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B Chauffert

Publications and source records attributed to B Chauffert.

At least 73 records · Page 4Linked to original sources
PubMed1992

[Intra-alveolar hemorrhages in systemic diseases].

Alveolar haemorrhage is usually, but often belatedly, diagnosed in patients presenting with haemoptysis and radiological alveolar syndrome. Its occurrence frequently marks a turn for the worst in the course of a systemic disease, since its prognosis is sombre. Recognizing its early signs might enable treatment to be instituted and prognosis to be improved. In the presence of typical alveolar haemorrhage, if high-dose corticosteroid therapy and immunosuppressants do not improve the symptoms within 48 hours plasmapheresis must be started. Alveolar haemorrhage must be considered a vital emergency justifying this therapeutic approach without waiting for the hypothetical diagnosis of the underlying systemic disease.

Adolescent↗
PubMed1992

Cinchonine, a potent efflux inhibitor to circumvent anthracycline resistance in vivo.

Circumvention of multidrug resistance is a new field of investigation in cancer chemotherapy, and safe and potent multidrug resistance inhibitors are needed for clinical use. We investigated several analogues of quinine for their ability to increase anthracycline uptake in resistant cancer cells. Cinchonine was the most potent inhibitor of anthracycline resistance in vitro, and its activity was little altered by serum proteins. Serum from rats treated with i.v. cinchonine produced greater uptake of doxorubicin in cancer cells (DHD/K12/PROb rat colon cells and K562/ADM human leukemic cells) than did serum from quinine-treated rats (ex vivo assay). Cinchonine was more effective than quinine in reducing tumor mass and increasing the survival of rats inoculated i.p. with DHD/K12/PROb cells and treated i.p. with deoxydoxorubicin. Moreover, the acute toxicity of cinchonine in rats and mice was lower than that of other quinine-related compounds. The lower toxicity and greater potentiation of in vivo anthracycline activity produced by cinchonine are favorable characteristics for its use as an anti-multidrug resistance agent in future clinical trials.

Animals↗
PubMed1992

Confluence-dependent resistance in human colon cancer cells: role of reduced drug accumulation and low intrinsic chemosensitivity of resting cells.

In vitro sensitivity of HT29 human colon cancer cells to doxorubicin (DXR), vincristine (VCR), etoposide (VP16), cisplatin (CDDP), melphalan (L-PAM) and 5-fluorouracil (5FU) was markedly reduced when cell-culture density increased. For some drugs, confluence-dependent resistance (CDR) was partly due to decreased intracellular drug accumulation; the ratio of mean intracellular drug content of non confluent to confluent cells (NC/C) was 2.5 for DXR, 4.1 for VCR and 7.4 for VP16. Altered drug penetration with confluence could be related to decrease of plasma membrane fluidity as measured by the fluorescence polarization method. Reduction of drug intracellular accumulation was nil or weak for L-PAM (NC/C = 1.0), CDDP (NC/C = 1.2) and 5 FU (NC/C = 1.8). Even if drug concentration was adjusted in culture medium to produce similar intracellular drug content in confluent and non confluent cells, higher intrinsic resistance of confluent cells was still evidenced for DXR and VP16 but not for VCR, the only agent without direct interaction with DNA. DXR- and VP16-induced DNA breakage was also less important in confluent than in non-confluent cells. CDR appeared closely related to an increased proportion of non-cycling cells at confluence, as demonstrated by flow cytometry, expression of nuclear antigen recognized by Ki67 MAb and expression of topoisomerase II. CDR is probably a major factor in the poor sensitivity of colorectal adenocarcinomas to chemotherapy.

Antineoplastic Agents↗
PubMed1992

Feasibility of using quinine, a potential multidrug resistance-reversing agent, in combination with mitoxantrone and cytarabine for the treatment of acute leukemia.

PURPOSE: We demonstrated previously that sera from quinine-treated patients reversed the multidrug resistance (MDR) of a human leukemic cell line. We now report a phase I and II clinical study that examined the toxicity of the combination of quinine with mitoxantrone and cytarabine (Ara-C). PATIENTS AND METHODS: Fifteen adult patients with relapsed or refractory acute leukemia were treated with quinine formiate (30 mg/kg/d in continuous intravenous (IV) infusion from day 1 through day 5 or 6) associated with Ara-C (1 g/m2 in 3-hour IV infusion twice a day for 5 days) and five increasing doses of mitoxantrone (from 8 mg/m2/d for 4 days to 12 mg/m2/d for 5 days). RESULTS: The main toxicity was severe myelosuppression: the mean times to leukocyte recovery (> 500/microL), granulocytes recovery (> 500/microL), and platelet count recovery (> 50,000/microL) were 23 days (range, 17 to 29 days), 30.6 days (range, 17 to 48 days), and 35.4 days (range, 14 to 75 days), respectively. The nonhematopoietic toxicity of this regimen was acceptable. Nausea and vomiting were common, but severe mucositis was observed in only two patients. Cardiotoxicity was limited to transient episodes of moderate supraventricular tachycardia and a clinically well-tolerated bradycardia. Tinnitus and vertigo were observed in 10 cases (67%), and mild hearing loss and transient increase of serum bilirubin were observed in six patients (40%). Total quinine serum levels reached a steady-state concentration between 6.4 and 18 mg/L in 24 hours. Complete remission (CR) was achieved in eight of 14 (57%) assessable patients, and partial response (PR) was achieved in two additional patients (14%). P-glycoprotein expression was detected on blast cells from five of 13 studied patients before treatment. A response was observed in all P-glycoprotein-positive cases. CONCLUSION: Quinine can be used safely as a potential reversing agent of MDR for the treatment of clinically resistant acute leukemias.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

[Experimental chemotherapy of peritoneal carcinomatosis of colonic origin in rats].

Animal models are useful in the evaluation of adjuvant or palliative treatment modalities of human colonic adenocarcinoma. In the present paper, the efficacy of 22 usual chemotherapeutic agents was evaluated in a model of peritoneal carcinomatosis of colonic origin in the BD IX rat. Mitomycin, cisplatine, carboplatine, cyclophosphamide, ifosfamide, and thiotepa were very effective agents on microscopic carcinomatosis (treatment given 3 days after an intraperitoneal inoculation of 1 x 10(6) DHD/K12/PROb cells). Intravenous administration was as effective as the intraperitoneal route, except for anthracyclines and 5-fluorouracil. Rats treated at early stages by thiotepa or cisplatin survived up to 4 months after cell injection and did not display tumor at autopsy. Administered late (15 days after cell injection), none of the drugs were able to cure the rats with carcinomatosis.

Animals↗
PubMed1991

Sufficient levels of quinine in the serum circumvent the multidrug resistance of the human leukemic cell line K562/ADM.

Reversal of multidrug drug resistance (MDR) has been achieved in vitro by a variety of agents including verapamil, quinidine, cyclosporine A, and amiodarone. The toxicity of these agents precludes the achievement of sufficient levels in the serum to circumvent efficiently the MDR in vivo. The authors previously demonstrated that quinine, the widely used antimalarial agent, is able to reverse primary resistance of rat colon cancer cells to anthracyclines. In this report, the efficiency of quinine formiate in reversing the doxorubicin (ADM) (Adriamycin, Adria Laboratories, Columbus, OH) resistance of the well-defined MDR human leukemic cell line K562/ADM was demonstrated. In culture medium, quinine is slightly less effective than verapamil in increasing the cytotoxicity and uptake of ADM when both drugs are used at the same concentration. A nontoxic dose of 5 micrograms/ml is necessary to reverse the MDR in K562/ADM cells. In patients receiving quinine formiate in a continuous intravenous infusion, a significant correlation (r = 0.84) was found between the serum levels of quinine and the ability of sera to increase ADM uptake in K562/ADM cells. When quinine is administered at a conventional dose (25 to 30 mg/kg/d), serum levels consistently reach more than 8 micrograms/ml without severe side effects; ear noises and vertigo are the dose-limiting side effects. At these concentrations, quinine induces a more than double increase in ADM uptake in K562/ADM cells. Pharmacokinetic data indicate that quinine should be administered 24 to 36 hours before anti-cancer drugs in clinical trials that test its efficiency as a modifier of MDR in human hematologic malignant neoplasms.

Doxorubicin↗
PubMed1991

Cytotoxic effects of acoustic cavitation on HT-29 cells and a rat peritoneal carcinomatosis in vitro.

Damage to cells and tissues exposed to shock waves (SWs) is thought to be secondary to cavitation phenomena involving the collapse of gas bubbles in a fluid. Using HT-29 cells and DHDK12PROb tumors, we tried to enhance SW-related damage by the simultaneous administration of gas microbubbles. Bubbles resulted from a mixture of air and gelatin (HT-29 cells) or from a carbonated NaCl solution (tumors). HT-29 cells in suspension received either SW (50, 250, or 1000 SWs) alone or in association with bubbles. Trypan blue-negative cells decreased as the number of SWs increased. Exposure to SWs and bubbles resulted in not only an increased but also a delayed mortality as compared to SWs only. One thousand SWs with bubbles induced a complete inhibition of cell growth, with cytoplasmic vacuolae, ruptured membranes, and abnormal nuclear shape and chromatin. Exponential and confluent cells exhibited a similar mortality and growth. DHDK12PROb tumors received either SWs only (50, 100, 250, 500, or 1000 SWs) or SWs with bubbles in vitro. Thymidine incorporation was significantly lower after exposure to SWs with bubbles as compared with controls and SWs only; it was nil by 1000 SWs with bubbles. Histopathological features of tumors exposed to SWs with bubbles included erosion and hemorrhage, disorganized structure, pyknotic nuclei, and cytoplasmic vacuolae. We conclude that cavitation, as produced by a combination of SWs and gas microbubbles, can achieve bioeffects which are relevant to cancer therapy.

Animals↗
PubMed1991

P-glycoprotein expression and in vitro reversion of doxorubicin resistance by verapamil in clinical specimens from acute leukaemia and myeloma.

The expression of the P-glycoprotein which is associated with the development of multidrug resistance in various cell lines was investigated in 87 fresh acute leukaemia and multiple myeloma samples using the specific mouse monoclonal antibody MRK16 in an indirect immunofluorescence assay. Considering a 10% positive cell cut-off value, a heterogeneous expression of P-glycoprotein was observed in 5/22 (22.7%) de novo acute leukaemias, 7/22 (31.8%) relapse or secondary acute leukaemias, 14/27 (51.8%) acute transformation of myeloproliferative or myelodysplastic syndromes and 5/16 (31.2%) multiple myelomas. This expression was not associated with specific cytogenetic abnormalities, especially alterations of chromosome 7q. Verapamil, a calcium channel blocker, has been demonstrated to circumvent the multidrug resistance in cell lines, possibly by interfering with P-glycoprotein function. Using the microculture tetrazolium assay, verapamil was demonstrated to increase the sensitivity of fresh leukaemic or myeloma cells to doxorubicin in 19/43 (43.1%) samples. The doxorubicin IC50 level and the capacity of verapamil to increase the sensitivity of blast cells to doxorubicin in vitro did not correlate with the expression of P-glycoprotein. We conclude that high non-cytotoxic concentrations of verapamil were able to increase the in vitro doxorubicin sensitivity of fresh acute leukaemia and myeloma cells without detectable expression of the P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

[Cavernous hemangioma of the liver associated with angiosarcoma: malignant transformation?].

Angiosarcoma of the liver is a rare tumor. Its treatment is usually regarded as unsuccessful and its prognosis extremely poor. The authors report the case of a solitary and encapsulated hepatic tumor characterized by the association of a cavernous hemangioma surrounded by an angiosarcoma. The hypothesis of an eventual malignant transformation of cavernous hemangiomas of the liver is raised.

Adult↗
PubMed1990

Mechanisms of resistance of confluent human and rat colon cancer cells to anthracyclines: alteration of drug passive diffusion.

Two colon cancer cell lines, HT-29 (human) and DHD/K12/TRb (rat), were grown as monolayer cultures to various confluence degrees. The cytotoxic efficacies of doxorubicin and 4'-deoxydoxorubicin, evaluated by a survival assay, and the nuclear drug concentrations, measured by microspectrofluorometry, were shown to progressively decrease with the augmentation of confluence. This confluence dependent resistance (CDR) to anthracyclines was demonstrated independent of the multidrug resistance drug efflux mechanism. The cellular uptake of three compounds (sodium [51Cr]chromate, D-[14C]alanine, L-[14C]glucose) known to passively diffuse across the cell membrane as anthracyclines do was also reduced in confluent cells. After trypsin cell detachment, the kinetics of reversion of the sodium [51Cr]chromate uptake decrease and that of CDR were similar. Therefore, CDR may be attributed to a reduction of anthracycline cell intake due to a general alteration of passive diffusion across the cell membrane. However, CDR is only partly explained by this phenomenon since a reduced sensitivity of confluent cells was observed compared with nonconfluent cells for a similar amount of drug in their nuclei. CDR could explain the high resistance to anthracyclines of some solid tumors, such as colon tumors, in which cancer cells are tightly aggregated.

Animals↗
PubMed1990

Potential usefulness of quinine to circumvent the anthracycline resistance in clinical practice.

Quinine, the widely used antimalaria agent, was found to increase the cytotoxicity of epideoxorubicin (epiDXR) in resistant DHD/K12 rat colon cancer cells in vitro. Quinine appeared as slightly less effective than quinidine or verapamil for anthracycline potentiation but its weaker cardiotoxicity could counterbalance this disadvantage in vivo. Serum from six patients treated by conventional doses of quinine (25-30 mg kg-1 day-1) was demonstrated to enhance the accumulation of epiDXR in DHD/K12 cells as judged by fluorescence microscopy and HPLC assay (1.6 to 6-fold compared with control serum). In this patients quinine concentrations in serum ranged from 4.4 to 10.1 micrograms ml-1. Our results suggest that quinine could be safely used as anthracycline resistance modifier in clinical practice.

Animals↗
PubMed1990

Treatment of experimental liver metastases in the rat by continuous intraportal infusion of 5-fluorouracil and heparin: a pilot study.

Continuous portal venous infusion of 5-fluorouracil (5-FU) and/or heparin immediately following injection of tumor cells into the portal system in unrestrained rats has been assessed as a pilot study to examine whether the incidence of liver metastases could be reduced and survival therapy improved. Thirty-six rats were divided into four groups according to the treatment administered for 7 days by portal infusion: heparin, 5-FU, 5-FU + heparin and physiological saline solution as a control. After a 90-day follow-up, metastases were observed in every rat injected with tumor cells with the exception of one rat in the heparin group. The 90-day actuarial survival rates for the treatment groups of heparin, 5-FU, 5-FU + heparin and control were 44% (4/9), 11% (1/9), 33% (3/9) and 22% (2/9) respectively, with the survival curves not differing significantly. The apparently improved survival rate in the heparin group may be due to the insufficient period of observation. The conclusions of this study may be only preliminary owing to both the insufficient period of observation and the small number of rats, but the inhibitory effect of 5-FU on the development of liver metastases was disappointing as a result of the large number of tumor cells injected into the portal system. The technique used in this study, which enabled continuous portal venous infusion of drugs to be performed in unrestrained rats, may provide a useful model for the study of continuous infusion in the rat.

Adenocarcinoma↗
PubMed1990

Quinine circumvents the doxorubicin resistance of a multidrug resistant human leukemic cell-line, K562/DXR.

Reversal of multidrug resistance (MDR) has been obtained in vitro by a variety of agents but clinical use of these resistance modifiers is hampered by their own toxicity. Quinine, the natural isomer of quinidine, is demonstrated to circumvent doxorubicin (DXR) resistance of an MDR human leukemic cell-line, K562/DXR. In culture medium, quinine (5 mu/ml or more) significantly increases cytotoxicity and accumulation of DXR in the resistant cells but not in the parental sensitive cells. When quinine is administered by continuous intravenous infusion in the doses conventionally used in chloroquino-resistant malaria (30 mg/kg/d), serum levels reach 8-11 micrograms/ml without prohibitive toxicity. Sera from quinine-treated patients enhance DXR uptake in K562/DXR cells in dose-dependent fashion. The conditions for the safe use of quinine as an MDR modifier in the treatment of refractory human hemopoietic malignancies are defined.

Doxorubicin↗