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M F Poupon

Publications and source records attributed to M F Poupon.

At least 73 records · Page 4Linked to original sources
PubMed1994

Uptake of doxorubicin from loaded nanoparticles in multidrug-resistant leukemic murine cells.

Previous studies have clearly demonstrated that polyisobutylcyanoacrylate (PIBCA) doxorubicin-loaded nanoparticles (NS-Dox PIBCA) can overcome the resistance of P388/ADR cells. In the present paper, we found that overcoming multidrug resistance with the aid of doxorubicin (Dox) loaded onto these nanoparticles was associated with an increased intracellular drug content. Indeed, after a 6-h incubation period, the amount of cell-associated drug was 5 times higher when the cells were incubated with NS-Dox PIBCA as compared with free Dox. Further experiments, such as uptake studies in the presence of cytochalasin B or efflux studies, indicated a possible mechanism of nanoparticle/cell interaction. These results suggested that nanoparticles did not enter the cells by an endocytic process, in contrast to a previous hypothesis.

Animals↗
PubMed1994

Characterization of somatostatin receptors and growth inhibition by the somatostatin analogue BIM23014 in small cell lung carcinoma xenograft: SCLC-6.

Human small cell lung cancer (SCLC) is a neuroendocrine tumour with a very poor prognostic. Receptors for somatostatin-14 and its synthetic analogue BIM23014 (Lanreotide) were characterized in 3 human SCLC xenografts (SCLC-6, SCLC-10 and SCLC-75) transplanted in nude mice. The binding activity of both iodinated ligands was tested by cross-linking assay. One major complex of 57kDa was identified by both ligands in all 3 tumours. Two other minor complexes were only detected by the natural ligand: 90kDa in all 3 tumours and 70kDa in 2 out of the 3 tumours (SCLC-6 and SCLC-75). Analysed by Northern hybridization, the expression of the gene encoding for the receptor subtype I was detected in all 3 tumours whereas the expression of the receptor subtype II was only detected in 2 out of the 3 tumours (SCLC-6 and SCLC-75). No receptor subtype III transcript was observed. The relative quantification of the detected messengers and of the cross-linked complexes determined by densitometry suggested that SCLC-6 contained a large amount of somatostatin receptors. SCLC-6 growing in nude mice was used to evaluate the antiproliferative effect of BIM23014. BIM23014 (250 micrograms, b.i.d. for 5 days) significantly inhibited tumor growth and had an additive effect with cis-platinum (1.5 mg/kg/day for 2 days) when given concomitantly. Values of the relative tumour volume as compared to control were: BIM23014 alone 57%, cis-platinum alone 57% and BIM23014 + cis-platinum: 78%. These experimental data suggest that BIM23014 given alone or in combination with cis-platinum could have a therapeutic potential in the treatment of somatostatin receptor positive SCLCs.

Amino Acid Sequence↗
PubMed1994

[The metastatic process].

All the malignant tumors possess the same characteristic to form distant secondary tumors or metastasis. The acquisition of the metastatic potential takes place in random accumulation of different genetic and cellular changes. Their combination allows one or several tumor cells to achieve the whole metastatic process. The metastatic process involves numerous interactions between the tumor cells and the host cells of the tumor cells and the extracellular matrix. The attachment of the metastatic cells to the extracellular matrix specific glycoproteins involves cell surface receptors as integrins, sialyled residues or CD44. On the other hand, other adhesive molecules (Cadherins) display inhibitory action on the metastatic process. The enzymatic lysis is carried out by glycolytic enzymes and proteases: metalloproteases (inhibitors TIMP1 et TIMP2), serine proteases (tPA, uPA-inhibitors: PAI1 and PAI2). Cathepsin D or Heparanases. Several enzymes may be necessary for the degradation of the basal membrane. The crossing of both basal membrane and stroma can be made on account of the cell motility. Some factors can modify this property as AMF (Autocrin Motility Factor) or ATX (Autotoxin) but the molecular mechanisms involved in the migration are not yet completely understood. The last stage is relative to the cells proliferation in the site organ; it depends on autocrine (CSF1, IL2, Bombesine...) or some paracrine growth factors. However, the formation of metastasis is possible only in the site organ attaching the cells.

Animals↗
PubMed1994

[Orthotopic implantation of human colon cancers into nude mice. Methodology and physiopathological value].

OBJECTIVE: The xenograft of human cancers into athymic nude mice makes it possible to obtain abundant tumour material and deepen biological characterization. Usually, the tumours are grafted into the subcutaneous tissue whose environment is indeed different from that of original colon cancer. METHODS: In order to transplant tumours into an orthotopic environment, intra-caecal implantation of colon cancers was performed. A tumour fragment (30 mm3) was deposited at the surface of serous membrane of the caecum, previously scrapped, fixed with a thread and recovered with biologic glue. Six different types of colon tumour, previously adapted to transplantation in nude mice, were similarly grafted. RESULTS: Twenty to forty days after transplantation, tumour takes were observed with a similar rate by the subcutaneous or intra-caecal graft (93% of 115 and 96.8% of 154 transplantations, respectively). Tumour growth varied between the tumours implanted into the two sites. Moreover, only the tumours intracaecally transplanted developed nodal and liver metastases. Histological examination revealed the invasion of the muscle layer, submucosal tissue and mucosal membrane by tumour cells and the mixture of normal glands and neoplastic glands. CONCLUSIONS: This technique of orthotopic implantation of colon cancer samples will contribute to obtain an experimental model for colon cancer research.

Animals↗
PubMed1993

Response of small-cell lung cancer xenografts to chemotherapy: multidrug resistance and direct clinical correlates.

BACKGROUND: Patients with small-cell lung carcinomas (SCLCs) initially respond to combination chemotherapy. Only a few benefit in terms of long-term survival because most relapse. Such outcome may be attributable to development of multidrug resistance. PURPOSE: The response of SCLC to chemotherapy was examined in terms of (a) patient survival, (b) drug sensitivity of tumors in patients and of tumor xenografts in nude mice, and (c) expression of multidrug resistance gene MDR1 and GST-pi gene. METHODS: Tumor samples obtained from seven untreated patients and from one patient both before and after chemotherapy were transplanted into nude mice. The patients were treated with a combination of cyclophosphamide (C'), cisplatin (C), doxorubicin (A), and etoposide (V) (C'CAV) or C'AV and radiotherapy. Drug sensitivity of SCLCs was tested in nude mice that had received tumor xenografts from these seven patients. The expression of MDR1 and GST-pi genes was assessed in the mRNA extracted from xenografts by Northern blot analysis. P-glycoprotein was quantified by enzyme immunoassay. RESULTS: The patients' responses to C'CAV closely correlated with those of the corresponding xenografts. The tumors of the two patients who showed long-term survival after C'CAV completely regressed when they were transplanted into nude mice and subsequently treated with C'CAV. Despite initial complete response, the remaining five patients died during year 1. A high percentage of mice receiving the tumor grafts from these five patients showed only partial tumor regression after C'CAV treatment. The MDR1 transcript was detected in all five of these xenografts. Four of five xenografts were from untreated patients, and the fifth was from a treated patient. MDR1 mRNA expression was absent in the tumor of this fifth patient before chemotherapy, but both the mice receiving the corresponding xenograft and the patient showed expression of MDR1 after C'CAV treatment. MDR1 mRNA expression was absent in the tumor xenografts obtained from two patients with long-term survival. Expression of P-glycoprotein correlated with MDR1 mRNA expression. All xenografts except one expressed the GST-pi gene. CONCLUSIONS: The absence of MDR1 gene expression during chemotherapy for SCLC indicates a favorable prognosis, gene expression is often coincident with ineffective chemotherapy, and tumor xenografts can be appropriately used to predict response to chemotherapy. IMPLICATIONS: Failure of chemotherapy to control SCLC seems to be related to an acquired multidrug resistance involving the MDR1-mediated mechanism. Therapeutic benefit could therefore be expected from chemotherapy combined with inhibitors of MDR1.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Expression of synaptotagmin and syntaxin associated with N-type calcium channels in small cell lung cancer.

The presence of synaptic proteins involved in excitation/secretion coupling was examined in ten small cell lung cancer lines. N-Type calcium channels (omega-conotoxin receptors), synaptotagmin (p65) and syntaxin (HPC-1) were detected in eight. Co-immunoprecipitation experiments indicated that syntaxin can form a complex with synaptotagmin and calcium channels. The expression of synaptotagmin in small cell lung cancer may elicit an autoimmune response that reduces transmitter release at the nerve terminal.

Animals↗
PubMed1993

Reversion and cell hybridization of a dedifferentiated rat hepatoma cell: dissociation of mechanisms establishing the hepatic traits.

The expression of a mouse serum albumin (MSA) gene introduced into differentiated and dedifferentiated variant cells of a rat hepatoma line depends on the overall differentiated state of the recipient cell. Thus, the transcription rate of this mouse gene is very high in differentiated cells compared to that in the variant. Furthermore, the activation of its expression is observed during the course of reversion of the variant cell. In well-differentiated hybrids between the variant and cells of the original line, the expression of the MSA gene depends on the phenotype of the transfected parental cell: transcription of this foreign gene is detected only in hybrids in which it was initially integrated into the genome of the differentiated parent. Gene dosage effects are not involved as the copy number of the MSA gene is identical in both types of transfected cells. These results demonstrate that the establishment of the liver phenotype in differentiated hybrids and revertants is due to different mechanisms.

Animals↗
PubMed1993

Response of a multidrug-resistant human small-cell lung cancer xenograft to chemotherapy.

Small-cell lung carcinomas (SCLC) are highly responsive to various chemotherapies. However only a minority of patients benefit from long survival. SCLC patients treated at the Institut Gustave Roussy received a combined chemotherapy (CCAV) including cisplatin, cyclophosphamide (Cpa), Adriamycin (doxorubicin; Adm) and vepeside (VP16). We report here the intrinsic sensitivity of a small-cell lung carcinoma, designated SCLC-6, grafted in nude mice. This xenografted tumour was derived from an untreated patient. The CCAV regimen given to the patient donor of the tumour sample resulted in a complete response followed by recurrence and death, 8 months after the initial cure. The expression of P-glycoprotein encoded by the MDR1 gene was detected with the C219 antibody on the membrane of SCLC-6 tumour cells. When given to SCLC-6-tumour-bearing nude mice, CCAV induced a strong inhibition of tumour growth (84% of growth inhibition, 20 days after start of the treatment), but no cure. Intensification of CCAV doses did not improve the response. The efficacy of individual agents of the CCAV, given at maximal tolerated doses was analysed. Only cisplatin (10 mg/kg) and Cpa (3 x 50 mg/kg) inhibited SCLC-6 growth (79% and 100% inhibition respectively), VP16 (3 x 24 mg/kg) was poorly efficient (42%) and Adm (10 mg/kg) not at all. Two-drug combinations such as cisplatin plus VP16 or cisplatin plus Cpa inhibited tumour growth (81% and 70%, respectively). Curiously, the efficacy of Cpa, given in combination with cisplatin was less than that of Cpa alone. Repeated treatments with CCAV administered to mice at each in vivo passage of the tumour induced a loss of chemosensitivity, which was observed until the ninth passage. An improvement of the therapeutic response was obtained by adding a headline reverser of multi-drug resistance, verapamil (25 mg/kg), to CCAV (81% versus 63% inhibition). MDR1-related resistance appeared to play a role in the failure of SCLC-6 chemotherapy; frequent recurrences after treatment with cisplatin and Cpa, two drugs that are not recognized by the P-glycoprotein, indicated that other modes of resistance were simultaneously active.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Pharmacology and antitumour effects of intraportal pirarubicin on experimental liver metastases.

Early liver metastases have a predominant portal blood supply. Intraportal (i.port.) vein administration of cytotoxics could theoretically achieve enhanced drug concentrations in tumour cells and be effective as adjuvant therapy after resection of colorectal carcinoma. Pirarubicin (which has a higher hepatic extraction than doxorubicin) was investigated on liver metastases of the VX2 rabbit tumour, which were of less than 2 mm in diameter 7 days after cells injection into the portal vein. To evaluate antitumour activity, 24 rabbits were randomised into three groups 7 days after implantation: (a) control, (b) i.v. pirarubicin, (c) i.port. pirarubicin at doses of 2 mg kg-1 in both groups. Portal infusions led to no hematological or hepatic toxicity. Pharmacokinetic parameters showed a significantly reduced systemic exposure after i.port. administration. Fourteen days after treatment, livers and lungs were analysed. The mean number (+/- s.d.) of tumour foci was (a) 8.62 (+/- 5.4), (b) 4.62 (+/- 3.2), (c) 2.25 (+/- 1.4) (P < 0.05 a vs c). The mean tumour area was (a) 6.31 (+/- 6.1), (b) 1.31 (+/- 2.2), (c) 0.43 (+/- 0.4 cm2) (P < 0.05 a vs c) and the percentage (95% C.I.) of rabbits with lung metastasis was: (a) 87.5% (47-99%), (b) 75% (35-97%), (c) 12.5% (3-52%) (P < 0.02 b vs c). Intraportal pirarubicin seems to be well tolerated and more efficient than i.v. administration, particularly in preventing extrahepatic dissemination.

Animals↗
PubMed1993

[Cancers of the kidney: multiple drug resistance].

The treatment of kidney cancers raise difficult problems. Usual treatments combining surgery, radiation therapy, chemotherapy and hormonotherapy are poorly effective. The immunotherapy gave only an objective response rate of 25% in metastatic renal cell carcinomas. Among cellular resistance mechanisms of renal carcinoma, the multi-drug resistance (MDR) phenotype and the glutathione redox cycle have been studied. The MDR is related to overexpression of a 170 kDa membrane glycoprotein, the so-called P glycoprotein (Pgp). This protein is a pump able to extrude from cytoplasm drugs with various structures and mechanisms. The Pgp is encoded by the MDR1 gene expression is very low in most of the normal tissues, except in colon, liver and kidney. In these tissues, the Pgp would ensure a detoxifying function related to cellular toxic compounds, elimination or transfer of molecules synthesized by the cells. According to the intrinsic resistance of renal carcinoma, MDR1 gene expression has been determined. Approximately, 80% of fresh kidney cancer before chemotherapy express resistance phenotype. Reversal compounds specifically inhibiting Pgp were found, such as verapamil, cyclosporin or quinidine. Unfortunately, the two first compounds give cardiac toxicity and immunosuppression, respectively. So far, clinical trials have not been demonstrating, but no biological resistance measures were determined, in parallel. According to the multifactorial resistance the association of reversals to chemotherapy should be introduced in clinical trials, in correlating clinical response to biological mechanisms of resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Antitumoral activity of bombesin analogues on small cell lung cancer xenografts: relationship with bombesin receptor expression.

Gastrin releasing peptide (GRP), the human homologue of bombesin (BN), is an autocrine growth factor for small cell lung cancer (SCLC) cells. The synthetic octapeptides [D-cpa1-beta-Leu8-des-Met9]litorin (BIM 26182) and [D-Phe6-Leu13-CH2NH-Cpa14]bombesin(6-14)NH2 (BIM 26189) are potent GRP/BN antagonists of the proliferation of 3T3 and rat pancreas cells. The effect of these analogues on the proliferation of four SCLC cell lines (SCLC 6, SCLC 41, SCLC 75, SCLC 74R) was tested in vitro and in vivo. Two of these SCLC lines (SCLC 41M and SCLC 75) had receptors for BN/GRP and expressed the prepro-GRP mRNA. BIM 26182 and BIM 26189 inhibited [3H]thymidine incorporation into the DNA of SCLC 41 cells, stimulated [3H]thymidine incorporation in SCLC 6, and had no effect on the two other cell lines. The SCLC implanted s.c. in nude mice were treated with either BIM 26182 or BIM 26189. BIM 26182 and BIM 26189 injected at the doses of 50 micrograms twice a day (s.c.) around the tumor for 10 to 21 days delayed the growth of SCLC 41 and of SCLC 75. The maximal effect was observed during the treatment period, after which the tumors regrew, suggesting a cytostatic effect of these peptides. No inhibitory effect of the peptides on SCLC 74R or SCLC 6 growth was observed. These data suggest that GRP antagonists are able to inhibit the in vitro and in vivo growth of BN/GRP receptors-positive SCLC.

Animals↗
PubMed1992

Doxorubicin-loaded nanospheres bypass tumor cell multidrug resistance.

We have demonstrated that in vitro resistance of tumor cells to doxorubicin (Dox) can be fully circumvented by using doxorubicin-loaded nanospheres (Dox-NS), consisting of biodegradable polyisohexylcyanoacrylate polymers of 300 nm diameter and containing 2.83 mg of Dox per 31.5 mg of polymer. Five different multidrug-resistant cell lines, characterized by mdr1 amplification, were used in this study: Dox-R-MCF7, a human breast adenocarcinoma; SKVBL1, a human ovarian adenocarcinoma; K562-R, a human erythroleukemia; and two murine lines: P388-Adr-R, a monocytic leukemia of DBA2 mouse, and LR73MDR, a Chinese hamster ovarian cell line. These lines were 38.7, 210, 232, 143 and 20 times more resistant than their corresponding sensitive counterparts, respectively. Using Dox-NS, we obtained complete reversion of drug resistance in vitro, i.e. cell growth inhibition comparable with that obtained with sensitive cells exposed to free Dox. In vivo, we significantly prolonged the survival of DBA2 mice which had previously received P388-Adr-R cells by i.p. injections of Dox-NS, while free Dox injection was ineffective toward this rapidly growing tumor. (Prolongation of survival time: 115% vs 167% after Dox vs Dox-NS treatment, respectively.) Using the MCF7 cell line and its resistant variant, we studied the intracellular concentration and the cytoplasmic and nuclear distribution of Dox by laser microspectrofluorometry (LMSF). In sensitive cells, we observed a similar accumulation and distribution of Dox whatever the form of Dox delivery, i.e. whether free or carried by nanospheres. Analysis by LMSF showed that 99% of intranuclear Dox was bound to DNA after treatment with both forms of Dox. Of Dox, 81 and 83% were found in the intranuclear compartment of sensitive cells incubated with free Dox and Dox-NS, respectively. Resistant cells incubated with Dox-NS accumulated the same amount of Dox as sensitive cells incubated with free Dox or with Dox-NS. Dox, when loaded in nanospheres, bypasses the efflux mechanism responsible for multidrug resistance. LMSF analysis showed that Dox, transported and released by nanospheres, interacts with DNA identically in sensitive and resistant cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

[How do cancers resist to chemotherapy?].

Resistance is often defined as a lack of therapeutic response. Cellular resistance involves a decrease in intracellular levels of the antitumor agent due to a variety of mechanisms. These mechanisms are active in tumors with initial resistance as well as in those which respond initially but fail to be completely destroyed by chemotherapy. Although acquired forms of resistance seem to be the result of selection, some studies suggest that antitumor agents may induce resistance. Four main mechanisms of resistance are currently being investigated: 1) multidrug resistance, involving expression of a membrane P-glycoprotein, responsible for resistance to hydrophobic cationic agents; 2) detoxification of hydrophilic agents by the enzyme glutathione-S-transferase; 3) increased production of enzymes targeted by antimetabolites; 4) mutation or decreased synthesis of topoisomerases I and II which are the targets of very recent antitumor agents. New data were presented at the 1992 symposium of the American Association for Cancer Research; expression of P-glycoprotein is controlled by the mutant protein P53, the oncogene ras and differentiation agents. Physiological effects of this molecule are related to the chloride pump. Bone marrow stem cells from transgenic mice obtained by transfection of the gene MDR1 in germ cells exhibit resistance. Many agents can reverse P-glycoprotein-related resistance. Results from three phase I trials with Cyclosporin A as reversion agent were reported. It is essential to conduct clinical trials in order to assess the true value of these new data which hold promise for improving the performance of antitumor agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗