Determination of the optical purity of ibuprofen using X-ray powder diffraction.
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Anti-Inflammatory Agents, Non-Steroidal↗
Biomedical subjects
C A Russell
Publications and source records attributed to C A Russell.
Megestrol acetate and aminoglutethimide/hydrocortisone in sequence or in combination as second-line endocrine therapy of estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group phase III trial.
PURPOSE: A phase III randomized trial was performed to determine whether combination hormonal therapy with aminoglutethimide (AG) and hydrocortisone (HC) plus megestrol acetate (MA) improved response rates, response duration, or increased survival over the sequential use of each hormone in women with estrogen receptor-positive metastatic breast cancer (MBC) who had maintained stable disease for at least 6 months or responded to tamoxifen. PATIENTS AND METHODS: Two hundred eighty-eight postmenopausal women with progressive estrogen receptor-positive MBC were randomly selected to receive MA 40 mg four times daily (arm I), AG 250 mg four times daily with HC 40 mg daily in divided doses (arm II), versus the combination of MA plus AG given at the same dosages (arm III). Patients on arms I and II who progressed after an adequate trial were crossed over to the other treatment arm. RESULTS: Two hundred thirty-five eligible patients were evaluated for response, time to treatment failure, and survival. Response was only reported for patients with measurable disease and was not statistically different among the three arms. There were two partial responses (PRs) on MA (6%), four complete responses (CRs) and six PRs on AG (24%), and eight PRs and three CRs on MA plus AG (23%) in 32, 42, and 48 measurable patients, respectively. Median times to treatment failure were also similar at 5, 4, and 7 months. Survival was also not statistically different among the three arms at 26, 27, and 26 months for arms I, II, and III, respectively. Toxicity was greater in the two AG arms with respect to fatigue, nausea and vomiting, and rash. CONCLUSION: With the exception of toxicity, there is no response, time to treatment failure, or survival benefit for any one group when comparing MA, AG, or the combination at their stated doses in women with estrogen receptor-positive MBC who had previously responded to or stabilized with tamoxifen.
Adult↗
Thymidylate synthase as a target for growth inhibition in methotrexate-sensitive and -resistant human head and neck cancer and leukemia cell lines.
Thymidylate synthase (TS) inhibitor effects on growth of human head and neck squamous cell carcinoma (HNSCC) cell lines and CCRF-CEM human leukemia cells and sublines with acquired methotrexate (2,4-diamino-10-methylpteroylglutamic acid) (MTX) resistance were studied. During 120-h treatment, HNSCC cell lines A253 and FaDu are equally sensitive to MTX, whereas the polyglutamylatable TS inhibitors ZD1694 and BW1843U89 are 5- to 35-fold more potent than MTX and the lipophilic AG331 is approximately 10(2)-fold less potent than MTX. A253 is intrinsically resistant to intermittent (24 h) MTX and BW1843U89 exposure (higher EC50 values and shallower slopes of concentration-response curves relative to FaDu); AG331 and ZD1694 largely overcome this intrinsic resistance to intermittent exposure. Thymidine (TdR) protects against growth inhibition by these inhibitors, confirming that TS is their target in HNSCC; at high AG331 levels, TdR only partially protects, implying that a second site of action exists. Growth inhibition of HNSCC by ZD1694 and BW1843U89 is protected by leucovorin (LV) at > or = 10(-7) and > 10(-3) M, respectively; 10(-4) M LV cannot protect HNSCC cells against AG331. Results similar to protection studies are obtained if LV addition is delayed < or = 24 h after ZD1694 or BW1843U89 exposure. CCRF-CEM sublines with acquired MTX resistance resulting from dihydrofolate reductase (DHFR) overexpression, defective MTX transport, or defective MTX polyglutamylation retain full sensitivity to AG331. Cells with defective MTX transport are highly cross-resistant to ZD1694 and BW1843U89, implicating the reduced folate/MTX carrier in their transport. Minor cross-resistance of the DHFR overexpressing line to ZD1694 and BW1843U89 is observed. A subline with highly defective MTX polyglutamylation is cross-resistant to 120-h exposure to ZD1694, but not to BW1843U89, suggesting a profound contribution of polyglutamylation to the mechanism of action of ZD1694.
Antimetabolites, Antineoplastic↗
A comparison of a computer-based orthognathic surgery prediction system to postsurgical results.
This retrospective study analyzes the accuracy of a prediction algorithm from Quick Ceph Image. Pre- and postsurgical lateral cephalograms of 35 adult patients were computer imaged and specific landmarks digitized. Digitization error was assessed from duplicate digitizations. Sixteen measurements of the predicted and actual postsurgical hard and soft tissue landmarks were compared using Student's t test, one- and two-way analysis of variance, and a modified Bradley-Blackwood test. Results showed a good correlation between repeated digitization of all variables except soft tissue point B and E-plane. Comparison of the predicted and actual changes found that all differences were less than 1.8 mm or 3.1 degrees. Student's t test showed 10 of the 16 measurements did not differ significantly, and interclass correlation demonstrated moderate to good correlations for 13 of 16 variables. Overall the results of this study suggest that the magnitude of the differences were within clinically acceptable limits.
Adult↗
Deciduous teeth in tuberous sclerosis.
Shed deciduous teeth from patients with tuberous sclerosis, cerebral palsy, Down syndrome, phenylketonuria and healthy persons were examined with a surface microscope. We found enamel pits in all 87 deciduous teeth from the 20 patients with tuberous sclerosis, but in none of the 253 deciduous teeth from 142 controls constituting patients with cerebral palsy, phenylketonuria and Down syndrome as well as healthy persons. Enamel pits always occurred in the facial surface of the central incisor, lateral incisor and canine, while the number of enamel pits in the other surfaces of the deciduous teeth varied from none to nine. Ground sections examined microscopically revealed an undisturbed pattern of incremental lines (Retzius striae) surrounding the pits. In five dental sacs from patients with tuberous sclerosis, microscopic examination showed that the inner surface of the operculum was remarkably more irregular than in control patients.
Adolescent↗
Longitudinal study of anticentromere and antitopoisomerase-I isotypes.
The isotypes of anti-CENP-B, the major anticentromere antibody (ACA), and antitopoisomerase I in patients with scleroderma and Raynaud's disease were studied longitudinally in order to determine whether there was evidence of isotype switch. One hundred and three sera samples from 13 ACA(+) patients and 6 antitopoisomerase I patients were studied over a period from 3 to 17 years. Anti-CENP-B was always IgG, whereas antitopo-I was IgG and IgA. IgM anti-CENP-B and IgM antitopoisomerase I, when present, were always found with IgG and/or IgA. Three patients developed IgG anti-CENP-B during the study. We conclude that anti-CENP-B and antitopoisomerase I show evidence of isotype switch with persistence of IgG expression which suggests a continued antigen-driven immune response.
Adult↗
Review of the organized support network for infertility patients in licensed units in the UK.
In acknowledging that 'counselling is generally recognized as beneficial', the Human Fertilization and Embryology Authority (HFEA) Code of Practice requires that all infertility units provide counselling facilities to be available for patients. In this study, we intended to evaluate the support and counselling services made available by the licensed units in the UK. A questionnaire consisting of 30 questions was designed and sent to every licensed treatment unit in the UK. The data were coded on a nominal scale and, using a data entry program, loaded onto a computer. Using the Statistical Package for the Social Sciences program, a non-parametric frequency analysis was performed. Associations were examined with cross-tabulations and chi 2 analysis. A total of 62 units (61.4%) responded to the questionnaire, from both the private and National Health Service sectors. Of these, 95% have their own counsellor, most of whom (84%) practised on the premises. One-third of these counsellors had a dual role, mainly as nurses, social workers or in administration; 98.6% were trained in counselling, with only 28% having either the Certificate or Diploma in Counselling. One-third (32.2%) of centres charged for counselling, with only 13 units indicating their charges. The majority of centres (78.8%) do not actively follow-up patients after counselling and one-quarter (25.5%) did not have a specific counselling room. Over two-thirds (68.4%) of centres described their support network as adequate. The results of this survey suggest that, although the requirements of the HFEA Code of Practice are being adhered to reasonably well, overall patient uptake of counselling is low.(ABSTRACT TRUNCATED AT 250 WORDS)
England↗
Phase II clinical trial of carboplatin, ifosfamide, with oral mesna for metastatic breast carcinoma.
Twenty-five women with advanced breast carcinoma refractory to first-line chemotherapy entered a phase II trial to evaluate the efficacy of ifosfamide and carboplatin. Additionally the trial assessed the clinical usefulness of oral 2-mercaptoethane sulfonate (mesna) for urothelial protection. Two partial remissions were observed (8%); toxicity was significant but acceptable, with no treatment-related deaths. The combination of ifosfamide and carboplatin had little activity as the second-line treatment in our population of patients with heavily pretreated metastatic breast cancer. Oral mesna was effective for urothelial protection, permitting outpatient administration of ifosfamide.
Adenocarcinoma↗
Evolution of drug resistance in CCRF-CEM human leukemia cells selected by intermittent methotrexate exposure.
A clinically relevant mechanism of acquired methotrexate (MTX) resistance is decreased MTX polyglutamate (MTXGn) synthesis (McCloskey et al. J. Biol. Chem. 266:6181, 1991) secondary to deficient folylpolyglutamate synthetase (FPGS) activity. Earlier studies showed that this mechanism resulted after intermittent MTX treatment, but did not define its evolution in populations or its clonal frequency of occurrence and heterogeneity. We thus studied evolution of resistance in CCRF-CEM human leukemia cell populations and clones after repeated treatment with 30 microM MTX for 24 h. In populations, MTX resistance was detectable after 1 treatment and increased in degree as total cycles increased to 7. Defective MTXGn synthesis in populations was the only resistance mechanism detected, and FPGS activity in extracts decreased with treatment cycle. After 1 treatment, defective MTXGn synthesis was the major (27/48 clones) form of resistance; 18 clones were sensitive, while 1 clone with a DHFR-related change, no clones with decreased MTX uptake, and 2 complex phenotypes were observed. Sporadic clones with DHFR-mediated resistance appeared up to cycle 4, but defective MTXGn synthesis remained the major resistance mechanism. The degree of clonal resistance tended to increase with treatment cycle, but 1 clone in cycle 2 was similar to the clones from cycle 7. No change in FPGS gene copy number or restriction pattern, or FPGS mRNA level or size (2.3 Kb) was detected in populations. Decreased FPGS activity must result from decreased translation, increased protein turnover, or a point mutation affecting catalysis.
Antimetabolites, Antineoplastic↗
Novel 6,5-fused ring heterocyclic antifolates: biochemical and biological characterization.
Six novel antifolates with 2,4-diaminopyrimidine-fused five-membered rings containing either pyrrole or cyclopentene rings were characterized at the cellular and biochemical level. Five of these antifolates were more growth inhibitory to the CCRF-CEM human leukemia cell line than methotrexate [MTX; drug concentration effective at inhibiting cell growth by 50% relative to untreated control (EC50), 12 nM], the antifolate used in the clinic, and two were more potent than 10-ethyl-10-deazaaminopterin (EC50, 2.7 nM); similar patterns of response were obtained in the FaDu and A253 squamous carcinoma cell lines. In addition, the growth inhibitory potency of these antifolates was generally less dependent on exposure time than was MTX. Growth inhibitory effects could be reversed by leucovorin, indicating an antifolate mechanism. These antifolates targeted dihydrofolate reductase (DHFR) based on direct human DHFR inhibition assays [drug concentration inhibiting enzyme activity by 50% (IC50), 0.6-28 nM; MTX IC50, 0.8 nM] and the cross-resistance of MTX-resistant CCRF-CEM cells containing elevated DHFR. Inhibition of human thymidylate synthase was generally weak. These 6,5-fused ring heterocyclic antifolates utilized the reduced folate/MTX transporter for uptake, based on the cross-resistance of MTX uptake-impaired CCRF-CEM cells, and were efficient substrates for this uptake system, based on inhibition of [3H]MTX uptake (IC50, 0.3-5.8 microM; aminopterin IC50, 2.6 microM). These analogues were substrates for CCRF-CEM folylpolyglutamate synthetase, with several being among the most active substrates now known (highest Vrel/Km 0.73; MTX and 10-ethyl-10-deazaaminopterin, 0.013 and 0.24, respectively). Substrate activity for murine intestinal folylpolyglutamate synthetase was also assayed, and a different specificity pattern was observed. These new antifolates are apparently not substrates for aldehyde oxidase. Analogues containing the fused cyclopentene ring are preferred to those containing the fused pyrrole ring based on growth inhibitory potency, effectiveness against decreased uptake mutants and apparent affinity for transport, and inhibition of DHFR. In addition, fused cyclopentene-containing analogues are efficiently polyglutamylated. The data indicate that antifolates with 2,4-diaminopyrimidine-fused five-membered rings, especially those containing the fused cyclopentene ring, are an important new class of antifolates which warrant further exploration at the synthetic and preclinical levels.
Aminopterin↗
Familial occurrence of Hirschsprung's disease.
We assessed the familial occurrence of Hirschsprung's disease from 224 probands born in Denmark after 1959. Probands who were still alive received a mailed questionnaire, and medical reports for the probands and their relatives with suspected Hirschsprung's disease were examined. The diagnosis of Hirschsprung's disease required a histologically verified biopsy or surgical colonic specimens, and exclusion of a secondary causes for Hirschsprung's disease. Familial occurrence was seen in 11 families. Ten first-degree, two third-degree and one fifth-degree relatives had Hirschsprung's disease. Both short segment agangliosis (the sigmoid colon or below) and long segment agangliosis (above the sigmoid colon) occurred in five of the 11 families, implying that the etiology of Hirschsprung's disease with short and long segment agangliosis is the same. Compared with the general population, the first-degree relatives of the 224 probands had a minimum of a 93-fold increased risk of Hirschsprung's disease. This strongly suggests that genetic factors play a role in Hirschsprung's disease.
Denmark↗
An epidemiological study of Hirschsprung's disease and additional anomalies.
The incidence of Hirschsprung's disease was studied in approximately 1.5 million consecutive live births in Denmark by hospital records. A diagnosis of Hirschsprung's disease required a histologic verified absence of ganglion cells in either biopsy or surgical colonic specimens. The incidence of Hirschsprung's disease was found to be 0.140 per 1000 live births (1:7,165) with a male: female ratio of 4.1:1 in short segment, and 2.4:1 in long segment Hirschsprung's disease (p = 0.36). Maternal age and birth order were unimportant factors. The association of Hirschsprung's disease and Down's syndrome was seen in 9 of the 207 patients and may represent a real association, whereas the association with congenital heart defects seen in 2% (not including patients with Down's syndrome) is more doubtful. A mortality of 16% among the patients with Hirschsprung's disease emphasizes the extreme importance of early diagnosis.
Abnormalities, Multiple↗
The toxicologic and oncogenic potential of JP-4 jet fuel vapors in rats and mice: 12-month intermittent inhalation exposures.
Three-hundred Fischer 344 rats and 300 C57BL/6 mice of each sex were divided into three treatment groups and exposed intermittently (6 hr/day, 5 days/week) to JP-4 jet fuel vapors at concentrations of 0, 1000, and 5000 mg/m3 for 12 months. At exposure termination, 10% of the animals were killed and those remaining were held for a 12-month postexposure tumorigenesis observation period. Pathologic findings in male rats revealed treatment-related renal toxicity and neoplasia consistent with the male rat unique alpha 2 mu-globulin nephropathy syndrome. Distinct JP-4-induced respiratory toxicity was not observed, and pulmonary neoplasms were not significantly increased in any treatment group. Benign hepatocellular adenomas were slightly increased in high-dose female mice, but the trend was reversed in male mice. Other pathologic findings were regarded as equivocal or compatible with expected biologic variation. The study did not demonstrate target organ toxicity or carcinogenesis which could be extrapolated to other species.
Administration, Inhalation↗
Studies on the cross resistance of folylpolyglutamate synthetase-deficient, methotrexate-resistant CCRF-CEM human leukemia sublines.
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Antineoplastic Agents↗
Cross-resistance studies of folylpolyglutamate synthetase-deficient, methotrexate-resistant CCRF-CEM human leukemia sublines.
CCRF-CEM human leukemia sublines resistant to short-term methotrexate (MTX) exposure as a result of decreased folylpolyglutamate synthetase (FPGS) activity were examined for their response to other cytotoxic agents. The R3/7 and R30dm sublines display 25 and 1%, respectively, of the FPGS activity of CCRF-CEM cells as measured with MTX in vitro. Response to agents in outgrowth experiments was examined under both continuous exposure (120 h, where MTX resistance is not observed) and short-term (6-14.5 h) exposure. During continuous exposure to various classes of agents, cross-resistance of R3/7 and R30dm that correlated with FPGS level was not observed, although some minor (< or = 3-fold) stochastic variations in sensitivity were noted. These agents included actinomycin D, Adriamycin, etoposide, vincristine, cisplatin, cytosine arabinoside, 5-fluorouracil, and some other antifolates. Cross-resistance during continuous exposure that did correlate with FPGS level was noted, however, to glutamate-containing thymidylate synthase inhibitors (including ICI D1694) and, to a minor extent, to 6-mercaptopurine and 5-fluorodeoxyuridine. Slight collateral sensitivity during continuous exposure that apparently correlated with FPGS level was noted to the lipid-soluble antifolate trimetrexate and to 5,8-dideazapteroyl-L-ornithine, an FPGS-specific inhibitor. In short-term exposures (where MTX resistance of the sublines is observed), the resistant sublines displayed sensitivity or cross-resistance to each agent that was qualitatively similar to that observed for the same agent in continuous exposure. Because of the requirement for reduced folates in the anti-DNA mechanism of action of fluoropyrimidines and the current clinical use of leucovorin (LV) to enhance their effects, the interaction of LV and fluoropyrimidines was examined. The results suggest that even highly FPGS-deficient cells are as sensitive to the effects of LV modulation as are wild-type cells even at fluoropyrimidine exposure times as short as 4 h.
Antimetabolites, Antineoplastic↗
Biochemical and biological properties of methotrexate analogs containing D-glutamic acid or D-erythro, threo-4-fluoroglutamic acid.
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Cell Division↗
Decreased folylpolyglutamate synthetase activity as a mechanism of methotrexate resistance in CCRF-CEM human leukemia sublines.
Determinants of methotrexate (MTX) resistance in cell lines resistant to short, but not continuous, MTX exposure were investigated since such lines may have relevance to clinical resistance. CCRF-CEM R30dm (R30dm), cloned from CCRF-CEM R30/6 (a MTX-resistant subline of the CCRF-CEM human leukemia cell line), had growth characteristics similar to CCRF-CEM. R30dm was resistant to a 24-h exposure to levels as high as 300 microM MTX but was as sensitive as CCRF-CEM to continuous MTX exposure. MTX resistance of R30dm was stable for greater than 68 weeks in the absence of selective pressure. Initial velocities of MTX transport were comparable for R30dm and CCRF-CEM, as were dihydrofolate reductase specific activity and MTX binding. A 2-fold thymidylate synthase activity decrease for R30dm from that of CCRF-CEM was not a significant factor in R30dm MTX resistance. Decreased MTX poly(gamma-glutamate) synthesis resulted in lower levels of drug accumulation by R30dm. Decreased polyglutamylation was attributable to folylpolyglutamate synthetase (FPGS) activity in R30dm extracts which was 1, 2, and less than or equal to 10% of CCRF-CEM extracts with the substrates MTX, aminopterin, and naturally occurring folates, respectively. Comparison of cell lines with varying levels of resistance to short term MTX exposure indicated that the extent of MTX resistance was proportional to the reduction of FPGS activity. The evidence supported decreased FPGS activity as the mechanism of resistance to short MTX exposure in the cell lines investigated.
Drug Resistance↗
New chemotherapies for ovarian cancer. Systemic and intraperitoneal podophyllotoxins.
The epipodophyllotoxin derivatives etoposide and teniposide have been evaluated intermittently for possible use in the treatment of ovarian cancer. Conflicting studies suggest that variables such as dose and prior treatment have a major influence on outcome. Response rates ranged from 0% to 40% in five series with teniposide, and from less than a 10% overall response rate to greater than a 10% complete response rate in nine studies with etoposide. One study documented activity with oral etoposide. However, because all patients had received various prior chemotherapies, firm conclusions regarding the activity of etoposide could not be drawn. These results, and the expectation of synergy with etoposide and cisplatin, led to several studies that combined etoposide with platin compounds by the systemic and intraperitoneal (IP) routes. Various studies have used intravenous drug combinations of these agents in both previously treated and untreated patients. One study, which used carboplatin instead of cisplatin, reported only seven failures among 26 previously untreated patients. Conversely, the prominent toxicities reported by another study were discouraging, and responses did not exceed what might be expected from cisplatin alone. Studies of analogous combinations administered IP are ongoing. A favorable experience, which was initially reported by the University of California (San Diego group), is being confirmed by other investigators. This has prompted the incorporation of etoposide into first-line strategies. The pharmacologic advantage of etoposide by the IP route (related to its high protein binding) may provide appropriate dose intensity against IP disease while sparing systemic toxicities. Finally, systemic dose intensity with autologous bone marrow support indicates some promise for etoposide in combination with high-dose alkylating drugs.
Combined Modality Therapy↗