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R L Marquet

Publications and source records attributed to R L Marquet.

At least 19 recordsLinked to original sources
PubMed1997

Cyclosporin A enhances locoregional metastasis of the CC531 rat colon tumour.

The immunosuppressive drug cyclosporin A has been evaluated recently in phase II trials in cancer therapy as a reverter of P-glycoprotein-mediated multidrug resistance. As an immunosuppressive agent, cyclosporin A potentially can enhance tumour growth. We investigated this potency of cyclosporin A in the weakly immunogenic CC531 colon adenocarcinoma model, using the same dose that had previously been shown to intensify the antitumour activity of doxorubicin in vivo. In vitro cyclosporin A caused no growth acceleration and only in high doses was growth inhibition of CC531 cells observed. In vivo no evidence of growth enhancement was found in short-term assays but, after 4 weeks, rats treated with cyclosporin A had a significantly higher tumour load, mainly consisting of locoregional metastases. These experiments in the CC531 tumour model show that cyclosporin A, used as a reverter of multidrug resistance, may produce short-term improvement of antitumour activity but may also induce enhancement of tumour metastasis.

1,2-Dimethylhydrazine↗
PubMed1996

Synergistic antitumour effect of recombinant human tumour necrosis factor alpha with melphalan in isolated limb perfusion in the rat.

The efficacy of isolated limb perfusion (ILP) for 'intransit' metastases from malignant melanoma and irresectable soft tissue sarcoma has been improved considerably by the addition of tumour necrosis factor (TNF) alpha. A rat sarcoma tumour model was, therefore, developed to evaluate the effects of TNF-alpha, melphalan and the combination of these drugs in the treatment of sarcoma. In BN rats bearing the non-immunogenic BN 175 sarcoma ILPs were performed with perfusate only, TNF-alpha, melphalan alone, or in combination when tumours had grown to approximately 1.5 cm in diameter. All rats treated with sham perfusion or perfusion with 50 micrograms TNF-alpha showed progressive disease. After perfusion with 40 micrograms melphalan no change in tumour diameter was observed in any rats at 4 days. After a combined perfusion with 40 micrograms melphalan and 50 micrograms TNF-alpha complete remission was noted in 12 of 16 rats. This synergistic effect in vivo between relatively ineffective doses of TNF-alpha and melphalan was not observed in vitro.

Animals↗
PubMed1996

Induction of specific inhibition of alloreactivity in beagle dogs by intrathymic injection of donor splenocytes.

The aim of this study was to investigate whether intrathymic injection (ITI) of donor splenocytes in dogs might lead to specific immunomodulation as assessed by mixed lymphocyte culture (MLC) tests. Two groups of five beagles each were used. Group 1 contained animals that were 2 years old, group 2 consisted of animals that were 6 months old. One animal was splenectomized per experimental group and 1 x 10(9) splenocytes were injected into the thymic lobes or thymic remnant of the four remaining dogs. On the day of ITI the dogs were treated subcutaneously with a single dose of 2 ml/kg antilymphocyte serum (ALS). In group 1 the thymus of all dogs was found to be atrophic. ITI in this group did not result in a decreased immunoreactivity but rather in an enhanced immune response. In group 2 the thymus was still clearly present and ITI was easy to perform. ITI induced a significant reduction of specific MLC reactivity at 1 week after treatment. The effect was transient and not significantly further diminished at week 2. These results indicate that ITI is a technically feasible procedure in a preclinical animal model. It may induce temporary sensitization as well as immunosuppression, possibly depending on the age of the recipient.

Animals↗
PubMed1996

Laparoscopic surgery in the rat. Beneficial effect on body weight and tumor take.

BACKGROUND: The ability of laparoscopic techniques to treat malignant disease is controversial. We developed a rat model to assess metabolic and oncological effects of laparoscopic surgery. METHODS: Experiment I. The postoperative body weight in 10 rats having laparoscopic bowel resection (group I), 10 rats having open bowel resection (group II) and 5 rats having anesthesia only (group III) was determined. Experiment II. Tumor take was scored in 11 rats having laparoscopic bowel resection (group IV), 11 rats having open bowel resection (group V), 6 rats having CO2 pneumoperitoneum without bowel resection (group VI) and 6 rats having anesthesia only (group VII). All rats had CC531 cancer cells injected intraperitoneally postoperatively. RESULTS: Experiment I. Body weight loss in group I compared to group II (p<0.036). Rats of group III lost no weight postoperatively. Experiment II. Tumor take was less in the subcutis (p=0.005), parietal peritoneum (p<0.001) and bowel anastomosis (p=0.021) in group IV compared to group V. Tumor take was significantly greater at all sites except for subcutis in group VI compared to VII (all p<0.022). CONCLUSIONS: Laparoscopic surgery is associated with less postoperative weight loss and less tumor take compared to open surgery. CO2 insufflation appears to increase tumor take.

Adenocarcinoma↗
PubMed1996

Isolated limb perfusion with TNF alpha and melphalan in a rat osteosarcoma model: a new anti-tumour approach.

Isolated limb perfusion (ILP) with TNF alpha, IFN gamma and melphalan causes impressive tumour reduction in patients with irresectable soft tissue sarcomas with a high limb salvage rate. Since this therapy could be of value in patients with progressive osteosarcoma, we performed a study in an osteosarcoma tumour model in the rat. The ROS-1 osteosarcoma was implanted s.c. in the hind leg of WAG rats. Rats were divided in four groups: rats that underwent ILP with perfusate alone, TNF alpha alone, melphalan alone or their combination. Almost all rats, treated with a sham ILP or a perfusion with 40 micrograms melphalan, showed progressive disease (PD) (6/6 and 5/6). After perfusion with 50 micrograms TNF alpha alone a varied response was observed: 2/6 PD, 2/6 no change (NC) and 2/6 a complete remission (CR). After combined perfusion: 3/6 rats had a partial remission and 3/6 a CR. The best and most consistent responses are obtained by combining TNF alpha and melphalan. The discrepancy with the in vitro sensitivity of ROS-1 indicates that indirect effects are important in this tumour model.

Animals↗
PubMed1996

Chronic rejection of concordant aortic xenografts in the hamster-to-rat model.

Several groups have demonstrated that it is possible to obtain long-term graft survival of concordant xenografts. One of the important questions that remains is whether xenografts are susceptible to chronic rejection. To answer this question we used the aorta transplantation model. One centimetre of hamster aorta was interposed in the abdominal aorta of Lewis rat recipients. The recipients were either untreated (group 1), or treated with 10 mg/kg cyclosporine (CsA), given intramuscularly three times a week (group 2). Rats were sacrificed at day 7, 14, 21, 28, 56 and 84 and the thickness of the intima, the media and the adventitia was measured. Furthermore, the cellularity of the media and the adventitia was assessed by counting the number of nuclei per 0.05 mm2 and immunohistochemistry of the aortic grafts was performed. Graft arteriosclerosis developed in aortic xenografts of both group 1 and group 2. In group 1, intimal lesions were already present from day 21 onwards in all rats, whereas in group 2 they were present only in 33% (2/6) of the rats. At day 84 all the grafts in group 1 were totally occluded, while those in group 2 were still open. The thickness of the media was slightly increased in both groups during the whole observation period, mainly due to edema. Although a few infiltrating macrophages could be seen, the number of nuclei per 0.05 mm2 of the media remained constant during the first 21 days, but declined sharply from day 21 onwards, as a consequence of disappearing myocytes. Thickness of the adventitia in both groups increased after transplantation due to infiltrating macrophages and T cells, reaching a peak at day 14. After day 14 the adventitial thickness in group 1 decreased rapidly to reach values comparable to group 2 from day 28 onwards. In conclusion, graft arteriosclerosis, as a sign of chronic rejection, occurs in concordant aortic xenografts. The lesions in the xenografts develop extremely rapidly, and compared to data from the literature, faster than in aortic allografts. The process of chronic rejection in aortic xenografts can be reduced by CsA.

Animals↗
PubMed1996

Synergistic effects of TNF-alpha and melphalan in an isolated limb perfusion model of rat sarcoma: a histopathological, immunohistochemical and electron microscopical study.

Isolated limb perfusion (ILP) with tumour necrosis factor alpha (TNF-alpha) and melphalan has shown impressive results in patients with irresectable soft tissue sarcomas and stage III melanoma of the extremities. The mechanisms of the reported in vivo synergistic anti-tumour effects of TNF-alpha and melphalan are not precisely understood. We have developed an ILP model in the rat using a non-immunogenic sarcoma in which similar in vivo synergy is observed. The aim of this present study was to analyse the morphological substrate for this synergistic response of TNF-alpha in combination with melphalan to shed more light on the pathomechanisms involved. Histology of the tumours from saline- (n = 14) and melphalan-treated (n = 11) rats revealed apparently vital tumour cells in over 80% of the cross-sections. Interstitial oedema and coagulation necrosis were observed in the remaining part of the tumour. Haemorrhage was virtually absent. TNF-alpha (n = 22) induced marked oedema, hyperaemia, vascular congestion, extravasation of erythrocytes and haemorrhagic necrosis (20-60% of the cross-sections). Oedema and haemorrhage suggested drastic alterations of permeability and integrity of the microvasculature. Using light and electron-microscopy, we observed that haemorrhage preceded generalised platelet aggregation. Therefore, we suggest that the observed platelet aggregation was the result of the microvascular damage rather than its initiator. Remarkably, these events hardly influenced tumour growth. However, perfusion with the combination of TNF-alpha and melphalan (n = 24) showed more extensive haemorrhagic necrosis (80-90% of the cross-sections) and revealed a prolonged remission (mean 11 days) in comparison with the other groups of rats. Electron microscopical analysis revealed similar findings as described after TNF-alpha alone, although the effects were more prominent at all time points after perfusion. In conclusion, our findings suggest that the enhanced anti-tumour effect after the combination of TNF-alpha with melphalan results from potentiation of the TNF-alpha-induced vascular changes accompanied by increased vascular permeability and platelet aggregation. This may result in additive cytotoxicity or inhibition of growth of residual tumour cells.

Animals↗
PubMed1996

Impact of gas(less) laparoscopy and laparotomy on peritoneal tumor growth and abdominal wall metastases.

OBJECTIVE: A tumor model in the rat was used to study peritoneal tumor growth and abdominal wall metastases after carbon dioxide (CO2) pneumoperitoneum, gasless laparoscopy, and laparotomy. SUMMARY BACKGROUND DATA: The role of laparoscopic resection of cancer is under debate. Insufflation of the peritoneal cavity with CO2 is believed to be a causative factor in the development of abdominal wall metastases after laparoscopic resection of malignant tumors. METHODS: In the solid tumor model, a lump of 350-mg CC-531 tumor cells was placed intraperitoneally in rats having CO2 pneumoperitoneum (n = 8), gasless laparoscopy (n = 8), or conventional laparotomy (n = 8). After 20 minutes, the solid tumor was removed through a laparoscopic port or through the laparotomy. In the cell seeding model, 5 x 10(5) CC-531 cells were injected intraperitoneally before CO2 pneumoperitoneum (n = 12), gasless laparoscopy (n = 12), or laparotomy (n = 12). All operative procedures lasted 20 minutes. After 6 weeks, in the solid tumor model and after 4 weeks in the cell seeding model, tumor growth was scored semiquantitatively. All results were analyzed using the analysis of variance. RESULTS: In the solid tumor model, peritoneal tumor growth in the laparotomy group was greater than in the CO2 pneumoperitoneum group (p < 0.01). Peritoneal tumor growth in the CO2 group was greater than in the gasless group (p < 0.01). The size of abdominal wall metastases was greater at the port site of extraction of the tumor than at the other port sites (p < 0.001). In the cell seeding model, peritoneal tumor growth was greater after laparotomy in comparison to CO2 pneumoperitoneum (p < 0.02). Peritoneal tumor growth in the CO2 group was greater than in the gasless group (p < 0.01). The port site metastases in the CO2 group were greater than in the gasless group (p < 0.01). CONCLUSIONS: The following conclusions can be made: 1) that direct contact between solid tumor and the port site enhances local tumor growth, 2) that laparoscopy is associated with less intraperitoneal tumor growth than laparotomy, and 3) that insufflation of CO2 promotes tumor growth at the peritoneum and is associated with greater abdominal wall metastases than gasless laparoscopy.

Abdominal Neoplasms↗
PubMed1996

Ketanserin reduces graft arteriosclerosis after allogeneic aorta transplantation in rats.

The serotonin-2 receptor antagonist ketanserin has been suggested to diminish arteriosclerotic development by its effect on platelet function and on vascular smooth muscle cells. We investigated the ability of ketanserin in reducing immune-mediated arteriosclerosis using the BN-WAG and WAG-BN rat aortic transplantation models. Ketanserin (10 mg/kg/day) administered in drinking water significantly reduced posttransplant arteriosclerotic thickening of the intima in the BN-WAG rat model to 102 +/- 23 mu m as compared with 171 +/- 60 mu m in untreated BN-WAG allografts 8 weeks posttransplantation (p < 0.05). In the opposite WAG-BN combination, at 4 weeks posttransplantation, no significant reduction in intimal thickening was attained (112 +/- 42 vs. 152 +/- 49 mu m). Platelet aggregation to increasing amounts of collagen did not show a correlation between the effect of ketanserin on platelet function and reduction in intimal thickening. Ketanserin had no effect on systolic blood pressure or mononuclear cell infiltration. We conclude that ketanserin reduces graft arteriosclerosis by a mechanism other than by inhibition of platelet function, decrease in blood pressure, or immunosuppression. Because of this antiarteriosclerotic effect, ketanserin therapy might be beneficial to the long-term survival of vascular allografts.

Animals↗
PubMed1995

Tumour growth stimulation after partial hepatectomy can be reduced by treatment with tumour necrosis factor alpha.

This study investigated whether partial hepatectomy enhances the growth of experimental liver metastases of colonic carcinoma in rats and whether treatment with recombinant human tumour necrosis factor (TNF) alpha can reduce this increased growth. Resection of 35 or 70 per cent of the liver was performed in inbred WAG rats, with sham-operated controls (five to eight animals per group). Immediately after surgery 5 x 10(5) CC531 colonic tumour cells were injected into the portal vein. After 28 days the animals were killed and the number of liver metastases counted. A 35 per cent hepatectomy induced a significant increase in the median number of liver metastases (28 versus 3 in controls), whereas a 70 per cent resection provoked excessive growth, consistently leading to more than 100 liver metastases and a significantly increased wet liver weight in all animals. TNF-alpha was given intravenously to rats following 70 per cent hepatectomy or sham operation in a dose of 160 micrograms/kg three times per week. This had only a marginal effect on tumour development in sham-operated rats but was very effective following partial hepatectomy (median 45 liver metastases). These observations confirm previous findings that surgical metastasectomy may act as a 'double-edged sword' by provoking outgrowth of dormant tumour cells and suggest that adjuvant treatment with TNF-alpha may be of benefit in patients undergoing resection of metastases.

Animals↗
PubMed1995

Segmental intestinal transplantation can be an adequate therapy for short bowel syndrome in growing dogs.

This study was undertaken to investigate whether two-stage segmental small bowel allotransplantation can maintain growth and development of young dogs (16 weeks, 5 to 6 kg) with surgically created short bowel syndrome (SBS). After near-total small bowel resection (group 1; n = 3), irreversible weight loss was noted. After a sham operation (group 2; n = 3), no growth disturbances were found. Major histocompatibility matched small bowel transplantation (SBT) with cyclosporine A as immunosuppressant, was performed in two stages (group 3; n = 7). During the first stage, one meter of jejunoileum from an adult donor was placed as a Roux loop. Four weeks later, the native small bowel was removed and replaced by the graft. Only one dog survived long-term; the dogs died from infectious complications. The addition of selective decontamination of the digestive tract and early gastrostomy feeding (group 4; n = 10) resulted in long-term survival in 60%. Follow-up at 4 months showed that their growth was about 20% compromised compared with that of the sham-operated animals. Functional analysis showed that electrolytes, urea, and D-xylose were normal, but there was an increase in the lactulose:mannitol ratio, fecal fat excretion, and postheparin diamine oxidase release. These results show that under the conditions described, segmental SBT functions sufficiently to treat SBS but does not maintain normal growth.

Anastomosis, Roux-en-Y↗
PubMed1995

The effect of partial hepatectomy on tumor growth in rats: in vivo and in vitro studies.

Residual tumor in the remnant liver after partial hepatectomy (PH) for colorectal liver metastases is a serious clinical problem. This fact is reflected by the high number of recurrences after potentially curative liver resections. Liver regeneration, it appears, might influence the growth of remaining micrometastases in the liver. Using rats, we demonstrated enhancement of growth of a syngeneic colon carcinoma (CC 531) in the remnant liver after 70% PH. Fourteen days after PH, tumor weights in the liver were twice as high as those of sham-operated rats. This difference in tumor weight was not found in extrahepatic tumors. In vitro experiments did not show stimulation of cultured CC 531 cells by portal or systemic serum withdrawn 24 hours or 14 days after hepatectomy as compared with sera obtained after sham operation. Co-cultures of CC 531 cells and hepatocytes (in ratios of 1:10 or 1:1) demonstrated a higher 3H-thymidine incorporation than was the case in separately cultured cells. In co-cultures, bromodeoxyuridine (BrdU) incorporation in DNA was found primarily in CC 531 cells and rarely in hepatocytes. Cell density appeared to be of influence on 3H-thymidine incorporation in co-cultures. Hepatocytes were found to have a stimulating effect on CC 531 cells in low-density cultures, whereas high-density cultures exhibited an inhibiting effect after a culture time of 120 hours. These results show that, depending on cell density in co-cultures, a paracrine stimulating influence of hepatocytes on this type of colon carcinoma cells (CC 531) might be responsible for the increased tumor growth in vivo.

Animals↗