Biomedical subjects

Nicolas Magné

Publications and source records attributed to Nicolas Magné.

At least 19 recordsLinked to original sources

PubMed2006

Sequence- and concentration-dependent effects of acute and long-term exposure to the bisphosphonate ibandronate in combination with single and multiple fractions of ionising radiation doses in human breast cancer cell lines.

Both bisphosphonates and radiotherapy are highly effective for the management of bone metastases. Our in vitro study examined the cytotoxic effects resulting from combinations of ibandronate and ionising radiations (RX) in various sequences on breast cancer cells. Single radiation doses were given before, at halftime of, or after acute ibandronate incubation (48 h). Single or fractionated radiation doses were applied at the end of chronic ibandronate incubation (5 weeks). Combination of acute ibandronate exposure and single radiation doses led to synergistic cytotoxic effects in MDA-MB-231 cell line, but only with low ibandronate concentrations in MCF-7 cell line. In both cell lines, synergy was more marked when ibandronate followed RX. After long-term ibandronate exposure, only high single radiation doses induced synergistic effects in MDA-MB-231 cell line. Synergy was only detected with low ibandronate concentrations in MCF-7 cell line. In both cell lines, fractionated radiation doses exerted similar effects. The combination of ibandronate with radiation can exert synergistic effects on the inhibition of breast cancer cells growth, depending on cell line, drug sequence and dosage. Our data might provide a rationale for associating bisphosphonates and radiotherapy for the treatment of bone metastases from breast cancer.

Antineoplastic Agents↗

PubMed2006

[Metastasis of a lumbosacral ependymoma with very long disease-free survival: a case report and review of the literature].

Ependymoma is rare glial tumour of the central nervous system and is considered to be low-grade. The lumbosacral location of spinal ependymoma is the most common. Prognosis of ependymomas is dependent on tumour location, histological subtype and differentiation, extent of the tumour and of the completeness of the surgical resection. One of the characteristics of this kind of tumour is to present the possibility of a seeding of the entire cerebrospinal axis, by the way of cerebrospinal liquid. We describe the case of a young male patient operated by incomplete resection of a lumbar ependymoma. Six months later, the patient's symptoms reappeared and an external radiotherapy at curative doses and chemotherapy were delivered. Evolution of the remaining tumour was diagnosed 6 years after at the primary site and operated by large incomplete resection. A second session of radiotherapy was therefore administered. Twenty-four years after this episode, cervical pain and gait troubles appear. Complete imaging study concluded to a cervical extramedullary intradural tumour and to the persistence of the primary lumbosacral tumour. Macroscopical complete resection of the cervical tumour was performed and pathological findings concluded to a metastasis of his lumbar ependymoma. External radiotherapy was delivered on this site with a total dose of 50 Gy. Eight years after this episode, the patient is alive without evidence of distant disease. The primary lumbosacral ependymoma is stable. Ependymomas are often recurrent at the primary site, but can seed on the entire cerebrospinal axis. Awareness of such aberrant tumoral behaviour, even after such a long disease free interval, may warrant more careful follow-up of patients with this diagnosis.

Adolescent↗

PubMed2006

NF-kappaB modulation and ionizing radiation: mechanisms and future directions for cancer treatment.

NF-kappaB transcription factor regulates important cellular processes ranging from establishment of the immune and inflammatory responses to regulation of cell proliferation or apoptosis, through the induction of a large array of target genes. NF-kappaB is now considered as an important actor in the tumorigenic process mainly because it exerts strong anti-apoptotic functions in cancer cells. NF-kappaB is triggered by chimio- and radio-therapeutic strategies that are intended to eliminate cancerous cells through induction of apoptosis. Numerous studies have demonstrated that inhibition of NF-kappaB by different means increased sensitivity of cancer cells to the apoptotic action of diverses effectors such as TNFalpha or chemo- or radio-therapies. From these studies as emerged the concept that NF-kappaB blockade could be associated to conventional therapies in order to increase their efficiency. This review focuses on the current knowledge on NF-kappaB regulation and discusses the therapeutic potential of targeting NF-kappaB in cancer in particular during radiotherapy.

Apoptosis↗

PubMed2006

French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC-GORTEC).

BACKGROUND: Unresectable carcinomas of the oropharynx and hypopharynx still have a poor long-term prognosis. Following a previous phase II study, this phase III multicenter trial was conducted between November 1997 and March 2002. METHODS: Nontreated, strictly unresectable cases were eligible. Twice-daily radiation: two fractions of 1.2 Gy/day, 5 days per week, with no split (D1-->D46). Total tumor doses: 80.4 Gy/46 day (oropharynx), 75.6 Gy/44 day (hypopharynx). Chemotherapy (arm B): Cisplatin 100 mg/m2 (D1, D22, D43); 5FU, continuous infusion (D1-->D5), 750 mg/m2/day cycle 1; 430 mg/m2/day cycles 2 and 3. RESULTS: A total of 163 evaluable patients. Grade 3-4 acute mucositis 82.6% arm B/69.5% arm A (NS); Grade 3-4 neutropenia 33.3% arm B/2.4% arm A (p < 0.05). Enteral nutrition through gastrostomy tube was more frequent in arm B before treatment and at 6 months (p < 0.01). At 24 months, overall survival (OS), disease-free survival (DFS), and specific survival (SS) were significantly better in arm B. OS: 37.8% arm B vs. 20.1% arm A (p = 0.038); DFS: 48.2% vs. 25.2% (p = 0.002); SS: 44.5% vs. 30.2% (p = 0.021). No significant difference between the two arms in the amount of side effects at 1 and 2 years. CONCLUSION: For these unresectable cases, chemoradiation provides better outcome than radiation alone, even with an "aggressive" dose-intensity radiotherapy schedule.

Adult↗

PubMed2005

Radiation recall: a well recognized but neglected phenomenon.

INTRODUCTION: Radiation recall is an inflammatory skin reaction at a previously irradiated field subsequent to the administration of a variety of pharmacologic agents. Although skin has been the major site of radiation recall toxicity, instances involving other organ have been reported. MATERIALS AND METHODS: Data for this review were identified by searches of Medline and Cancerlit. The search terms "radiation", "recall", and "toxicity" were used. References identified from within retrieved articles were also used. There was no limitation on year of publication and no abstract forms were included. Only articles published in English were taken into consideration. RESULTS: Idiosyncratic drug hypersensitivity phenomenon is a recent hypothesis which correlates best with the available facts at this moment. The phenomenon may occur days to years after radiotherapy has been completed. The majority of the drugs commonly used in cancer therapy have been involved in the radiation recall phenomenon. A mixed non-specific inflammatory infiltrate seems to be the common histopathologic criteria in previous published reports. Universally, corticosteroids or the use of non-steroidal anti-inflammatory agents, in conjunction with withdrawal of the offending agent, produce prompt improvement. CONCLUSION: We propose to collect all future radiation recall phenomenon in a Rare Cancer Network database in order to augment our understanding of this rare reaction.

Humans↗

PubMed2005

Cardiac toxicity assessment in locally advanced breast cancer treated neoadjuvantly with doxorubicin/paclitaxel regimen.

BACKGROUND: The psychological difficulty of accepting a mastectomy for locally advanced breast cancer (LABC) justifies the use of chemotherapy as neoadjuvant primary treatment. The aim of this prospective study was to assess the efficacy of the doxorubicin/paclitaxel (AT) schedule neoadjuvantly administered in terms of response rates and survival in patients with LABC, with a special focus on cardiac toxicity. PATIENTS AND METHOD: All patients were treated by doxorubicin (60 mg/m2 i.v.) bolus followed by paclitaxel (200 mg/m2) as a 3-h infusion. Treatment was repeated every 3 weeks for four or six courses and followed by surgery, radiotherapy, and hormonotherapy for patients with positive hormonal receptors. Patients with significant cardiovascular history or ECG abnormalities were not eligible for the study. Measurements of left ventricular ejection fraction (LVEF) were performed at baseline and at the end of chemotherapy. RESULTS: From 1998 to 2001, 34 consecutive patients followed up in our institution were entered into this study. Median age was 49 years (range, 32-68 years). Seventeen patients had stage IIB, 5 patients stage IIIA, and 12 patients stage IIIB disease. Twenty-one patients underwent conservative surgery, 7 radical surgery, and 6 patients no surgery due to metastatic disease occurring during treatment. An objective clinical response was noted in 22 (65%) of 34 patients (6 patients with histological complete response, 10 patients with rare malignant cells, and 6 patients with a partial response), 6 patients presented a progressive disease, and 8 patients a stable disease. Twenty-four patients have kept normal cardiac function, 7 patients had a cardiac toxicity as defined by the institution [4 (24%) of 17 patients received 360 mg/m2 of doxorubicin (A), 2 of 4 presented congestive heart failure (CHF), and 3 (21%) of 14 patients received 240 mg/m(2) of A without CHF]. Three patients did not receive four or six cycles as initially planned due to the progressive disease during the chemotherapy courses. These patients were excluded from the final analysis, particularly cardiac toxicity analysis. At time of median follow-up (42 months), 28 of 34 patients were alive (one death due to CHF, five others due to progressive disease). CONCLUSION: The AT regimen in neoadjuvant treatment for LABC remains efficient, but cardiac toxicity reported in this study underlies the necessity to optimize the schedule of AT combination.

Adult↗

PubMed2005

Prognostic impact of the epidermal growth factor receptor levels for patients with larynx and hypopharynx cancer.

The aim of this study was to analyse prognostic factors for disease free interval (DFI) and overall survival (OS) among patients with larynx and hypopharynx cancer requiring a total laryngectomy. Three groups of patients were studied according to the type of treatment they received. Fifty-eight patients had total laryngectomy, 71 patients had organ preservation treatment including induction chemotherapy followed by exclusive radiotherapy, 26 patients received induction chemotherapy followed by salvage total laryngectomy. The studied potential prognostic factors were age, gender, performans status, primary tumor localization, T status, N status, tumor volume and tumoral EGFR level (fmol/mg protein). The multivariate analysis showed that both N status and tumor volume were significant for DFI and OS. EGFR level was significant only for patients treated by induction chemotherapy and exclusive radiotherapy (p = 0.05 and 0.05 for DFI and OS length, respectively). Among this group, patients with tumor EGFR levels lower and higher than 100 fmol/mg protein had 53% versus 22% and 51% versus 18% 5-year of DFI and OS rates, respectively (Log rank test: p = 0.001 and 0.0001). EGFR determination appears to be a powerful prognostic parameter for patients treated by induction chemotherapy followed by exclusive radiotherapy. Laryngectomy seems to erase the prognostic impact of EGFR expression. These results profile the use of EGFR targeting therapy for this category of patients.

Adult↗

PubMed2005

[Role of an exclusive concomitant radio-chemotherapy treatment in non operable esophageal cancer: results of a 10-year experience in Antoine-Lacassagne Center].

Treatment of non operable esophageal cancer still remains debatable. To date, radio-chemotherapy treatment could be considered as a standard, offers to the patients real hope and a new area of management in this unfavourable cancer. The aim of the present study was to report retrospectively a 10 year experience in concomitant radio-chemotherapy primary treatment in non operable esophageal cancer patients in Antoine Lacassagne anti cancer Center. Between January 1989 and June 1997, 63 consecutive, previously untreated patients with squamous cell carcinoma of the esophagus and who were inoperable for various reasons were majoritably treated with cisplatin (70 mg/m2) at J1 plus 5-fluorouracil (800 mg/m2/d) from J1 to J5 every 3 weeks (78% of patients) concomitantly with external beam radiotherapy (2 types). Two other chemotherapy regimens has been also used. Seventy-five percent (47/63) of the patients received the stipuled concomitant radio-chemotherapy dose. Neutropenia in the form of WHO grade 3-4 : 27% (17/63) was observed, grade 3-4 anemia and thrombopenia in 16 (26 %) and in 9 (15%) patients, respectively, grade 3-4 emesis in 6 % (4/63), grade 3-4 mucositis in 10 % (6/63). On 47 patients with accessible responder status, 18 of them presented a complete response, 20 a partial response, 6 a stable disease and 3 a progressive disease. The median follow up was 7 years. The median overall survival was 9.6 months with 11% estimated to be alive after 5 years. Combined treatment with cisplatin 5-fluorouracil and radiotherapy for inoperable cancer of the esophageal is relatively well tolerated and reasonably efficacious in a very selected group of patients.

Adult↗

PubMed2005

[Targeted therapies and radiotherapy in colorectal cancer].

Growing evidence suggests that intracellular signal pathways play a significant role in radiation response. Promising results have been obtained in experimental studies assessing the combined use of specific inhibitors and radiotherapy. Based on these data, a number of clinical trials were started to enhance tumor responses and thus to decrease the rate of locoregional recurrences. Several prognostic factors on tumoral radiosensitivity have been identified including intracellular signal pathways. Nevertheless, these factors do not correlate with responses to targeted therapies. Concerning rectal cancer, promising results have recently been obtained with concurrent radiotherapy and a monoclonal antibody against VEGF (bevacizumab). Studies combining cetuximab (anti-HER1) and radiotherapy will start soon in this setting. Other specific inhibitors combined with radiotherapy are still in preclinical evaluation.

Colorectal Neoplasms↗

PubMed2004

[Targeted therapies: last focus on EGF receptor inhibitors in breast cancer].

EGF receptor is slightly expressed in breast cancer without any sufficiently impact on patient outcome. Nevertheless determination of EGFR level represents a certain interest in order to orientate a targeted therapy notably in the case of hormone therapy resistance. Based on preclinical findings, preliminary clinical study results confirms in vitro observations about the possibility to encompass the hormonotherapy or anti-HER2 resistance. But, future large clinical trials are necessary to redefine a new strategy to treat breast cancer patients.

Antibodies, Monoclonal↗

PubMed2004

Dual HER 1-2 targeting of hormone-refractory prostate cancer by ZD1839 and trastuzumab.

Epidermal growth factor receptor (EGFR) and HER-2 are associated with a poor prognosis in various cancers, including prostate cancer. Inhibition of these receptors may provide a treatment for hormone-refractory prostate cancer. The presence of HER-2 (Western blot) and EGFR (5830 fmol/mg protein, ligand-binding assay) was assessed in the hormone-refractory human prostate cancer cell line, DU-145. Cells were exposed to the selective EGFR-TKI (EGFR tyrosine kinase inhibitor) gefitinib ('Iressa; ZD1839) and/or the HER-2-targeted monoclonal antibody trastuzumab ('Herceptin'), for 96 h. Irradiation (RX) at 6 Gy the dose causing 50% growth inhibition, was applied 48 h after the start of drug treatment. There was a dose-related effect on cell survival for both ZD1839 and trastuzumab treatments. Combining ZD1839 and trastuzumab led to less than additive effects on cell survival. Chou and Talalay representations further characterised this less than additive effect on cell survival. The application of ZD1839 led to a marked elevation in the level of the negative regulator of cell division, p27. The ZD1839-trastuzumab combination had less of an impact on p27 expression compared with the effect of ZD1839 treatment alone. The lowest expression of the apoptotic-related protein, Bax, was observed in the presence of the drug combination. There was a significant interaction (synergism) between RX and either ZD1839 or trastuzumab treatments. In contrast, the drug combination with RX resulted in antagonistic cytotoxic effects. These results indicate an antagonistic interaction between EGFR and HER-2 targeting and provide molecular mechanisms supporting this observation. Data from DU-145 cells suggest that dual targeting of EGFR and HER-2 may be inappropriate for the treatment of hormone-refractory prostate cancer, especially in the context of their combination with RX.

Antibodies, Monoclonal↗

PubMed2004

Methylenetetrahydrofolate reductase gene polymorphisms and response to fluorouracil-based treatment in advanced colorectal cancer patients.

Methylenetetrahydrofolate reductase (MTHFR) controls intracellular CH2FH4 concentrations (required for optimal fluoropyrimidine efficacy) by irreversibly converting CH2FH4 into 5-methyltetrahydrofolate. MTHFR 677C>T and 1298A>C polymorphisms are linked to altered enzyme activity. Thus, mutated MTHFR tumours should, in theory, be more sensitive to 5-fluorouracil (5FU) than wild-type tumours. MTHFR polymorphisms in position 677 and 1298 were analysed in 98 colorectal cancer patients with unresectable liver metastases (57 men, 41 women, mean age 64 years) receiving 5FU-folinic acid. 677C>T and 1298A>C genotypes were determined simultaneously by melting curve analyses on liver metastases. 677C>T genotype distribution was 46.9% wt/wt, 34.7% wt/mut and 18.4% mut/mut; that of 1298A>C was 52.0% wt/wt, 35.7% wt/mut and 12.3% mut/mut. The response rate was not related to 1298A>C genotype but was significantly linked to 677C>T genotype (response rate: 40%, 21% and 56% in wt/wt, wt/mut and mut/mut, respectively; P = 0.040), with an increased response rate in mut/mut tumours relative to wt/wt (odds ratio = 1.88). Thymidylate synthase activity measured in metastases was a significant predictor of 5FU responsiveness and the addition of the 677C>T genotype improved model prediction. MTHFR 1298A>C polymorphism was significantly linked to specific survival, with homozygous mutated patients having the worst prognosis (P = 0.009, relative risk = 2.48 in mut/mut versus wt/wt). MTHFR 1298A>C genotype remained a significant predictor in a multivariate analysis including metastasis characteristics. The results suggest that MTHFR genotypes are relevant and independent factors of patient outcome in 5FU-based treatment of advanced colorectal cancer.

Adult↗

PubMed2003

ZD1839 (Iressa) modifies the activity of key enzymes linked to fluoropyrimidine activity: rational basis for a new combination therapy with capecitabine.

PURPOSE: The efficacy of new oral fluoropyrimidines, including capecitabine, is improved in cells expressing high levels of thymidine phosphorylase (TP) and low levels of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase. We used a human head and neck cancer cell line (CAL33) to examine the influence of cell cycle modifications on TS, TP, and dihydropyrimidine dehydrogenase activity. EXPERIMENTAL DESIGN: Cells were exposed to the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa(2)) and 5'-deoxy-5-fluorouridine (5'-DFUR), alone and in combination, for up to 96 h, and modifications in cell cycle, enzyme activity, and gene expression were examined. RESULTS: ZD1839 (24- to 72-h exposure) markedly reduced proliferation and caused a rapid increase in G(0)-G(1) and a decrease in S phase; a 40-fold decrease in TS activity at 24 h and a 2.5-fold increase in TP activity at 48 h were observed. A significant link between TP activity and expression was observed (r(2) = 0.98; P = 0.0068). Additional investigations pointed out an increased cellular production of 5-fluorouracil anabolites from 5'-DFUR when cells were preincubated with ZD1839. Dose-effect curves of ZD1839 and 5'-DFUR, alone and in combination, were examined. Combination indices for ZD1839 + 5'-DFUR were 0.58 +/- 0.1 and 0.63 +/- 0.1 for 50% survival and 25% survival, respectively. Additional investigations pointed out an increased cellular production of 5-fluorouracil anabolites from 5'-DFUR when cells were preincubated with ZD1839. CONCLUSIONS: These data demonstrate a strong synergistic interaction between ZD1839 and 5'-DFUR when ZD1839 is applied before or concurrently with 5'-DFUR. Such a drug combination would have two advantages: (a) the theoretical advantage of tumor selectivity of epidermal growth factor receptor-targeted therapy; and (b) the practical advantage of a combination therapy that could be administered p.o.

Administration, Oral↗

PubMed2003

Oxaliplatin-5-fluorouracil and ionizing radiation. Importance of the sequence and influence of p53 status.

OBJECTIVES AND METHODS: The association oxaliplatin (OXA)-5-fluorouracil/folinic acid (FUFA) is currently a standard first-line treatment for advanced colorectal cancer. The main objective of this experimental study was to examine the cytotoxic effects resulting from the addition of ionizing radiation (Rgamma) to the combination OXA-FUFA on 2 human colon cancer cell lines (SW403, p53 wild type and WiDr, p53 mutated). A clinically relevant drug sequence was used consisting in OXA during 2 h followed by FUFA over 24 h. The impact of the position of radiation (1 and 4 Gy) was tested: radiation 2 h before drug application, in the middle of the drug application or 24 h after the drug application. RESULTS: Both cell lines exhibited similar dose response curves to Rgamma alone, WiDr being more radio-sensitive than SW403 (IC50: 4.8 Gy and 7 Gy, respectively). The effects of Rgamma-drug combinations were assessed using a conventional isobolographic method and by computing a potentiation factor (F) defined as the ratio of IC50 drug combinations/IC50 drug combinations combined with Rgamma. The results from both calculation methods concurred: the combination of OXA-FUFA with Rgamma led to additive-antagonistic effects for the p53 mutated cell line (WiDr), whatever the sequence. In contrast, for the p53 wild type cell line (SW403), additive-synergistic effects were observed with, in this case, an optimal position for Rgamma occurring when applied before or at mid-drug application. CONCLUSIONS: These results could be taken into consideration for an optimal design of clinical protocols associating Rgamma and OXA-FUFA.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

[Cardiac tolerance of the combination paclitaxel-anthracyclines in the context of the management of cancer of the breast].

Within the past decades there has been major interest in associating the paclitaxel into the management of breast cancer patients with a strong improvement of clinical results. Moreover, doxorubicin is historically one of the major chemotherapeutic agents in breast cancer treatment. So, investigations of the combination of the paclitaxel with doxorubicin have logically taken place in the strategy of breast cancer management. Also, this association became a standard of care neoadjuvantly in locally advanced breast cancer. The aim of this review of literature consists to make a special focus on cardiac toxicity occurring after doxorubicin and paclitaxel association and to give adequate directions for the next future in this promising combination.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

[Pharmacological consequences of the targeting of epidermal growth factor receptor].

Through clearly identified molecular mechanisms, EGFR targeting leads to cell physiology modifications as cell proliferation, apoptosis and DNA repair. These mechanisms can explain the proper activity of EGFR targeting drugs but also represent a strong rational basis on which several experimental studies have been designed with combinations of EGFR targeting and cytotoxic agents (chemotherapeutic drugs and radiotherapy). These data led to the development of clinical trials combining EGFR targeting agents and anticancer drugs. There is however a lack of experimental data concerning the importance of the drug sequences and above all the impact of EGFR tumoral expression on the effects of combinations. The lack of knowledge on resistance mechanisms to EGFR targeting is also a difficulty for an optimal development of EGFR targeting in the clinics.

Antineoplastic Agents↗

PubMed2002

The raltitrexed-vinorelbine combination: a phase I pharmacokinetic and pharmacodynamic trial in advanced breast cancer.

PURPOSE: Combinations of vinorelbine (VRB) and drugs targeting thymidylate synthase (TS) such as 5-fluorouracil (5-FU) have proven clinical efficacy in the management of advanced breast cancer. Raltitrexed (RTX) is a recent TS inhibitor which shows advantages over 5-FU in terms of a lower incidence of toxicity along with a simpler administration schedule. We conducted a phase I trial of the VRB-RTX combination in 12 patients with advanced breast cancer. MATERIALS AND METHODS: Most of the patients were refractory to taxane-anthracycline combination therapy. Their median age was 51 years (range 33-70 years). RTX was given on day 1 and VRB on days 1 and 5 on a 3-week cycle. Three dose levels were initially planned with VRB and RTX increasing from 22.5 to 25 mg/m(2) and from 2.5 to 3 mg/m(2), respectively. RESULTS: From a total of 50 cycles (mean 4 cycles per patient, range 1-11), the maximal tolerated dose (MTD) was reached at VRB 25 mg/m(2) and RTX 3 mg/m(2) with grade 3-4 neutropenia as the dose-limiting toxicity (7/16 cycles and 3/5 patients at the MTD). Nine pretreated patients were evaluable for treatment efficacy and three of these showed an objective response (one complete response, two partial responses; mean duration 26 weeks, range 17-38 weeks). Pharmacokinetic follow-up was done for both drugs (RTX by LC-MS-MS and VRB by HPLC-UV detection). There was no interaction between RTX and VRB pharmacokinetics since the VRB AUC was not significantly modified between day 1 and day 5. There was no relationship between RTX AUC and hematological toxicity. In contrast, there was a highly significant relationship between the mean VRB AUC (days 1-5) and the absolute neutrophil count decrease (Emax model, Hill constant=4.38+/-2.59, EC(50)=508+/-53.2 micro g.h/l, r=0.75, P=0.0013). A similar relationship was noted for the platelet decrease but at the limit of statistical significance. CONCLUSIONS: The VRB-RTX combination appears to be a valuable treatment option in second-line treatment of advanced breast cancer. It is deliverable on an outpatient basis, shows an acceptable toxicity profile potentially manageable by VRB pharmacokinetic follow-up, and has promising antitumor activity in taxane-anthracycline-refractory patients. The recommended dose for further studies is VRB 22.5 mg/m(2) and RTX 3 mg/m(2).

Adult↗

PubMed2002

Prognostic value of tumoral thymidylate synthase and p53 in metastatic colorectal cancer patients receiving fluorouracil-based chemotherapy: phenotypic and genotypic analyses.

PURPOSE: The aim of this multicenter prospective study was to evaluate the role of intratumoral parameters related to fluorouracil (FU) sensitivity in 103 metastatic colorectal cancer patients receiving FU-folinic acid. PATIENTS AND METHODS: Liver metastatic biopsy specimens were obtained for all patients and primary tumor biopsy specimens for 54 patients. Thymidylate synthase (TS), folylpolyglutamate synthetase, and dihydropyrimidine dehydrogenase were measured by radioenzymatic assays; TS promoter polymorphism (2R/2R v 2R/3R v 3R/3R) was determined by polymerase chain reaction; and p53 protein and mutations were analyzed by immunoluminometric assay and denaturing gradient gel electrophoresis, respectively. RESULTS: p53 mutations were observed in 56.7% of metastases. TS activity was significantly higher in 2R/3R tumors as compared with 2R/2R or 3R/3R. TS activity in metastasis was the only parameter linked to clinical responsiveness (responders exhibited the lower TS, P =.047). Univariate Cox analyses demonstrated that TS activity in primary tumor (the greater the TS, the poorer the survival; P =.040), TS promoter polymorphism in primary tumor (risk of death of 2R/3R v 2R/2R, 2.68; P =.035), and p53 stop mutation in metastasis (risk of death of stop mutations v wild type, 3.14; P =.018) were the only significant biologic predictors of specific survival. Stepwise analysis did not discriminate between TS activity and TS polymorphism. CONCLUSION: Present results confirm the value of tumoral TS activity for predicting FU responsiveness, point out the importance of detailed p53 mutation analysis for predicting survival, and suggest that TS genotype in primary tumor carries a prognostic value similar to that of TS activity.

Adult↗