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Biomedical subjects

B Desoize

Publications and source records attributed to B Desoize.

71 records · Page 4Linked to original sources
PubMedDate not supplied

Multicellular resistance: a paradigm for clinical resistance?

Research on resistance to cancer treatment was mainly focused for 20 years on multidrug resistance (MDR). No useful method of reversing MDR, suitable for clinical use, has yet emerged from this large quantity of work. The reason could be an inadequate evaluation of the target. When grown in spheroids, cancer cells exhibit a phenomenon known as 'multicellular resistance' (MCR). Tumours in patients seem to present the same characteristics. The mechanisms underlying MCR can be classified into two forms: contact resistance and resistance inherent in the spheroid structure. Mechanisms of MCR include: inhibition of apoptosis, high proportion of quiescent cells, modulation of protein expression (including topoisomerases and repair enzymes), potential permeability problems, presence of a hypoxic and necrotic centre and other possible mechanisms that remain to be discovered. A new therapeutic class of drugs is required to overcome MCR. Compounds, which are able to disrupt communication and binding between tumour cells and their microenvironment, seem to be able to circumvent MCR. Interesting results are obtained in vitro and in vivo in mice with specific antibodies or peptides recognised by cell binding proteins. Interestingly, these compounds also appear to be able to inhibit metastasis. Hyaluronidase has already been used with anticancer drugs in patients and was shown to increase drug potency. The explanation given is that it improves drug penetration into spheroids. We now hypothesise that hyaluronidase, in fact, decreases MCR and thus could be the first member of a new therapeutic class.

Animals↗
PubMedDate not supplied

Combination chemotherapy with cisplatin, etoposide and gallium chloride for lung cancer: individual adaptation of doses.

Twelve inoperable lung cancer patients were treated with a combination chemotherapy of cisplatinum (CDDP) and etoposide (VP16), as a continuous infusion for 5 days, every 21 days, and with a daily oral administration of GaCl3. Dosages of CDDP and VP16 were adapted in order to obtain an area under the curve (AUC) of 80,000 micrograms l-1.h for plasma total platinum and of 200 mumol.l-1 h for plasma VP16 during each 120 h infusion. GaCl3 was given at the dosage of 400 mg/24h from the time of diagnosis at least until the evaluation after 3 courses of chemotherapy. An objective response was observed in 5 non small cell (NSCLC) lung cancer patients (group 1) and 3 small cell (SCLC) lung cancer patients (group 2). In the other 4 patients with a NSCLC no partial response was noted (group 3). No significant difference in area under the curve (AUC) was noted between the 3 groups, either for plasma total platinum (group 1 = 89,598 +/- 20,843 micrograms l-1.h; group 2 = 88,081 +/- 15,431 micrograms l-1.h; group 3 = 83,820 +/- 13,455 micrograms l-1.h), or for VP16 (group 1 = 227 +/- 41 mumol.l-1 h; group 2 = 217 +/- 29 mumol.l-1.h and group 3 = 211 +/- 30 mumol.l-1.h). The maximal plasma Ga concentrations were 244 +/- 34 micrograms/l in group 1, 112 +/- 57 micrograms/l in group 3 (p less than 0.005) and 243 +/- 132 micrograms/l in group 2. It was then decided to increase the dose of GaCl3 in the further non-responding patients. In 6 responders, 3 additional courses of this combination chemotherapy could have been given without major toxicity, allowing a much more important decrease in the tumor volume in 4 of them. This schedule of treatment should permit the chemotherapy to continue for longer than 6 courses, in order to improve the survival time.

Adenocarcinoma↗
PubMedDate not supplied

Plasma acid and alkaline phosphatase in patients with breast cancer.

Acid and alkaline phosphatase were determined in 107 breast cancer patients to study their potential value in case of bone metastases. The patients were divided into 4 groups: A, patients without metastases (n = 34); B, metastatic patients without bone lesions (n = 37); C, patients with metastases in and outside of bones (n = 24), D, patients with bone-only metastases (n = 12). Tartrate resistant acid phosphatase (TR-ACP), and bone alkaline phosphatase (bone-ALP) were significantly higher in patients with metastases than in patients without. However, no difference in TR-ACP was observed between subgroups of metastatic patients.

Acid Phosphatase↗
PubMedDate not supplied

[The effect of cross-linked protein microcapsules on cell cultures].

Microcapsules (diameter range: 5 to 100 microns) prepared through interfacial cross-linking of proteins with terephthaloylchloride exhibited a cytotoxic effect on L 1210 cell cultures. IC50 was: 0.86 mg/ml +/- 0.24 for microcapsules prepared from human serum albumin (AT microcapsules) and 0.63 mg/ml +/- 0.05 for those obtained from egg white lysozyme (LT microcapsules). With K 562 cells IC50 were 0.42 +/- 0.11 mg/ml (AT microcapsules), 0.06 mg/ml (LT microcapsules). An increase in the cytotoxicity was observed when reducing the size of the microcapsules and when increasing the reaction pH or the terephthaloylchloride concentration, or the relative concentration of microcapsules vs cells. On the contrary, the cytotoxic effect decreased, when prolonging the cross-linking time. The activity was not affected when the microcapsules were washed with toluene or with an alkaline solute. The cytotoxic effect, which appears for relatively high doses, apparently involves a contact between the microcapsules and the cells and seems to be related with the degree of cross-linking of the constitutive protein.

Capsules↗
PubMedDate not supplied

Response of primary tumour, spontaneous metastases and recurrence of Lewis lung carcinoma (3LL) to flavone acetic acid (FAA, LM975).

B6D2F1 mice bearing 3LL were more sensitive to FAA than control mice, the LD50 being 180 x 2 and 336 x 2 mg/kg respectively. At a dosage of 140 mg/kg, injected i.p. at day 4 and 11, FAA significantly decreased the primary tumour growth, the occurrence and the growth of spontaneous pulmonary metastases. The effect of two injections was dose-dependent on the primary tumour and metastases; the survival time was also dose-related. Combined with primary tumour ablation, FAA administered before any dissemination (at day 3) was more efficient against metastases than when it was injected after the end of the dissemination (i.e. after primary tumour ablation). When all treatment schedules were pooled, the number of mice without metastasis was significantly higher in treated than in control groups. The effect of FAA on recurrences was also notable.

Animals↗
PubMedDate not supplied

Isoenzymes of alkaline and acid phosphatases as bones metastasis marker in breast cancer patients.

Bone alkaline phosphatase (B-ALP) and tartrate resistant acid phosphatase (TR-ACP) are markers of osteoblastic and osteoclastic activities respectively. During a period of up to two years, these isoenzymes have been assayed in the sera of 191 breast cancer patients; 80 had bone metastases (BM). In BM bearing patients, B-ALP activity was 261 IU/l and 63 IU/l for patients without BM; TR-ACP was respectively 6.6 and 3.3 IU/l. Specificity and sensitivity were calculated according to several criteria. These isoenzyme serum levels were well correlated with those of two breast cancer markers (CEA and CA15.3) and radiograph.

Acid Phosphatase↗
PubMedDate not supplied

Comparison of two dose prediction models for cisplatin.

Cisplatin toxicity could be decreased by adjusting its dosage to each patient. For this purpose, a limited sampling method was established and validated based on a Bayesian approach taken using the values of assays during a 5-day continuous infusion of cisplatin. Using this method, a dosing model to achieve a target plasma concentration of total platinum (Pt) was evaluated retrospectively; the calculated dose of cisplatin was 95.0 to 104.8% of the actual dose. This model was then studied prospectively and the actual plasma Pt concentration reached at the end of the infusion was 94.9% of the target concentration. A strong correlation was observed between the clearance of Pt and the calculated clearance of creatinine or Cockroft index (p = 1.7 x 10(-11), and this correlation was used to develop another cisplatin dosing model. With this model the actual concentration reached at the end of the infusion was 85.3% of the theoretical concentration. The Bayesian approach gave reliable results for most clinical uses, whereas the creatinine based model has to be improved.

Bayes Theorem↗
PubMedDate not supplied

Anticancer drug resistance and inhibition of apoptosis.

Apoptosis is a new concept which could be of great importance in the understanding and treatment of cancer. An important feature is the discovery of inhibitors of apoptosis, because they induce resistance to chemotherapeutic drugs and irradiation. Bcl-2 is the most well known of these apoptosis inhibitors. When it is overexpressed cells are less sensitive to cytotoxic drugs; on the contrary, when it is underexpressed they are more sensitive. Clinically, bcl-2 expression is associated with a poor prognosis in several cancers. Bcl-2 protein, p26-bcl-2, is located in the outer mitochondrial membrane, the nuclear envelope and the smooth endoplasmic reticulum. P26-bcl-2 is an antioxidant; this property could explain the anti-apoptotic activity since peroxides seem to be important mediators of apoptosis. Bcl-2 antisense oligonucleotides are able to reverse the apoptosis inhibition. New cancer treatments should take into account the expression of bcl-2.

Animals↗
PubMedDate not supplied

Culture conditions modulate the effects of aclacinomycin A on growth, differentiation and apoptosis of HL60 cells.

The continuous incubation for several days of HL60 cells, in exponential growth, with aclacinomycin A (ACM) induces growth inhibition, necrosis, differentiation and apoptosis. Differentiation and apoptosis were assessed by optical microscopy (OM) and flow cytometry (FCM). ACM displayed dose-dependent effects, except for the differentiation induction, which was biphasic. Differentiation and apoptosis could also be induced after a 1 h ACM exposure only. The poor reproducibility of apoptosis induction led us to study the culture conditions described in the literature (without renewing the medium) where control cells are not growing exponentially during the 5 day incubation period. During kinetic studies with different ACM concentrations, the differentiation was detected earlier by FCM than by OM, while it was not the case for apoptosis. This induction appeared more reproducible when non optimal conditions of culture were used.

Aclarubicin↗
PubMedDate not supplied

Characteristics of four Friend leukemia cell sublines resistant to adriamycin.

Resistance of Friend murine erythroleukemia cells was induced or selected by continuous stepwise exposure to adriamycin (ADM). The resistance index (R.I.) varied with different "mdr type" drugs, even when the compounds were closely related as ADM and daunorubicin (DNR). The cell uptake of anthracycline, evaluated by flow cytometry (FCM), was better correlated with the R.I. than the HPLC assessment. The quantitative cytology showed nuclear changes (size and color distribution); all the modifications were in part dependent on the degree of resistance. This study showed that the graded resistant sublines differed in their resistant phenotypes apart from their different degree of resistance.

Animals↗
PubMedDate not supplied

Chronology of combined chemotherapy (5FU) and radiotherapy. I. In vitro study.

Since radiotherapy or chemotherapy alone may be ineffective, they are more and more often combined. In this in vitro studies the effects of the chronology of the treatments and of the time interval between them are evaluated. In murine leukaemia L1210 cells and in murine mammary adenocarcinoma Ca755 cells the highest efficacy, i.e. the lowest survival fraction, was observed when radiotherapy was administered 6 h before Fluorouracil (FU). To mimic treatment in man, a daily combined treatment was also tested. Under these circumstances, the chronology of the treatments and the time interval between them had different consequences, the highest efficacy being noticed when both treatments were given at the same time.

Adenocarcinoma↗
PubMedDate not supplied

Chronology of combined chemotherapy (5FU) and radiotherapy. II. In vivo study.

In a previous study, we reported that repeated combined chemotherapy and radiotherapy, and a single combined treatment had different consequences. In this study the effect of the chronology of the repeated combined treatments was tested, i.e. it was determined whether the treatment is more efficient when the first treatment is Fluorouracil or irradiation, or when they are given simultaneously. It was first demonstrated that, under our conditions, neither radiotherapy nor chemotherapy were chronodependent. The combined treatments were more efficient that the single treatment although their chronology had no significant consequences. Nevertheless, the simultaneous treatment appeared slightly better than the administration of Fluorouracil 6 h before or 6 h after irradiation. These results confirm our in vitro experiments.

Adenocarcinoma↗
PubMedDate not supplied

Prognostic significance of routine clinical and laboratory data in advanced head and neck cancers.

Predictive factors for toxicity and response to chemotherapy in patients with advanced head and neck cancer are seldom reported. Therefore, from a short series of patients with a histologically proven cancer, who were treated by a neo-adjuvant protocol with cisplatin and fluorouracil, routine clinical and laboratory data were investigated. ALT (alanine aminotransferase) and Hb (hemoglobin) appeared to be predictive for efficacy. By multivariate analysis (principal component analysis), these laboratory data were involved in two independent axes: one which was considered as "inflammatory" and the other as "hepatic". Initial obesity indices were associated with the former. The predictive variables for toxicity (i.e. age, serum creatinine level, weight loss and plasma cisplatin) were probably biased in this series. Nevertheless cisplatin concentration regularly increased in each cycle. Hence it was dependent on the rank of the course. According to this preliminary study, it would be of interest to conduct future investigations on acquired protein-energy malnutrition, as well as on selected soluble mediators of cellular and humoral immune response.

Adult↗
PubMedDate not supplied

Evaluation of two dose individualisation methods for carboplatin.

The pharmacokinetics of carboplatin are usually evaluated by measuring plasma concentrations of ultrafiltered platinum (UP). This approach, however may be less reliable than measuring the plasma concentration of total platinum (TP). In a group of 14 patients, which constituted a reference group, the clearance of TP was highly correlated with creatinine clearance, as estimated by the method of Cockroft and Gault. This relationship, together with only morphological and biological parameters, was used to estimate TP clearance, Vc and AUC, in a validation group of 8 patients. Estimated TP clearance was 97.9 +/- 18% of the actual value. The TP pharmacokinetic parameters of the reference group were used to estimate those of the validation group, using only two or three plasma concentration measurements (Bayesian approach). With the Bayesian approach, the estimated TP clearance was up to 99.9 +/- 2.7% of the actual value. In conclusion, estimation of TP pharmacokinetics may be reliably estimated as an alternative to UP in clinical practice.

Adult↗
PubMedDate not supplied

Cell culture as spheroids: an approach to multicellular resistance.

Cells cultured as spheroids present an heterogeneity similar to that of tumours in vivo. In the spheroid peripheral layers, cells are proliferating, deeper cells are non-cycling, when in the aggregate centre, cells form often a necrotic core. A multicellular resistance is related on the cell contact to other cells or to the extracellular matrix. The mechanism of this resistance remains unknown. It seems to be linked to the spheroid centre hypoxia, quiescence of a large fraction of the cell population and to the apoptose inhibition. The "classical" or "unicellular" mechanisms of resistance, as mdr1, MRP, can coexist but are not responsible of this type of resistance. This culture model is a good opportunity to study a resistance which looks close to the patient tumour resistance. A new class of therapeutic molecules appears that can reverse multicellular resistance, inhibit tumours growth and preclude metastases. The mechanism of action of this new pharmacological class is the disruption of the cell adhesion forces.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Puzzles in the clinical pharmacokinetics of fluorouracil.

The pharmacokinetics of fluorouracil (5FU) were studied in two groups of patients, the administration of 105 i.v. as daily bolus (x5) or 5-day continuous infusions. The 5FU pharmacokinetics were extremely variable from day to day, i.e. from one bolus to the next or during the continuous infusion, especially in some patients. The variations were lower for the daily bolus, but still remained high. The pharmacokinetics of cisplatin, given simultaneously during continuous infusions did not show the same variability; therefore the variability could be specific for 5FU. The role of implantable subcutaneous ports as the most probable source of this extraordinary variability is discussed. We hypothesise that in some patients the implantable subcutaneous ports used for 5FU infusion, could cause transient and extremely high plasma concentrations, exacerbated by the very short half life of the drug and by saturation of its catabolism.

Antimetabolites, Antineoplastic↗