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1.
Purpose: We set out to measure drug binding to serum proteins. These have been shown to reduce the free plasma concentrations of
a number of anticancer drugs, particularly of those of complex organic structure, in both experimental studies and clinical
trials. Methods: We have used cultures of murine Lewis lung carcinoma cells as sensors of available drug to measure the effects of two drug-binding
plasma proteins, α-acid glycoprotein (AAG) and human serum albumin (HSA), as well as of bovine serum albumin (BSA) on drug
activity. Results: The concentrations required for 50% growth inhibition (IC50 values) of a number of anticancer drugs were found to be linear functions of the added proteins. Assuming that cells respond
to free drug, the data provide estimates of the product K · n, where K is the binding constant of the protein and n is the number of drug binding sites per protein molecule. Amsacrine, the amsacrine analogue asulacrine, camptothecin, DACA
(N-[2-(dimethylamino)ethyl]acridine-4-carboxamide), doxorubicin, etoposide, mitoxantrone, paclitaxel and vincristine were tested.
The K · n values for AAG were 30, 2400, 8.7, 340, 29, 290 × 103 M
−1 and 120 × 103 M
−1, respectively, and the K · n values for HSA were 16, 580, 530, 10, 6.2, 4.3 × 103 M
−1 and 0.0 × 103 M
−1, respectively. The combined data allowed the estimation of free fractions of drug in plasma, assuming that AAG and HSA contributed
most to protein binding. The data were in general comparable with that reported using equilibrium dialysis and ultrafiltration.
Data for drug binding to BSA were different from those for HSA, in some cases by a large factor with values for HSA generally
higher. The applicability of the method to analogue development was illustrated by examining the binding to AAG of a series
of DACA analogues, and binding was found to be primarily related to lipophilicity. Conclusion: IC50 determinations provide a rapid means of estimating drug binding to plasma proteins and have utility in the assessment of
new anticancer drugs.
Received: 20 July 1999 / Accepted: 5 November 1999 相似文献
2.
Evaluation of toremifene for reversal of multidrug resistance in renal cell cancer patients treated with vinblastine 总被引:8,自引:0,他引:8
Braybrooke JP Vallis KA Houlbrook S Rockett H Ellmén J Anttila M Ganesan TS Harris AL Talbot DC 《Cancer chemotherapy and pharmacology》2000,46(1):27-34
Purpose: Expression of P-glycoprotein (Pgp), which confers the multidrug resistance (MDR) phenotype, is thought to contribute to
the insensitivity of renal cell cancer (RCC) to chemotherapy. The development of Pgp inhibitors for clinical application has
been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration. Toremifene is able to
reverse MDR and sensitise RCC to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in
particular the acute phase protein α1-acid glycoprotein (AAG), which may limit tissue availability. In this phase I–II study we assessed the tolerability of short
courses of high dose toremifene in combination with vinblastine and evaluated the key determinants of MDR reversal in vivo.
Methods: Twenty-seven patients with metastatic RCC received escalating doses of oral toremifene for 3 days every 2 weeks in combination
with vinblastine 6 mg/m2 i.v. on day 3 of each cycle. The serum concentration of toremifene, its metabolites and AAG were measured and the effect
of patients' serum on inhibition of Pgp in vitro was determined. Results: Twenty-six patients were evaluable for response. Eight patients (31%) had stable disease and 18 patients (69%) progressive
disease. The mean serum concentration of toremifene at 780 mg daily for 3 days was 7.82 μM [standard deviation (SD) 2.48, range 2.50 to 14.70], which exceeds that known to reverse MDR in vitro. The serum concentration
of the major metabolite of toremifene, N-demethyltoremifene, which also reverses MDR, was 5.13 μM (SD 1.78, range 1.80 to 9.00). In 60% of patients the pre-treatment AAG concentration was above that known to block the effects
of toremifene in vitro. However, addition of serum from patients on toremifene to MCF-7 adr cells in vitro inhibited Pgp-mediated
efflux of rhodamine 123. Conclusions: We have shown that short course, high-dose toremifene in combination with vinblastine is generally well tolerated and that
the concentration of toremifene required to reverse MDR in vitro is achievable in vivo.
Received: 7 July 1999 / Accepted: 15 November 1999 相似文献
3.
Zahra Mojtahedi Bijan Khademi Seyed Basir Hashemi Seyed Mohammad Bagher Abtahi Mohammad Ali Ghasemi Mohammad Javad Fattahi Abbas Ghaderi 《Pathology oncology research : POR》2011,17(1):7-10
Inflammation has been linked to various steps in tumorigenesis. Interleukin (IL)-6 and IL-18 are two inflammatory cytokines
whose serum concentrations are elevated in several types of cancer, including head and neck squamous cell carcinoma (HNSCC)
in some studies. This study was designed to analyze the serum concentrations of these cytokines in Iranian HNSCC patients.
Serum IL-6 and IL-18 concentrations were assayed by ELISA commercial kits in 65 untreated patients and 20 healthy volunteers.
Serum IL-6 concentration was significantly increased in patients compared to healthy individuals (p < 0.000). IL-6 concentration increased as the tumor stage progressed, and a significant difference appeared between stage
IV vs. stage I/II/III (p = 0.03) disease. Although serum IL-18 concentration was higher in patients than in healthy individuals, the difference was
not statistically significant (p = 0.06). Moreover, there was no association between serum IL-18 concentration and tumor stage (p = 0.47). A significant difference was observed in serum IL-18 concentration according to the gender with higher IL-18 concentration
in male patients (p = 0.01). In conclusion, serum concentration of IL-6 might correlate with the stage of tumor progression in Iranian HNSCC
patients. Further studies with larger numbers of patients are required to exclude the possible minor correlation of serum
IL-18 concentration with tumor stage. 相似文献
4.
Janneta Tcherkassova Carolina Abramovich Rafael Moro Chen Chen Ralph Schmit Angela Gerber Ricardo Moro 《Tumour biology》2011,32(4):831-838
Ovarian cancer can be cured in up to 90% of cases if diagnosed early. CA125, the most studied ovarian cancer biomarker, exhibits
poor sensitivity for detecting early disease stages and low specificity to malignancy. RECAF, the alpha-fetoprotein receptor,
is a wide-spectrum oncofetal antigen with clinical potential for cancer diagnosis, screening, and monitoring. This study evaluated
the performance of RECAF as a diagnostic tool and the sensitivity of a combination of RECAF and CA125 to detect early stages
of ovarian cancer at a cutoff resulting in 100% specificity among healthy women. This retrospective case–control study was
designed to measure the serum levels of RECAF and CA125 in normal individuals (n = 106) and cancer patients stages I/II (RECAF, n = 32; CA125, n = 35) and III/IV (RECAF, n = 49; CA125, n = 51). A competitive chemiluminescence assay was developed to measure the circulating RECAF. To eliminate any false positives,
we classified as positive any patient with a RECAF or a CA125 value higher than their respective 100% specificity cutoff.
We have shown that RECAF discriminated cancer and healthy donors better than CA125, particularly in the early stages (AUCRECAF = 0.96 and AUCCA125 = 0.805). CA125 sensitivity was lower in the early stages than in the advance stages; RECAF sensitivity was high at all stages.
A combination of CA125 and RECAF detected three out of four early-stage patients, with no false positives. In conclusion,
the combination of RECAF and CA125 serum values provides the specificity and the sensitivity necessary to screen for ovarian
cancer and in particular, to detect early stages of the disease. 相似文献
5.
Elevated serum epidermal growth factor receptor level is correlated with lymph node metastasis in lung cancer 总被引:4,自引:0,他引:4
Sasaki H Yukiue H Mizuno K Sekimura A Konishi A Yano M Kaji M Kiriyama M Fukai I Yamakawa Y Fujii Y 《International journal of clinical oncology / Japan Society of Clinical Oncology》2003,8(2):0079-0082
Background: Using an enzyme immunoassay for epidermal growth factor receptor (EGFR), we investigated whether serum EGFR levels could
be used as predictors of the development and extent of lung cancer.
Methods: The study included 106 lung cancer patients and 16 patients with nonmalignant thoracic disease. Serum samples were collected
before clinical treatment.
Results: There was no difference between serum EGFR levels in patients with lung cancer (21.275 ± 22.035 fm/ml) in comparison with
those in nonmalignant-disease controls (22.630 ± 7.330 fm/ml; P = 0.8083). However, lung cancer patients with lymph node metastasis (23.515 ± 20.065 fm/ml) had significantly higher EGFR
levels compared with those in patients without lymph node metastasis (16.390 ± 10.970 fm/ml; P = 0.0228). The serum EGFR levels were similar in samples from lung cancer patients with various pathological subtypes. There
was no difference in the prognosis between the lung cancer group with normal EGFR levels (<850 ng/ml) and the group with elevated
EGFR levels (>850 ng/ml).
Conclusion: Serum EGFR levels may serve as a marker that can be used as an indicator of lymph node metastasis in lung cancer. However,
there was no difference between levels in patients with lung cancer and those in nonmalignant-disease controls, indicating
that the measurement of serum EGFR levels was of limited value in the detection of lung cancer.
Received: April 18, 2002 / Accepted: January 6, 2003
Correspondence to:H. Sasaki 相似文献
6.
Shang-Ying P. King Allison M. Agra Huey-Shin L. Shen Cecilia L. Chi David B. Adams Violante E. Currie Joseph R. Bertino Henry J. Pieniaszek Jr. Check Y. Quon 《Cancer chemotherapy and pharmacology》1994,35(2):101-108
The protein binding of weakly acidic and basic drugs has been shown to be altered in cancer patients. Brequinar is a weakly acidic, low-clearance, and highly protein-bound (>98% bound) antitumor agent. The pharmacokinetic parameters of brequinar are subject to large interpatient variability. This large interpatient variability may be related to brequinar's plasma protein-binding capacity (assuming no change in the intrinsic clearance of the unbound drug). The objectives of this study, therefore, were (a) to characterize brequinar's protein binding in the plasma of healthy donors and cancer patients and (b) to examine the relationships between brequinar's plasma protein binding and its pharmacokinetics in patients. Brequinar protein binding was determined in human serum albumin (HSA) solution, drug-free donor plasma, and brequinar-free, predose plasma samples obtained from a phase I cancer trial. Pharmacokinetic results from this study were used to examine relationships between plasma protein binding and drug disposition. In HSA solution and healthy donor plasma, brequinar's protein binding as determined using spiked samples was concentration-dependent. The unbound brequinar fraction increased by a factor of 3 (from 0.3% to 0.9% free) in 4% HSA solution and by a factor of 4 (from 0.4% to 1.6% free) in donor plasma as the brequinar concentrations increased from 0.1 to 2.3 mM in the HSA solution and from 0.076 to 1.5 mM in the donor plasma. Analysis of brequinar binding characteristics using the binding ratio and Rosenthal binding plots showed that albumin was the primary protein for brequinar binding in human plasma. The addition of various concentrations of 1-acid glycoprotein to 4% HSA solution did not affect the protein binding of brequinar to HSA. The protein binding determined in the plasma of cancer patients was not quantitatively different, except for variability, from that observed in the plasma of healthy donors. Examination of relationships between the unbound brequinar fraction and pharmacokinetics suggested that plasma protein binding was not a major determinant of brequinar disposition in cancer patients. 相似文献
7.
David M. Vigushin Grace K. Poon Alan Boddy Jacqueline English Gavin W. Halbert Christos Pagonis Michael Jarman R. Charles Coombes 《Cancer chemotherapy and pharmacology》1998,42(2):111-117
Purpose: d
-Limonene is a natural monoterpene with pronounced chemotherapeutic activity and minimal toxicity in preclinical studies. A
phase I clinical trial to assess toxicity, the maximum tolerated dose (MTD) and pharmacokinetics in patients with advanced
cancer was followed by a limited phase II evaluation in breast cancer. Methods: A group of 32 patients with refractory solid tumors completed 99 courses of d-limonene 0.5 to 12 g/m2 per day administered orally in 21-day cycles. Pharmacokinetics were analyzed by liquid chromatography-mass spectrometry.
Ten additional breast cancer patients received 15 cycles of d-limonene at 8 g/m2 per day. Intratumoral monoterpene levels were measured in two patients. Results: The MTD was 8 g/m2 per day; nausea, vomiting and diarrhea were dose limiting. One partial response in a breast cancer patient on 8 g/m2 per day was maintained for 11 months; three patients with colorectal carcinoma had prolonged stable disease. There were no
responses in the phase II study. Peak plasma concentration (Cmax) for d-limonene ranged from 10.8 ± 6.7 to 20.5 ± 11.2 μM. Predominant circulating metabolites were perillic acid (Cmax 20.7 ± 13.2 to 71 ± 29.3 μM ), dihydroperillic acid (Cmax 16.6 ± 7.9 to 28.1 ± 3.1 μM ), limonene-1,2-diol (Cmax 10.1 ± 8 to 20.7 ± 8.6 μM ), uroterpenol (Cmax 14.3 ± 1.5 to 45.1 ± 1.8 μM ), and an isomer of perillic acid. Both isomers of perillic acid, and cis and trans isomers of dihydroperillic acid were in urine hydrolysates. Intratumoral levels of d-limonene and uroterpenol exceeded the corresponding plasma levels. Other metabolites were trace constituents in tissue. Conclusions:
d-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports
further clinical evaluation.
Received: 25 June 1997 / Accepted: 6 November 1997 相似文献
8.
Nuhad K. Ibrahim Gabriel N. Hortobagyi Michael Ewer Mohammed K. Ali Lina Asmar Richard L. Theriault Giuseppe Fraschini Debra K. Frye Aman U. Buzdar 《Cancer chemotherapy and pharmacology》1999,43(6):471-478
Purpose: Correlation between aging and doxorubicin-induced congestive heart failure in patients with metastatic breast cancer was
studied to determine whether doxorubicin-induced congestive heart failure in elderly patients with metastatic breast cancer
is a clinically significant issue. Methods: This was a retrospective study with a median follow-up of 16.8 years. The setting was a comprehensive cancer center in a
large city. A group of 682 consecutive patients with metastatic breast cancer presented to The University of Texas M.D. Anderson
Cancer Center between 1973 and 1980. All patients received doxorubicin by bolus infusion. Patients in group 1 (n = 538) were aged 50 to 64 years; patients in group 2 (n = 144) were aged 65 years and older. Medical records of all patients were reviewed. Patients who had congestive heart failure
were identified and analyzed. The diagnosis of doxorubicin-induced congestive heart failure was made and confirmed by a cardiologist
at the time of its development. The main outcome measure was the cumulative probability of developing doxorubicin-induced
congestive heart failure in elderly patients with metastatic breast cancer compared to a younger age group. Results: In group 1, 33 patients, and in group 2, 13 patients developed doxorubicin-related congestive heart failure. The cumulative
doses of doxorubicin administered to patients with congestive heart failure were 410 mg/m2 (range 150–550 mg/m2) and 400 (range 100–570 mg/m2), respectively. The time interval from the last date of doxorubicin treatment to the development of congestive heart failure
was, respectively, 5 months (range <1–65 months) and 9 months (range <1–28 months). There was no statistically significant
difference between the two congestive heart failure subgroups, nor were we able to identify risk factors that could have increased
the risk of congestive heart failure among these patients. Conclusion: Older patients with metastatic breast cancer and no significant comorbidity can be treated with doxorubicin-based chemotherapy
with no added risk of developing congestive heart failure beyond that in the younger age group.
Received: 2 June 1998 / Accepted: 6 October 1998 相似文献
9.
Effect of high-dose cyclosporine on etoposide pharmacodynamics in a trial to reverse P-glycoprotein (MDR1 gene) mediated drug resistance 总被引:1,自引:0,他引:1
Lum BL Kaubisch S Fisher GA Brown BW Sikic BI 《Cancer chemotherapy and pharmacology》2000,45(4):305-311
Purpose: The consequences of using cyclosporine (CsA) therapy to modulate P-glycoprotein-mediated multidrug resistance include increased
myelosuppression, hyperbilirubinemia, and altered disposition of the cytotoxin. The purpose of this study was to analyze further
the relationship between the degree of leukopenia, and etoposide pharmacokinetic factors. Methods: Each patient initially received intravenously-administered etoposide alone (150–200 mg/m2/d × 3). Later it was given in combination with CsA administered at escalating loading doses (range 2–7 mg/kg) as a 2 hour
intravenous (IV) infusion followed by a 3 day continuous infusion, at doses ranging from 5 to 21 mg/kg/day. Serial plasma
etoposide concentration-time samples were assayed by high-performance liquid chromatography (HPLC). The area under the curve
(AUC) of unbound etoposide was calculated from the total plasma etoposide AUC using a previous published equation [22] where
% unbound etoposide = (1.4 × total bilirubin) – (6.8 × serum albumin) + 34.4. The percent decrease in white blood cell (WBC)
count and the total or unbound etoposide AUC relationship was fitted to a sigmoid Emax model adapted for paired observations,
where:
In this equation, Z was the variable describing the two treatment groups (0=no CsA and 1=CsA). The fitted parameters were
PDRV50, the pharmacodynamic response variable (PDRV) producing 50% of the maximal response; parameter β, which describes the effect
of the treatment group on the PDRV50; parameter H (Hill constant), which defines the slope of the response curve and parameter δ, which describes the effect of
the treatment group on parameter H. Results: CsA at a median concentration of 1,938 μg/ml resulted in a median increase in the total plasma etoposide AUC by 103% and
the calculated unbound plasma etoposide AUC by 104%. This paralleled a 12% greater median percent decrease in WBC count during
etoposide + CsA treatment (72% vs. 84%, P=0.03). The percent decrease in WBC count and total or unbound etoposide AUC relationship was fitted to the sigmoid Emax model.
The model using the unbound etoposide AUC described the data adequately (r=0.790) and was precise, with a mean absolute error of 6.4% (95% confidence interval: −4.9, 7.8). The fitted parameter-estimates
suggested that at equivalent unbound etoposide AUC values above 10 μg × h/ml, the sigmoid Emax model predicted a 5% greater
WBC count suppression when CsA was added to the treatment regimen. Conclusion: These findings suggest that a small degree of the enhanced myelosuppression observed with CsA combined with etoposide might
be attributable to inhibition of P-glycoprotein in bone marrow precursor cells. However, the majority of the effect observed
appears to be due to pharmacokinetic interactions, which result in increases in unbound etoposide.
Received: 14 December 1998 / Accepted: 15 September 1999 相似文献
10.
Szarvas T Jäger T Droste F Becker M Kovalszky I Romics I Ergün S Rübben H 《Pathology oncology research : POR》2009,15(2):193-201
Angiogenesis plays a critical role in tumor growth. VEGF, angiopoietins (Ang-1, Ang-2) and their tyrosine kinase receptor
Tie2 are major regulators of angiogenesis. The aim of this study was to evaluate the prognostic value of the serum levels
of these factors in bladder cancer. We analyzed the serum samples of 117 bladder cancer patients and 64 healthy volunteers
by enzyme linked immunosorbent assay (ELISA) for Ang-1, Ang-2, VEGF and the extracellular domain of Tie2. The statistical
evaluation of the obtained data was performed via Kaplan–Meier log-rank test, univariate Cox analyses as well as Cox proportional
hazards regression model. Serum Ang-1 levels of bladder cancer patients were significantly higher (p < 0.001), while soluble Ang-2 and Tie2 levels were significantly lower (p = 0.016 and p = 0.001 respectively) in patients than those in controls. Cox univariate analysis revealed high sTie2 serum level as a risk
factor for metastasis and as a borderline significant risk factor for disease related death (p = 0.022 and p = 0.081 respectively). These correlations were independent from tumor stage and grade in a Cox multivariate model (p = 0.016 and p = 0.069). These data indicate that the serum levels of analyzed angiogenic factors do change characteristically in bladder
cancer. The soluble extracellular serum level of Tie2 may provide a stage and grade independent diagnostic tool to select
a high risk group of bladder cancer patients. 相似文献
11.
Pelley R Ganapathi R Wood L Rybicki L McLain D Budd GT Peereboom D Olencki T Bukowski RM 《Cancer chemotherapy and pharmacology》2000,46(3):251-254
Purpose: To perform a phase II trial of pyrazoloacridine (PZA), a novel DNA intercalator, in patients with metastatic colorectal
carcinoma and no previous therapy. Methods: PZA was administered at a dose of 750 mg/m2 intravenously over 3 h every 21 days. Pharmacokinetic studies to determine PZA plasma concentrations were performed. Results: No responses were seen in 14 response-evaluable patients. Patients received a median of two cycles of PZA (range 1–6). Toxicity
included neutropenia and neurologic side-effects, which were ≥ grade III in 73% and 14%, respectively. High plasma concentrations
of PZA (Cmax) correlated with low neutrophil counts (P=0.04). Conclusions: PZA is inactive at this dose and schedule in colorectal cancer, and produces moderately severe toxicity.
Received: 18 October 1999 / Accepted: 16 March 2000 相似文献
12.
Laurent Nguyen Etienne Chatelut Christine Chevreau Brigitte Tranchand Isabelle Lochon Jean-Marc Bachaud André Pujol Georges Houin Roland Bugat Pierre Canal 《Cancer chemotherapy and pharmacology》1997,41(2):125-132
A population pharmacokinetics study using the NONMEM program was undertaken to determine the effects of different covariates
on the pharmacokinetic parameters of etoposide. A total of 1,044 plasma etoposide concentrations were determined by high-performance
liquid chromatography (HPLC) in 100 patients (pts; 75 men and 25 women aged 25–85 years) treated for various tumor types with
i.v. (57 pts) or oral (43 pts) etoposide. For 67 pts, etoposide plasma protein binding was determined by equilibrium dialysis;
the unbound fraction ranged from 4% to 24%. A linear two-compartment model with first-order absorption (for oral dosing) accurately
described the concentration versus time data. The central and peripheral volumes of distribution were significantly correlated
with the body surface area [Vc (L) = 5.5 × BSA (m2) and Vp = 4.1 × BSA], but even after BSA had been taken into account, the interindividual variability of the two volumes
remained high (34% and 57%, respectively). The clearance (CL) was not correlated with the following covariates: age, BSA,
sex, height, and levels of serum bilirubin and liver enzymes. The final regression model for CL was CL (ml/min) = 49.8 × (1 − 0.009 × PRO) ×
WT/Scr + 33.8 × (1 − 0.29 × META) × (1− (1 − 0.012 × ALB), where ALB
,
PRO
,
WT
,and Scr, respectively, were albuminemia, proteinemia (g/l), weight (kg), and serum creatinine (μM ) and META = 1 if the patient had liver metastases (otherwise, META = 0). The interindividual variability in CL (mean value
30 ml/min) decreased only from 32% to 26% when these covariates were taken into account. The mean oral bioavailability was
66%, showing an interindividual variability of 37%. The plasma clearance of the unbound fraction was strongly and negatively
correlated with Scr but was not dependent on either PRO or ALB. These data show that modifications in PRO levels do not directly
affect plasma exposure to unbound etoposide. This analysis makes possible the rational consideration of modifications of covariates
such as Scr in etoposide dosing. This population data base will constitute the prerequisite for adaptative control with feedback
dosing for continuous oral administration of etoposide.
Received: 12 January 1997 / Accepted: 9 June 1997 相似文献
13.
Cristiane Oliveira Gustavo J. Lourenço Priscilla M. R. Silva Cassio Cardoso-Filho Maira H. C. Favarelli Neiva S. L. Gonçales Maria S. C. Gurgel Carmen S. P. Lima 《Tumour biology》2011,32(2):295-300
The wild and the variant alleles of the C936T and G634C vascular endothelial grow factor (VEGF) polymorphisms seem to be linked to higher angiogenic phenotype than the remaining alleles and may act on breast cancer (BC)
origin. We investigated the influence of the VEGF C936T and G634C polymorphisms on the occurrence and clinicopathologic characteristics of sporadic breast cancer (SBC) in
235 patients and 235 controls. Peripheral blood samples of all individuals were analysed by the polymerase chain reaction
for identification of genotypes and by enzyme-linked immunosorbent assay (ELISA) for quantification of serum VEGF levels.
The variant 634CC genotype isolated (16.2% versus 10.7%, P
= 0.01) and in combination with the wild 936CC genotype (10.6% versus 5.5%, P
= 0.01) were more common in patients than in controls. The carriers of the respective genotypes were under a 2.20-fold and
a 3.08-fold increased risks for the disease. Additionally, the frequency of the wild 936CC genotype was higher in patients
with tumours of histological grade III compared to those with tumours of I+II histological grades (84.0% versus 64.7%, P
= 0.004) and in patients with positive oestrogen receptor tumours compared to those with tumours lacking oestrogen receptor
expression (84.7% versus 73.9%, P
= 0.02). Similar serum values of VEGF were seen in patients and controls with the distinct genotypes of the VEGF. The data suggest that the VEGF wild 936CC and the variant 634CC genotypes constitute inherited determinants of SBC and SBC aggressiveness in Brazil, but
are not significant predictors of circulating VEGF levels. 相似文献
14.
Teresa Warchoł Łukasz Kruszyna Margarita Lianeri Andrzej Roszak Paweł P. Jagodziński 《Pathology oncology research : POR》2011,17(1):133-137
We examined the distribution of the CCND1 A870G (rs9344) polymorphic variant in patients with cervical cancer (n = 129) and healthy individuals (n = 288) in a sample of a Polish cohort. We showed that patients with advanced cervical cancer bearing the CCND1 A/A and A/G genotypes displayed a 1.811-fold increased risk of cervical cancer (95% CI = 1.150–2.852, p = 0.0098). We also found a significantly higher frequency of the CCND1 870A allele in patients with cancer than in controls, p = 0.0116. Our investigation confirmed that the CCND1 870A gene variant may be a genetic risk factor in the incidence of advanced cervical cancer. 相似文献
15.
Circulating tumor stem cells (CTSC), a subpopulation of circulating tumor cells (CTC), may lead to recurrent diseases. The
aim of this study was to detect CTC (CD45−EpCAM+) and CTSC (CD45−EpCAM+CD44+CD24−) of breast cancer (BC) patients, as well as to explore their clinical relevance. CTC and CTSC in peripheral blood (PB) of
45 female BC patients were detected by using flow cytometry (FCM). SKBR-3 cells were mixed with MNC of four healthy volunteers
at different ratios in order to evaluate the sensitivity of FCM. Real-time quantitative polymerase chain reaction (QRT-PCR)
was conducted and compared with FCM. The expression of EPCAM between CTC < 50 and CTC ≥ 50 groups (19.98 ± 23.93 versus 29.46 ± 29.27 × 10−5), and the expression of CD44 between CTSC negative and positive groups (0.85 ± 0.91 versus 0.81 ± 0.75) were statistically
the same. FCM had higher specificity than QRT-PCR. Statistical differences were obtained between CTC < 50 and CTC ≥ 50 groups
among different TNM stages, histology stages, estrogen receptor (ER) status and progesterone receptor (PR) status (P < 0.05). Statistical differences between CTSC negative and positive groups within different TNM stages and regional lymph
node metastasis (RLNM) status (P < 0.05) were also obtained. Moreover, the percentage of CTC on CD45 negative cells (CD45−C) among different clinical pathology was statistically different, P = 0.000. Additionally, the percentage of CTSC on CD45−C with TNM stage was rising (0: 0.00 ± 0.00‰, I: 0.03 ± 0.05‰, II: 0.06 ± 0.14‰, III: 0.10 ± 0.09‰, IV: 0.29 ± 0.35‰, P = 0.034). Statistical difference in the percentage of CTSC on CD45−C among different RLNM status (P = 0.001) was also obtained. FCM to detect CTC and CTSC may be used to diagnose disease at early stage, to guide clinical
therapy or to predict prognosis. 相似文献
16.
H. S. Haugnes N. Aass S. D. Fosså O. Dahl O. Klepp E. A. Wist T. Wilsgaard R. M. Bremnes 《Journal of cancer survivorship》2008,2(3):128-137
Introduction We examined if testicular cancer (TC) treatment is associated with any risk for cardiovascular morbidity or predicted mortality
according to the SCORE model, in which a 10-year future risk of ≥5% for developing a fatal cardiovascular event qualify for
high-risk status.
Methods One thousand one hundred thirty-four TC survivors treated 1980–1994 participated in this study (1998–2002). Patients were
categorised in four treatment groups: surgery (n = 225), radiotherapy (n = 445), and two chemotherapy groups: cumulative cisplatin dose ≤850 mg (n = 375) and >850 mg (cis>850, n = 89). Patients with cardiovascular disease, diabetes or SCORE ≥5% constituted a high-risk group, and those with SCORE >1%
an intermediate/high risk group.
Results Age-adjusted mean SCORE was 0.93% for the surgery group. In comparison, chemotherapy treated patients had significantly higher
SCORE (1.07%, p = 0.01). Only 15% of patients were scored to be at high-risk, while 53% qualified for the intermediate/high risk group. Patients
in the cis>850 group had increased odds for having intermediate/high risk, compared with the surgery group (OR 3.4, 95% CI
1.3–8.7). Only 23 cardiovascular events had occurred since the testicular cancer diagnosis.
Conclusion The SCORE model indicates that patients treated with cisplatin-based chemotherapy have a significantly increased future risk
of a fatal cardiovascular event.
Implications for cancer survivors TC survivors should be followed regularly with respect to cardiovascular risk profile beyond the routine 10-year clinical
follow-up. 相似文献
17.
Hun-Taek Kim D.-K. Kim Yong-Baik Cho Taek-Soo Kim I. Jung Key H. Kim Dae Seog Heo Yung-Jue Bang Sang-Goo Shin Noe Kyeong Kim 《Cancer chemotherapy and pharmacology》1997,41(2):109-116
The effect of exposure time on the in vitro cytotoxicity of a new platinum complex, cis-malonato- [(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI 2053R) and cisplatin (CDDP) toward two human lung-adenocarcinoma
cell lines (PC-9, PC-14) and two human stomach-adenocarcinoma cell lines (KATO III, MKN-45) was investigated by variation
of the exposure time (1, 4, 12, and 24 h) and drug concentration to yield a constant product of drug concentration times exposure
time (C × T). Exposure of cancer cells to low concentrations of SKI 2053R for 12 or 24 h resulted in a greater killing effect
than did 1- or 4-h exposure to 24- or 6-fold higher concentrations; the inhibitory effects of SKI 2053R on the colony formation
of all tumor cell lines except for KATO III were significantly increased with increasing exposure time (P < 0.05). However, the inhibitory effects of CDDP against all tumor cell lines tested except for PC-14 were inversely correlated
with increasing exposure time (P < 0.05). The intracellular accumulation of SKI 2053R and CDDP was measured under the same conditions used in the cell-survival
assay using MKN-45 cells. The amount of platinum accumulated from SKI 2053R into MKN-45 cells was greater for the treatment
involving low concentrations and long-term exposures (12 and 24 h) than for that using high concentrations and short-term
exposures (1 and 4 h) at the constant C × T values; however, the increased accumulation of CDDP was more prominent as the
concentration was increased, even if the exposure time became shorter. The pharmacokinetics studies of SKI 2053R following
1-, 4-, 12-, and 24-h infusions were performed in beagle dogs. A single dose of SKI 2053R (5.0 mg/kg) was successively given
over various infusion periods to three beagle dogs at 3-week intervals. The peak levels of ultrafiltrable platinum observed
for SKI 2053R at the 1-, 4-, 12-, and 24-h infusions were 3.10 ± 0.49 (mean ± SD), 1.24 ± 0.06, 0.43 ± 0.07, and 0.25 ± 0.04 μg/ml,
respectively. The mean binding ratios of platinum from SKI 2053R to plasma protein at the end of 1-, 4-, 12-, and 24-h infusions
were approximately 91%, 73%, 53%, and 51%, respectively. The steady-state level of free platinum was maintained during long-term
infusions (12 and 24 h) after short periods (1–3 h) from the start of the infusion. This study strongly suggests that the
therapeutic efficacy of SKI 2053R given by continuous long-term infusion should be investigated in future clinical studies.
Received: 21 July 1996 / Accepted: 9 June 1997 相似文献
18.
N-myc downstream-regulated gene-1 (NDRG1) has been identified as a protein involved in the differentiation of epithelial cells.
As a newly metastasis suppressor gene, whether it contributes to carcinogenesis of breast cancer is still unknown. This study
aimed to clarify the possible role of NDRG1 for breast cancer carcinogenesis, and further to investigate its clinicopathological
significance in invasive breast cancer. We examined the expression of NDRG1 in normal epithelium of breast (n = 35), usual ductal hyperplasia (n = 22), atypical ductal hyperplasia (n = 33), atypical lobular hyperplasia (n = 8), ductal carcinoma in situ (n = 16), lobular carcinoma in situ (n = 6), invasive ductal carcinoma (n = 50), and invasive lobular carcinoma (n = 45) by immunohistochemistry and analyzed the correlation between NDRG expression and clinicopathological features of invasive
breast cancer. Western blot analysis was carried out to investigate the expression of NDRG1 in 20 invasive ductal breast cancer
and the paired non-tumor portion of the same case. NDRG1 expression in invasive breast cancer (70/95, 73.7%) was higher than
that in noninvasive breast lesions (29/85, 34.1%; p < 0.05) which was higher than that in normal breast epithelium (5/35, 14.3%; p < 0.05). Statistical analysis revealed a significant correlation between NDRG1 expression with tumor stage in invasive breast
cancer, and its expression in invasive ductal carcinoma is significantly higher than invasive lobular carcinoma (p < 0.05). It was not associated with age, menopausal status, tumor size, and lymph node metastasis. NDRG1 protein levels were
significantly higher in invasive ductal breast cancer compared to the paired non-tumor portion of the same case by Western
blot analysis (p < 0.05). Increased NDRG-1 expression is associated with breast atypia-to-carcinoma progression. NDRG1 expression might participate
in the carcinogenesis and progression of invasive breast cancer. These findings provide further evidence that NDRG1 may serve
as an important biomarker for invasive breast cancer. 相似文献
19.
Jimmy Bok-Yan So Khay-Guan Yeoh Shabbir Moochala Naresh Chachlani Jean Ho Wai-Keong Wong Peter Mack Peter M.-Y. Goh 《Gastric cancer》2002,5(4):0228-0232
Background: Our aim was to study the serum pepsinogen levels in gastric cancer patients in our population in relation to histology and
the presence of
Helicobacter pylori
.
Methods:
Forty-six patients with gastric cancer and 70 controls were studied prospectively in a 1-year period. Serum levels of pepsinogen
I (PG I), pepsinogen II (PG II), and gastrin were measured by radioimmunoassay.
Results: The mean PG I levels for cancer patients and controls were 83.5 μg/l and 60.9 μg/l, respectively (
P
= 0.03), the mean PG II levels were 27.2 μg/l and 12.1 μg/l respectively (
P
< 0.0001). The PG I/II ratio was significantly lower in cancer patients (
P
= 0.04) and in those with Helicobacter infection. Serum pepsinogen levels were not affected by any pathological characteristics.
Histology showed that the prevalence of chronic gastritis, intestinal metaplasia, and gastric atrophy was 97%, 56%, and 15%,
respectively.
Conclusion: The prevalence of gastric atrophy is low in our population, and serum pepsinogen measurement is not useful as a screening
tool for gastric cancer in this population.
Received: July 8, 2002 / Accepted: September 2, 2002
Offprint requests to: J.B.-Y. So 相似文献
20.
Apostolos Zaravinos Maria Chatziioannou George I. Lambrou Ioannis Boulalas Dimitris Delakas Demetrios A. Spandidos 《Pathology oncology research : POR》2011,17(2):181-190
RKIP has been shown to regulate the RAS-RAF-MEK-ERK kinase cascade acting as modulator of apoptosis and metastasis in prostate
cancer. Our goal was to examine the expression of the RAF (A-RAF, B-RAF and RAF-1) and RKIP genes in urinary bladder cancer. Microarray analysis and qPCR was employed to investigate the expression of RAF and RKIP, in 30 patients with transitional cell carcinoma (TCC) of the urinary bladder vs. the corresponding levels of adjacent normal
tissue. Computational analysis was also performed on Gene Expression Omnibus (GEO) datasets, to unravel differences in the
expression of RAF or RKIP between tumor and control samples, and between superficial and muscle invasive tumors. Microarray analysis revealed >2-fold
expression of BRAF and RKIP in T2, T3, grade III tumors vs. controls. B-RAF over-expression was verified by qPCR in pT1, grade III tumors vs. their normal counterparts (p = 0.016). qPCR revealed a significant RKIP reduction in TCC vs. normal tissue (p = 0.002 and p < 0.001 for T1, grade II and Ta-T1, grade III, respectively); All RAF genes were positively correlated among each other (A-RAF/B-RAF, p = 0.003; A-RAF/RAF-1, p < 0.001; B-RAF/RAF-1, p = 0.050), whereas B-RAF was negatively correlated with RKIP in TCC (p = 0.050). Further computational analysis revealed different expression profiles for the genes of interest, among muscle invasive
carcinomas, superficial TCCs, cystectomy specimens and normal tissue. The reduced RKIP mRNA levels in TCC and the elevated levels of B-RAF in pT1, grade III tumors vs. normal tissue, corroborate that these genes are involved in the pathogenesis of urinary bladder
cancer. 相似文献