.35) will be necessary for clinical detection of the benefit of a new modality, even if 135 patients are included in each arm of a trial. Two dose levels in the new treatment arm would ensure that therapeutic advantage could be assessed, and would also generate prospective dose response information.

Animals↗
PubMed1984

Radiation induced renal damage in mice: influence of overall treatment time.

The influence of overall treatment time on the radiation response of the mouse kidney was studied by varying the time over which 2 or 5 fractions of X-rays were administered. Two functional assays (urine output and 51Cr-EDTA excretion), and renal weight at sacrifice were used to obtain dose-response curves and estimate isoeffective doses. Split dose experiments showed Elkind recovery of about 5 Gy in 24 h. With a 7-day interval between fractions a transitory increase in isoeffect dose was observed in the first experiment. In the second, more extensive, experiment the recovered dose did not increase significantly even if the interval between two fractions was prolonged up to 25 days. Therefore, if slow repair occurred it was not worth more than 1 Gy because this was the limit of resolution of the assays used. As overall time was prolonged to 60 days an additional 1-2 Gy were recovered: it is difficult to explain this delayed sparing effect on the basis of a compensatory proliferative response, because the labelling indices of the likely target cells in the kidney are so low. Whatever the mechanisms involved, an increase in overall time had only a slight effect on isoeffect dose in these experiments and values for the "T" exponent were low (0.0-0.09). Recovery from sublethal injury between fractions has a much larger effect.

Animals↗