Early biotransformations of oxaliplatin after its intravenous administration to cancer patients.

This article deals with the fate of oxaliplatin 1 and 3 h after its i.v. administration (130 mg/m(2)) to three patients. Its binding to plasma proteins and penetration into red blood cells were monitored by chromatography on-line with inductively coupled plasma mass spectrometry. Oxaliplatin biotransformations in plasma ultrafiltrate (PUF) and in urine were studied by chromatography coupled to inductively coupled plasma mass spectrometry or to electrospray ionization mass spectrometry. In plasma, four platinum (Pt) compounds were found. The peaks at 200 and 160 kDa corresponding to gamma-globulins contained 40% of the Pt bound; the peak at 60 kDa corresponding to albumin contained 40% of the Pt found. The peak <2 kDa could correspond to oxaliplatin, to its degradation products, or to adducts between Pt compounds and low-molecular-weight species such as glutathione, L-methionine, and L-cysteine. In PUF and urine, oxaliplatin itself, its degradation products, Pt(dach)Cl(2), [Pt(dach)(OH(2))Cl](+), and species that have the same retention times as Pt(dach)(methionine) and [Pt(dach)](2)(glutathione) were found. One hour after infusion, oxaliplatin in PUF and urine represented 12 and 50% of the total Pt, respectively. Three hours after infusion, oxaliplatin, undetectable in PUF, represented 10% of total Pt in urine. Inside red blood cells, two Pt compounds were found. The Pt peak at 60 kDa corresponding to hemoglobin and the peak <2 kDa corresponding to low-molecular species contained, respectively, 60% and 40% of Pt found. This study demonstrates that in the first hours after its infusion, oxaliplatin, in addition to other Pt compounds, is present in plasma and urine and that Pt is bound to albumin, gamma-globulins, and hemoglobin.

Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer: A potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage.

PURPOSE: Patients with genetic fluorouracil (5-FU) catabolic deficiencies are at high risk for severe toxicity. To predict 5-FU catabolic deficiencies and toxic side effects, we conducted a prospective study of patients treated for advanced colorectal cancer by high-dose 5-FU. PATIENTS AND METHODS: Eighty-one patients were treated with weekly infusions of 5-FU and folinic acid. The initial 5-FU dose of 1,300 mg/m(2) was individually adjusted according to a dose-adjustment chart. Plasma concentrations of uracil (U) and its dihydrogenated metabolite, dihydrouracil (UH(2)), were measured before treatment, and the ratio of UH(2) to U was calculated. Pharmacokinetic and pharmacodynamic studies were conducted to look for a relationship between the ratio of UH(2) to U and 5-FU metabolic outcome and tolerance. RESULTS: The UH(2)-U ratios were normally distributed (mean value, 2.82; range, 0.35 to 7.13) and were highly correlated to (1) 5-FU plasma levels after the first course of treatment (r =.58), (2) 5-FU plasma clearance (r =.639), and (3) individual optimal therapeutic 5-FU dose (r =.65). Toxic side effects were observed only in patients with initial UH(2)-U ratios of less than 1.8. No adverse effects were noted in patients with UH(2)-U ratios of greater than 2.25. CONCLUSION: The UH(2)-U ratio, easily determined before treatment, could help to identify patients with metabolic deficiency and, therefore, a risk of toxicity.

Cytosolic p53 protein and serum p53 autoantibody evaluation in breast cancer. Comparison with prognostic factors.

Mutations of the TP53 gene induce the production of an abnormal protein (p53) with a prolonged half-life allowing its detection by monoclonal antibodies and leading to a development of serum p53 autoantibodies. We have quantified the protein p53 in 196 cytosols of primary breast cancer tissues, by an immunoluminometric method and searched for p53 autoantibodies in the sera of 101 patients, by an immunoenzymatic assay. The median value has been chosen as cut-off (0.26 ng/mg protein). 18.4% of tumors had a p53 level < 0.10 ng/mg protein, and 8.2% had a p53 level > or = 2.5 ng/mg protein (range: 0.43.37). We found a significant difference between p53 distribution (p = 0.003) and median level (p = 0.001) in ductal and lobular carcinomas. The p53 median levels were significantly different between the grade III versus the grade I tumors (p = 0.01) and versus the grade II tumors (p = 0.008). An inverse correlation was obtained between p53 levels and ER (p = 0.003) alone or with PR (p = 0.006). p53 autoantibodies were detected in 7.9% of cases (8/101). This p53 study shows correlations with some poor prognostic factors, but would require further evaluation to better define the patient groups with poor prognosis. The p53 detection autoantibodies is neither correlated with the p53 cytosolic assay nor with prognostic factors of breast cancer, and should therefore not be used for patient the selection of the patient groups with poor prognosis.

Specific H-Ras minisatellite alleles in breast cancer susceptibility.

Mutations in BRCA1 and BRCA2 genes account for the majority of familial aggregation of breast and ovarian cancers but other common genes in the population with low penetrance should be also involved in susceptibility to breast cancer. The H-ras minisatellite, located downstream of H-ras oncogene, is considered to be a likely candidate. Previous findings have estimated that as many as 1 in 11 cancers of the breast might be attributed to this region, but other studies observed inconsistent results. We propose to elucidate the potential role of H-ras locus in breast cancer, by looking at somatic alterations occurring in tumor DNAs such as the instability or the loss of heterozygosity (LOH) and by determining a potential correlation between constitutional specific H-ras alleles and clinical and/or pathological characteristics. DNA was extracted from 123 sporadic breast tumors and matched peripheral blood lymphocytes. 143 DNA samples from of peripheral blood lymphocytes from healthy donors served as a control population. The allelic diversity was determined by polymerase chain reaction analysis. Rare H-ras alleles were found to be present in about 9% of breast cancer patients while they were detected in only 1.4% of lymphocytes from healthy donors (P = 0.0044). Therefore, the risk of breast cancer is increased in patients with one or two rare alleles (odd ratio = 7.14 and 95% confidence interval = 1.94-22.27). Analyses of somatic alterations in tumor DNA have shown the lost of one allele, in general the longest, in 6.7% informative cases and an instability to H-ras locus in 6.5% tumors that appeared as a size increase of one of the two alleles. No correlation of rare H-ras alleles with clinicopathological parameters was found. Our results demonstrated an association of rare H-ras alleles with breast cancer and suggest that minisatellite H-ras may be considered as an informative marker for the breast cancer risk.

p185 overexpression in 220 samples of breast cancer undergoing primary surgery: comparison with c-erbB-2 gene amplification.

In breast cancer, DNA amplification of the oncogene c-erbB-2, encoding for the p185 protein, is associated with a poor prognosis. A retrospective study on a population of 220 cases of primary breast cancer permitted a quantitative measure of p185 oncoprotein overexpression by an immunoenzymetric assay and the determination of c-erbB-2 amplification by the Southern blot method. A correlation existed between the two measurements (r=0.85) using the double cut-off: DNA 2 copies and p185 400 U/mg protein, and only 2.7% of the cases were discordant. 13.2% of the tumors showed p185 overexpression. The percentage of tumors overexpressing p185 was significantly different between the groups with amplified and non-amplified c-erbB-2. We observed a significant correlation between p185 levels and tumor grade (p=0.03), and an inverse correlation with hormonal receptors (p=0.0001). The p185 assay could be an additional prognostic factor to better define patient subgroups with node negative, grade II, and positive or negative hormonal receptors.

Influence of scanning doses of iodine-131 on subsequent first ablative treatment outcome in patients operated on for differentiated thyroid carcinoma.

UNLABELLED: The therapeutic outcome after (131)I first ablative treatment in patients operated on for nonmedullary differentiated thyroid carcinoma was compared after both the currently used scanning dose of 111 MBq (131)I and a scanning dose of 37 MBq (131)I. METHODS: Two-hundred twenty-nine consecutive patients with no known metastases were retrospectively studied. They were divided in two populations according to the scanning dose (127 patients with 111 MBq and 102 patients with 37 MBq). All patients received 111 or 37 MBq (131)I for diagnostic purposes and 3.7 GBq (131)I for ablative therapy 9 days later. To assess the efficacy of the treatment, all patients were studied with (131)I and with thyroglobulin plasma assays 6-17 mo later. RESULTS: Successful outcome was significantly more frequent after a scanning dose of 37 MBq (131)I than after a scanning dose of 111 MBq (76% versus 50%, p < 0.001). The treatment efficacy was particularly enhanced after 37 MBq in patients with associated lymphocytic thyroiditis. CONCLUSION: In patients with no known metastases, our data suggest that the impairment of the treatment efficacy observed after a scanning dose of 111 MBq (131)I is related to a stunning effect on the thyroid remnants. The threshold amount above which this effect begins to occur in thyroid remnants could be between 37 and 111 MBq (131)I. Consequently, a scanning dose of only 37 MBq (131)I could be recommended before first ablative treatment. The absence of metastatic patients in our study prevents any conclusion about the possible stunning of the neoplastic tissue. Nevertheless, we must suspect such an effect and try to avoid it, especially during follow-up after first radioiodine therapy. For instance, one may consider postponing radioiodine treatment several weeks or even months after scanning dose administration or using only thyroglobulin measurement for patients who are likely to receive a subsequent radioiodine treatment.

[Flow cytometry in cancer of the bladder]. / Cytométrie en flux dans les cancers de la vessie.

We reassessed the use of DNA flow cytometry in bladder cancers on the basis of our research and already published findings. We discuss technical aspects underlying the validity of the results. Currently, the validity of DNA flow cytometry is established by parametric analysis of the DNA content of tumor cells found in the course of multiple biopsies of the tumor. In addition, we examine the results obtained with bladder washings and, in some cases, the results of biopsies of the bladder mucosa which may appear normal under cystoscopy. The complementarity of these examinations appears to be essential. Our experience confirms the results already published, suggesting that the frequency of DNA aneuploidy increases significantly according to the grade and the tumor stage. However, clinical interpretation of DNA flow cytometry results calls for some caution. There is a general consensus not to use these results in the screening of bladder cancers. However, DNA flow cytometry is particularly useful in the follow-up of carcinoma in situ since DNA aneuploidy is almost always present. DNA flow cytometry is also useful in the stratification of superficial grade 2 tumors. Finally, during the follow-up of invasive tumors, the persistence or appearance of DNA aneuploidy may be attributed to therapeutic resistance.

Association between H-ras minisatellite and colorectal cancer risk.

BACKGROUND: The H-ras locus has been suggested to play an important role in susceptibility to cancer. However, the results remain controversial. METHODS: In order to elucidate the potential role of the H-ras locus in colorectal carcinogenesis, 142 colorectal tumors with matched normal samples were studied for genomic instability and loss of heterozygosity (LOH), and 143 healthy samples of white blood cell DNA were examined by PCR, for H-ras allelic polymorphism. RESULTS: Nine percent of colorectal cancer patients constitutionally presented at least one rare allele versus 1.4% of healthy individuals (P = 0.0034). The risk of developing colorectal cancer increased significantly with the presence of rare H-ras alleles (odds ratio = 7.10 and 95% confidence interval = 1.92-26.35). The genotype associating one common allele and one rare allele was overrepresented in cancer patients (P < 0.01). No associations were observed between the rare alleles and tumor site or with the aggressiveness of cancer. Low frequencies of LOH (5%) and genetic instability (0.7%) at the H-ras locus were found in our colorectal cancer set. CONCLUSIONS: Consequently, the presence of uncommon alleles at the H-ras locus appeared to be an informative genetic marker.

Suppression of heparinization of central venous catheters between cycles of chemotherapy. Results of a phase I study.

A phase I study to evaluate heparinization of tunnelled subclavian catheters (TSC) was conducted in 42 patients who each had a TSC for chemotherapy. They were enrolled in the study from August 1994 to December 1995. The inclusion criteria were: age 18-70, no general anticoagulant treatment, TSC used only for chemotherapy, informed consent. Heparinization was performed at the end of each cycle and then at increasing intervals: 11, 13, 15, 17, 19, and 21 days. A 21-day interval was intended to mimic the suppression of heparinization between cycles. Heparinization was performed with a 250 IU/ml heparin solution. Anti-Xa activity was studied before each heparinization. For each interval, at least 5 patients were followed up for two cycles. If no blockages were present progression to the next step was authorized. If one blockage was observed 5 additional patients were required to have their TSCs heparinized after the same interval. Two blockages (block) after the same interval meant that the previous interval was recorded as the longest tolerable. There were no blocks with the 11-day interval (6 patients), 1 block after 13 days (10 patients), 1 block after 15 days (10 patients), and no blocks after 17 days (5 patients), 19 days (6 patients), or 21 days (5 patients). The median anti-Xa activity (curative rate 0.2-0.6) was, respectively 11 days 6.74; 13 days 5.47; 15 days 4.71; 17 days 3.61; 19 days 3.67; 21 days 5.10 (NS). Heparinization between two cycles of chemotherapy is unnecessary. A high level of heparin activity persisted constantly inside the catheter lumen through the 3-week observation period.

Determination of unbound platinum after oxaliplatin administration: comparison of currently available methods and influence of various parameters.

Variations in plasma protein binding may have profound effects on both disposition and activity of drugs, especially for those which are tightly bound to proteins, such as anticancer platinum derivatives. Methods of separation of the non-protein-bound fraction and some technical parameters may influence the results. We have compared ultrafiltration and ultracentrifugation, as well as the effect of potentially interfering factors, upon the determination of the plasma unbound platinum fraction after oxaliplatin administration to cancer patients. Ultrafiltration and ultracentrifugation provided very closely correlated results, so that either technique can be used. The ultrafiltration cut-off (3000-30,000 Da) devices, the type of tube for blood sampling and the type of anticoagulant (none, lithium heparinate or EDTA) did not influence the results markedly. In contrast, results were greatly influenced by freezing: erratic results were obtained on thawed plasmas when compared with those on fresh serum or plasma. Consequences may be important in usual practice, since many pharmacokinetic studies are carried out in multicentric trials with plasma processing centralized in one reference laboratory. The methods for the determination of protein-drug binding should be standardized and guidelines elaborated where optimal conditions for each type of binding assay are given.

Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients.

PURPOSE: A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial. PATIENTS AND METHODS: Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined. RESULTS: A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a > or = 50% dose increase. CONCLUSION: Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.

Predicting the efficacy of first iodine-131 treatment in differentiated thyroid carcinoma.

UNLABELLED: The purpose of this study was to search for predictors of (131)I first ablative treatment efficacy in patients with postsurgical remnants after total thyroidectomy for nonmedullary differentiated thyroid carcinoma with no known metastasis. METHODS: Thirty-seven patients were retrospectively studied. None presented antithyroglobulin antibodies. All patients received 111 MBq of (131)I for diagnostic purpose and, 9 days later, 3.7 GBq of (131)I for ablative therapy (IAT). To assess the efficacy of treatment, all patients were studied with (131)I and with thyroglobulin (Tg) plasma assays 6-15 mo later. Treatment was considered successful if no abnormal uptake was seen on whole-body scan and if the Tg plasma level was lower than 1 ng/ml. RESULTS: Ablative treatment was found to be successful in 17 patients [IAT(+)] and unsuccessful in 20 [IAT(-)]. There was no significant difference between the two groups for clinical and histological data, size of thyroid remnants on a 1:1 dot scan and TSH level just before treatment. Although Tg levels were not different in the two groups before scanning dose administration (D0), Tg levels were higher in IAT(-) group 9 days later, just before radioiodine treatment administration (D9) and, in contrast, Tg levels were higher in the IAT(+) group 5 days after treatment administration (D14). Tg percentage change between D9 and D14 was significantly higher in the IAT(+) group and, with an optimal cutoff value of 750%, this parameter would have been able to predict successful treatment in 9 of 10 cases and unsuccessful treatment in 18 of 21 cases. Conversely, Tg percentage change between D0 and D9 was significantly higher in the IAT(-) group and of 11 patients with more than 100% change, 10 belonged to this group. CONCLUSION: The increase in Tg during the first (131)I ablative treatment could be a good predictor of treatment efficacy for patients with nonmetastatic differentiated thyroid carcinoma. Conversely, the increase in Tg observed after the administration of the scanning dose of (131)I just before ablative therapy is associated with a more frequent incomplete ablation, perhaps reflecting a stunning effect on the thyroid remnants.

Rapid and sensitive high-performance liquid chromatographic analysis of halogenopyrimidines in plasma.

Recent studies have stressed the need for individual adjustment of 5-fluorouracil (5-FU) dosage. Most of the techniques previously reported are not well adapted to routine application. We describe a sensitive, selective and simple HPLC technique under isocratic conditions for the quantitation of 5-FU and other halogenopyrimidines. The proportion of reagents and internal standard were optimised to allow the use of minitubes, particularly adapted to large series of plasma assays. High extraction yield, 75% for 5-FU and 90% for 5-bromouracil and 5-chlorouracil, was obtained using 1.2 ml isopropanol-ethyl acetate (15:85, v/v) following precipitation of plasma proteins with 300 mg ammonium sulfate. The mobile phase was 0.01 M phosphate buffer (pH 3.0). Uracil and 5-fluorouracil were fully resolved with Spherisorb ODS2 column. The limits of quantitation and detection in human plasma were 6 ng ml(-1) and 3 ng ml(-1), respectively, for all compounds studied. The total analysis time required for each run was 25 min. Final results could be given within 90 min of blood sampling. At least 50 plasma samples could be analysed per day. This method has been successfully used for monitoring 5-FU-based treatments.

[Prognostic value of flow cytometry in squamous cell bronchogenic cancer. A retrospective study of 61 cases]. / Valeur pronostique de la cytométrie en flux dans les cancers bronchiques épidermoïdes. Etude rétrospective à propos de 61 cas.

To assess the prognostic value of flow cytometric analysis, 61 cases of operated squamous cell lung carcinoma were studied in terms of desoxyribonucleic acid (DNA) nuclear content and percentage of cells in DNA synthesis phase (% S). These parameters were determined on a fresh surgical sample. The S % was obtained in 25 cases. DNA index (DI) and % S were compared with survival and usual clinicopathologic characteristics for the prediction of survival. DNA content classified as DNA-diploid and DNA-aneuploid is not a prognostic factor for survival. DI higher than 2 seems to be predictive but needs confirmation. The % S and multiploidy are not predictive factors for survival.

Cumulative pharmacokinetic study of oxaliplatin, administered every three weeks, combined with 5-fluorouracil in colorectal cancer patients.

The cumulative pharmacokinetic pattern of oxaliplatin, a new diamminecyclohexane platinum derivative, was studied in patients with metastatic colorectal cancer. Oxaliplatin was administered by i. v. infusion (130 mg/m2) over 2 h every 3 weeks, and 5-fluorouracil and leucovorin were administered weekly. A very sensitive method, inductively coupled plasma-mass spectrometry, allowed for the determination of total plasma and ultracentrifugable (UC) and RBC platinum levels on day 1, at 0, 2, and 5 h, and on days 8, 15, and 22. Sixteen patients underwent three or more courses, and six of them underwent six or more courses. The platinum concentration curves were quite similar from one course to another, with a high peak value 2 h after administration (day 1, Cmax = 3201 +/- 609 microgram/liter) and a rapid decrease (day 8, 443 +/- 99 microgram/liter). Cmax of both total and UC platinum levels in plasma remained unchanged throughout the treatment. The mean total platinum half-life in plasma was 9 days. We found residual levels of total platinum on day 22 (161 +/- 45 microgram/liter), but we observed no significant accumulation for the four first cycles (P = 0.57). In contrast, platinum accumulated significantly in RBCs after three courses (+91% at day 22 of the third cycle versus day 22 of the first cycle, P = 0.000018), and its half-life there was equivalent to that of RBCs. The patterns of UC and total platinum concentration curves were very similar and correlated significantly (P < 10(-6)) at all sampling times. The mean UC:total platinum ratio was 15% at day 1 and 5% at days 8, 15, and 22 in the 3-week treatment course. Unlike cisplatin, which rapidly accumulates in plasma as both free and bound platinum, oxaliplatin does not accumulate in plasma, but it does accumulate in RBCs, after repeated cycles at the currently recommended dose (130 mg/m2) and schedule of administration (every 3 weeks).

Plasma sialic acid as a marker of the effect of the treatment on metastatic colorectal cancer.

The concentration of total sialic acid (TSA) is increased in the plasma of patients with many types of cancer. The purpose of this study was to assess the usefulness of the TSA marker in predicting the efficacy of the treatment, and to compare TSA with two common markers, carcinoembryonic antigen (CEA) and the carbohydrate antigen 19-9 (CA 19-9). The study was performed on 44 patients treated for advanced colorectal carcinoma by a weekly 8 h continuous infusion of 5-fluorouracil (1300 mg/m2) plus bolus injection of L-folinic acid (100 mg/m2). TSA, CEA and CA 19-9 levels were measured before and after 3 months of treatment and their variations analysed as a function of the response to the treatment. TSA levels of patients with metastatic colorectal carcinoma before treatment (959 +/- 265 mg/l) were significantly higher than those of 32 healthy people (584 +/- 99 mg/l). The percentage of patients with TSA concentration above the cut-off level (782 mg/l) was 73% before treatment and 23% after. All patients who experienced an objective response to the treatment (complete, partial or minor response) (n = 29) had a significant decrease of TSA levels (t = 5.96; P < 0.001). When the disease was considered as stabilised (n = 10), TSA changed slightly, but it increased with progressive disease (4 out of 5 patients). Changes in CEA and CA 19-9 did not correlate as well as TSA to the treatment efficacy. Initial levels of TSA did not permit prediction of the efficacy of the treatment since they were not significantly different between the five response groups. TSA seems to be more likely involved in tumour changes than in tumour volume. Its determination could provide useful information about the spreading and metastatic properties of the tumour. TSA normalisation is an indicator of probable tumour growth arrest and its elevation could be a marker of relapse.

Evaluation of the automated fluorescent analysis of the H-ras minisatellite after optimized PCR amplification in comparison with a standardized Southern blot technique.

Determination of allele sizes? loss of heterozygosity or genetic instability at minisatellite VNTR loci, are routinely performed by the conventional Southern technique. We have investigated the potential use of automated DNA sequencer for the analysis of the H-ras minisatellite. We report the modifications of amplification parameters and electrophoresis conditions on the sequencer. Seventy-one colorectal carcinomas and the corresponding normal tissues were amplified with fluorescent-labeled primers, analyzed on sequencer, and concurrently controlled by Southern blotting. The results on sequencer showed that a Hydrolink matrix used in non-denaturing conditions and a specific analysis software facilitate a more accurate fragment size calculation.

1,25-Dihydroxyvitamin D3 induces programmed cell death in a rat glioma cell line.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), a seco-steroid hormone with potential antitumoral activities, has been recently reported to exert cytotoxic effects on C6 glioma cells. However, the molecular mechanisms which trigger this cell death remain unknown. We show here that this 1,25(OH)2D3-induced cell death is dependent upon protein synthesis and is accompanied by the expression of c-myc, p53, and gadd45 genes. Two other genes, coding for interleukin-6 and vaso-endothelial growth factor, are also upregulated after addition of 1,25(OH)2D3. This programmed cell death can be suppressed when cells are treated with forskolin, a drug which increases intracellular cAMP concentration, or with genistein, an inhibitor of tyrosine protein kinases. However, in spite of the demonstration of fragmented DNA in 1,25(OH)2D3-treated cells, the C6.9 cells used in this study do not show the classical morphological features of apoptosis. These results provide the first evidence for the existence of a programmed cell death triggered by 1,25(OH)2D3 in glioma cells and may provide a basis for the development of new therapeutic strategies. In addition, these data also suggest that the treatment of C6.9 cells with 1,25(OH)2D3 may be a useful model to study the molecular mechanisms involved in the programmed cell death of a cell of glial origin.

Relationship between 5-fluorouracil (5-FU) dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing 5-FU.

BACKGROUND: A phase II prospective trial was carried out to study the concept of 5-fluorouracil (5-FU) dose-intensity in patients with advanced colorectal cancer. Forty patients were treated with 5-FU plus leucovorin (LV), with individually increasing doses of 5-FU. A 5-FU pharmacokinetic follow up was performed and a relationship was sought between its metabolism and its response to treatment, and between 5-FU's toxicity and patient survival. METHODS: 5-FU was administered weekly by 8 hour continuous infusion. The initial dose of 1000 mg/m2 was individually increased every 3 weeks by 250 mg/m2 steps, potentiated by 400 mg/m2 LV. 5-FU plasma concentrations were determined weekly by liquid chromatography. RESULTS: Eighteen overall objective responses and 22 minor responses, stabilizations, or progressions (NR) were observed. 5-FU plasma levels were significantly higher in cases of complete or partial response, whatever the dose. They reached about 2000 micrograms/l as early as the second dose level (1250 mg/m2). Only seven patients who experienced NR reached equivalent levels after the fourth step (1750 mg/m2). High 5-FU plasma levels were predictive of an objective response and better survival (difference not significant). The acute toxicity, whatever the type, was correlated with 5-FU levels > 3000 micrograms/l and not with the dose. CONCLUSIONS: This study shows the wide variability of 5-FU metabolism, whatever the dose, the clear relationship between 5-FU plasma levels, toxicity, and efficacy. This relationship points out the problem of the polymorphism of 5-FU metabolism, the usefulness of the therapeutic range determination and the usefulness of the individual 5-FU dose adaptation.

[Maintenance of the dose-intensity of chemotherapy combining carboplatin, cyclophosphamide, etoposide in women with ovarian cancer aged 70 and over]. / Maintien de l'intensité de dose d'une chimiothérapie associant carboplatine, cyclophosphamide et étoposide chez la femme de plus de 70 ans atteinte d'un cancer de l'ovaire.

Elderly patients are often considered as subjects at risk for bad tolerance to chemotherapy. They are therefore treated in a less aggressive way compared with younger women. In a retrospective study, we evaluated the dose-intensity of a chemotherapy for 15 patients older than 70 years of age, presenting an ovarian carcinoma. Median age was 73 years. All but one were classified in stage III-IV and only four were presented with a complete surgery or with a pathological residue < 2 cm. Six patients were considered as non operable. Performance status (PS) was in 11 cases equal to 0 or 1. The treatment associated from D1 to D4: carboplatine 75 mg/sqm/day, cyclophosphamide 250 mg/sqm/day, etoposide 50 mg/sqm/day for six cycles each over four weeks. We compared for each drug the delivered dose-intensity (DID) all along the six cycles to the forecast dose-intensity (FID). Except for the patients with a PS > or = 2, treated in first intention by a 2/3 dose, the DID/FID ratio was > 90%. It decreased between the 1st and 3rd cycles, then remained unchanged. Treatment was well tolerated by patients with a PS < 2 whose 4/11 have presented a grade III-IV hematologic toxicity. In return, despite the initial dose reduction, 3/4 patients with a PS > or = 2 had severe complications. There were no toxic deaths. Three patients only had a delay for reinduction. Three out of six non operables at first had a surgical second-look with possibility of residual masses cutting of (3 PRh). Four patients were alive in first CR at 18, 22, 23 and 28 months. Women older than 70 years with a good performance status presenting an ovarian carcinoma can be treated as younger women are. A chemotherapy using efficient drugs can be delivered with an acceptable toxicity and a high dose-intensity.