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81.
The occurrence of preferential repair in Saccharomyces cerevisiaeof the active MAT locus compared with the inactive HML locuswas confirmed after 254 nm UV irradiation. Experiments carriedout using the UvrABC excinuclease assay with the monofunctionalfurocoumarin 3-carbethoxypsoralen (3-CPs) plus UVA radiationwhich induce mainly monoadducts in DNA demonstrated preferentialrepair of the active MAT locus compared with the inactive HMLlocus in a SIR+ strain. However, as after 254 nm UV irradiation,no difference in the rate of removal of 3-CPs plus UVA inducedlesions was observed between the two loci in the sir-3 mutantin which both loci are active. Thus, it appears that 3-CPs plusUVA induced monoadducts as well as pyrimidine dinners a e subjectto preferential repair.
3To whom correspondence should be addressed 相似文献
82.
Jan Piet Franke Jaap Wijsbeek Jan E. Greving Rokus A. de Zeeuw 《Archives of toxicology》1978,42(2):115-121
The potentials of XAD-columns for the isolation of quaternary ammonium compounds from aqueous media have been investigated. When adequate amounts of counter ions (perchlorate, chloride, phosphate, nitrate) were added to the aqueous sample, to the column pretreatment fluid and to the aqueous washing fluid, most quaternary compounds investigated were retained on the column and could be recovered by elution with methanol. This approach proved also suitable for urine. Quantitation of quaternaries isolated in this way from urine samples could be performed on silicagel thin layer plates through visualization with iodine, followed by densitometric evaluation. For decamethonium detection limits were 0.1 g/ml. Recoveries at the 1 g/ml level were between 80–90% with variation coefficients of less than 10%.Presented at the European Meeting of The International Association of Forensic Toxicologists, July 4–7, 1978, Utrecht, The Netherlands 相似文献
83.
84.
Ernest C Borden Laurence H Baker Robert S Bell Vivien Bramwell George D Demetri Burton L Eisenberg Christopher D M Fletcher Jonathan A Fletcher Marc Ladanyi Paul Meltzer Brian O'Sullivan David R Parkinson Peter W T Pisters Scott Saxman Samuel Singer Murali Sundaram Allan T van Oosterom Jaap Verweij Jill Waalen Sharon W Weiss Murray F Brennan 《Clinical cancer research》2003,9(6):1941-1956
Sarcomas--like leukemias, which are also mesodermal malignancies--carry biological significance disproportionate to their clinical frequency. Identification of mutations and translocations associated with these tumors has illuminated aberrant signaling pathways that cause these diseases, determine their behavior, and are therapeutic targets. Activated receptor-associated tyrosine kinase c-kit, mutated in most gastrointestinal stromal tumors, has proven a clinically effective target for enzyme inhibition. A translocation involving a single gene family, consisting of EWS and related genes, has been identified in five different sarcomas, and its chimeric protein products could prove similarly amenable to inhibitors. Resolution of the histopathological complexity is being aided by data from molecular and chromosomal characterization. Improvements in imaging, definition of prognostic factors, and surgical and radiotherapeutic treatment have resulted in improved local control. Continued progress will depend on further adapting the rapidly evolving technologies of genomics and proteomics. It will also depend upon accurate histopathological diagnosis based on validated reagents and consistent methodologies applied to adequate tissue samples derived from patients with complete clinical data. Finally, multicenter, coordinated trials, such as those that occurred with assessment of imatinib mesylate in metastatic gastrointestinal stromal tumors, will assure the most rapid reductions in morbidity and mortality. 相似文献
85.
Hans Gelderblom Ramon Salazar Jaap Verweij George Pentheroudakis Maja J A de Jonge Martin Devlin Christel van Hooije Francis Seguy Rosendo Obach Joan Pru?onosa Paola Principe Chris Twelves 《Clinical cancer research》2003,9(11):4101-4107
PURPOSE: Diflomotecan (BN80915) is an E-ring modified camptothecin analogue that possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors, a potential advantage for antitumor activity. As with other camptothecins, oral administration has pharmacological and clinical advantages. This Phase I study was performed to assess the feasibility of the administration of oral diflomotecan, to determine the maximum-tolerated, dose its bioavailability, and to explore the pharmacokinetics. EXPERIMENTAL DESIGN: An initial i.v. bolus was administered to assess the bioavailability of diflomotecan. Fourteen days later, diflomotecan was administered p.o. once daily for 5 days to adult patients with solid malignant tumors and repeated every 3 weeks. BN80915 and its open lactone form BN80942 were measured. RESULTS: Twenty-two patients entered the study and received a total of 57 cycles of oral diflomotecan at flat dose levels of 0.10, 0.20, 0.27, and 0.35 mg. The main toxicity was hematological, but some patients experienced alopecia, mild gastrointestinal toxicity, and fatigue. At the 0.35-mg dose level, 2 of 4 patients experienced dose-limiting toxicity comprising grade 3 thrombocytopenia with epistaxis and febrile neutropenia in 1 patient and uncomplicated grade 4 neutropenia lasting for >7 days in another. Toxicity was acceptable at the 0.27-mg dose level at which dose-limiting toxicities were observed in 3 of 12 patients (grade 4 neutropenia > 7 days, complicated by fever in 1 patient but without other signs of infection). After two cycles of diflomotecan, 6 patients had disease stabilization, which was maintained in 2 patients for 9 months and >1 year, respectively. Diflomotecan pharmacokinetics were linear over the dose range studied. Systemic exposure correlated with the fall in WBC counts. The mean oral bioavailability (+/-SD) was 72.24 +/- 59.2% across all dose levels. Urinary excretion of BN80915 was very low. CONCLUSIONS: The recommended oral diflomotecan dose for Phase II studies is 0.27 mg/day x 5 every 3 weeks. This regimen is convenient and generally well tolerated with a favorable pharmacokinetic profile and high but variable bioavailability. 相似文献
86.
Dr Ole S. Nielsen Jean-Yves Blay Ian R. Judson Martine van Glabbeke Jaap Verweij Allan T. van Oosterom 《American Journal of Cancer》2003,2(3):211-221
In the present paper the treatment of advanced and metastatic soft tissue sarcoma is reviewed with the primary emphasis on chemotherapy. One of the major advances in the treatment of soft tissue sarcomas is their treatment by multidisciplinary teams in specialized centers. Despite optimal local treatment of the primary tumor, disseminated disease will develop in many patients. Consequently, chemotherapy has been extensively studied but, unfortunately, the responsiveness of these tumors to chemotherapy has been disappointingly low. Doxorubicin and ifosfamide appear to be the most effective drugs — the latter with a somewhat higher toxicity at effective dosages. Other drugs with some first line activity are dacarbazine, liposomal doxorubicin and possibly trabectedin (ET-743). Imatinib is very effective in gastrointestinal stromal tumors (GIST) where it is now the treatment of choice. The combination of doxorubicin and ifosfamide increases the response rate without affecting overall survival. For these reasons, single agent doxorubicin is, in many centers, considered the standard treatment for advanced soft tissue sarcoma, and combination chemotherapy should be reserved for special subgroups of patients such as young patients with chemosensitive tumors. Chemotherapy for patients with advanced and metastatic soft tissue sarcoma is inadequate at present and new drugs are desperately needed. Fortunately, exciting new drugs are under development and hopefully they will improve the treatment of patients with this disease. 相似文献
87.
Rahul A.K. Samlal M.D. Jacobus van der Velden M.D. Marten S. Schilthuis M.D. Dionisio González González M.D. Fiebo J.W. Ten Kate M.D. Augustinus A.M. Hart M.D. Frits B. Lammes M.D. 《Gynecologic oncology》1997,64(3):463-467
The purpose of the present study was to identify a subset of high-risk patients among surgically treated node-positive patients with stage IB and IIA cervical carcinoma. From 1982 through 1991, 334 patients underwent radical hysterectomy for FIGO stage IB and IIA cervical carcinoma. In 68 patients pathological analysis of the surgical specimen revealed positive pelvic nodes. In this group, a Cox proportional hazard analysis was performed to examine the prognostic significance of clinicopathological variables. Only for adenocarcinoma (P= 0.002) and parametrium infiltration (P= 0.003) was evidence of an association with prognosis found. Based on these two factors, patients with positive pelvic nodes were categorized into a low-risk group (squamous cell carcinoma without parametrium infiltration,N= 33) and a high-risk group (squamous cell carcinoma with parametrium infiltration or adenocarcinoma,N= 34). The 5-year disease-specific survival in the low-risk group was 94% compared with 60% in the high-risk group (P= 0.003). For patients in the high-risk group, there is an urgent need for alternative adjuvant treatment to improve outcome. 相似文献
88.
Steinar Aamdal Uta Bruntsch Jean Kerger Jaap Verweij Wim Bokkel Huinink Jantien Wanders Ram Rastogi Hillary R. Franklin Stan B. Kaye 《Cancer chemotherapy and pharmacology》1997,40(5):439-443
The antitumor activity of zeniplatin, a third-generation, water-soluble platinum compound that has shown broad preclinical
antitumor activity and no significant nephrotoxicity in phase I trials, was tested in patients with advanced malignant melanoma
and advanced renal cancer. Patients who had not previously been treated, except with local limb perfusion and immunotherapy,
were given zeniplatin as bolus injections at 125 mg/m2 every 3 weeks. The main hematological toxicity was leukopenia (7/30 patients, WHO grade ≥ 3) and the main nonhematological
toxicity was nausea and vomiting (21/30 patients, WHO grade ≥ 2). Serious nephrotoxicity was observed early in the renal cancer
study and, later, also in the melanoma study. Hyperhydration did not prevent the nephrotoxicity, and the studies were stopped
after 6 renal cancer patients and 24 malignant melanoma patients had been included. Zeniplatin gave objective responses in
3 of the 21 evaluable malignant melanoma patients [2 complete responses (CRs) in patients with lymph-node metastases lasted
5 and 14 months, respectively; 1 partial response (PR) in a patient with lymph-node and liver metastases lasted 6 months].
In the renal cancer study, only four patients were evaluable for response and none responded. The results show that zeniplatin
has some activity (14%) in patients with advanced malignant melanoma, but no conclusion can be drawn regarding the activity
of zeniplatin in renal cancer as the number of patients was too low. The main toxicities were leukopenia and nausea and vomiting.
Unexpected and serious nephrotoxicity was observed, and for this reason the studies were terminated before the planned number
of patients had been included. A possible explanation for the nephrotoxicity may be drug interactions, but no firm conclusion
can yet be drawn.
Received: 16 March 1996 / Accepted: 25 March 1997 相似文献
89.
Jianguo Ma Marc Maliepaard Herman J. Kolker Jaap Verweij Jan H. M. Schellens 《Cancer chemotherapy and pharmacology》1997,41(3):186-192
The parental IGROV-1 human ovarian adenocarcinoma cell line was intermittently exposed to increasing concentrations of cisplatin
to obtain resistant sublines. A stable resistant subline with a resistance factor of 8.4 had been developed after 9 months
and 28 passages, which was denoted IGROVCDDP. A high correlation coefficient of 0.97 was found between the log cell survival and the DNA-adduct peak level during the
process of resistance development. IGROVCDDP was strongly cross-resistant to carboplatin and doxorubicin and moderately cross-resistant to etoposide, docetaxel, and topotecan.
Only minor resistance against 5-fluorouracil was observed, whereas IGROVCDDP was not cross-resistant to methotrexate. Intracellular accumulation of cisplatin was 65% lower in IGROVCDDP as compared with parental IGROV-1 at 37 °C under normal conditions. Coincubation of cisplatin with the Na+/K+-ATPase inhibitor ouabain resulted in a more pronounced decrease in platinum accumulation in IGROV-1 (44% decrease) than in
IGROVCDDP (26% decrease). Under energy-depleting conditions the accumulation of cisplatin in the parental cell line was approximately
60% lower than that observed under normal (energy [i.e., ATP] rich) culture conditions. In contrast, the accumulation in IGROVCDDP was not affected by ATP-depletion. There appeared to be no significant difference between the intracellular accumulation
of platinum in the resistant and sensitive cells under conditions of energy deprivation or when the uptake was studied at
0 °C. In conclusion, abrogation of energy-dependent accumulation in IGROVCDDP seems to be a major mechanism of resistance to cisplatin in this cell line.
Received: 21 January 1997 / Accepted: 22 July 1997 相似文献
90.
Cognitive disorders in patients with occlusive disease of the carotid artery: a systematic review of the literature 总被引:5,自引:0,他引:5
We present a systematic review of the literature on the prevalence, nature, severity, course, and causes of cognitive deficits
in patients with occlusive disease of the carotid artery prior to surgery (if surgery was under discussion). Searches were
carried out on Medline and Psychlit from 1980 to 1999 using neurovascular and psychological index terms, and papers and books
were checked for further references. Studies describing neuropsychological assessment of groups of patients with carotid obstruction
were included. Eighteen studies were found. We extracted from the papers data on study design, demographic characteristics
of patients, clinical diagnosis, carotid obstruction, cerebral imaging, time interval between ischemic episode and neuropsychological
assessment, neuropsychological asessment procedures, integration and interpretation of test performances, and conclusions
of authors. Fourteen studies concluded that there are cognitive deficits both in patients with symptomatic and in those with
asymptomatic carotid obstruction; four studies denied cognitive impairment. There were no differences in patient characteristics,
study design, or neuropsychological assessment procedures between the 14 studies that found deficits and the 4 that did not.
There are indications for a mild, diffuse, detrimental effect of carotid occlusive disease on cognitive functioning. However,
methodological problems prevent a definitive conclusion. Further research is needed to confirm these findings and to ascertain
the neurovascular risk factors for and the natural course of cognitive impairment in patients with carotid occlusive disease.
Received: 12 July 1999/Received in revised form: 10 November 1999/Accepted: 26 January 2000 相似文献