Reduction of peritoneal trauma by using nonsurgical gauze leads to less implantation metastasis of spilled tumor cells

OBJECTIVES: To evaluate whether infliction of peritoneal trauma would promote tumor cell adherence to damaged peritoneal surfaces; to investigate whether peritoneal damage could promote tumor growth of extraperitoneal tumors; and to evaluate whether the amount of trauma correlated with the degree of tumor cell adherence and local and distant tumor growth. BACKGROUND DATA: After potentially curative resection of colorectal carcinoma, the most common site for recurrence is locoregional. We previously demonstrated that surgical trauma induces a cascade of events leading to adhesion formation. The same mechanisms may be responsible for improved tumor cell adherence and growth facilitation in early local recurrence. METHODS: A reproducible rat model was used in which peritoneal damage was inflicted by standardized rubbing of the peritoneum with surgical gauzes of different texture. In the first experiment, tumor cell adherence and growth at traumatized and nontraumatized peritoneal sites were assessed semiquantitatively 3 weeks after perioperative intra-abdominal injection of CC-531 tumor cells. In the second experiment, the effect of peritoneal trauma on ectopic tumor growth was investigated (CC-531 implanted under the renal capsule). In the final experiment, we evaluated how soon after peritoneal traumatization tumor cell adhesion and growth-promoting factors were active and whether they could be passively transferred to naive nontraumatized abdominal cavities. RESULTS: A significant correlation between the amount of peritoneal trauma and the degree of tumor take at damaged peritoneal surfaces was found (p < or = 0.018). Tumor take at remote peritoneal sites not directly traumatized was also significantly higher after severe trauma than after moderate trauma of the peritoneum (p < or = 0.005). In addition, a significant correlation between the degree of peritoneal trauma and the growth of ectopic tumors under the renal capsule was observed (p < or = 0.009). The final experiment demonstrated that within a few hours after infliction of peritoneal trauma, tumor growth-promoting effects could be passively transferred to naive recipients. CONCLUSIONS: Surgical trauma is an important factor in the promotion of local recurrence. The enhancing effect of trauma is not restricted to the inflicted site but rather has a generalized character. Avoidance of unnecessary surgical trauma by using gentle techniques and materials is therefore indicated

Scavenging of reactive oxygen species leads to diminished peritoneal tumor recurrence

Previously, we demonstrated that RBCs inhibit the recurrence of perioperatively spilled tumor cells. The aim of this study was to identify on which RBC component(s) the inhibitory effect is based. By using a cell-seeding model in rats, the effect of RBC-related antioxidant scavengers [hemoglobin, catalase, and superoxide dismutase (SOD)] on peritoneal tumor recurrence was investigated. i.p. injection of hemoglobin caused 45% more tumor load (P < 0.0001). At least 40% inhibition of tumor recurrence was achieved with the use of catalase or SOD (P < 0.05). Combining SOD and catalase did not lead to additional inhibition of tumor recurrence. Inhibition of the overwhelmin

Effects of thyroid status and thyrostatic drugs on hepatic glucuronidation of lodothyronines and other substrates in rats - Induction of phenol UDP-glucuronyltransferase by methimazole

Glucuronidation of iodothyronines in rat liver is catalyzed by at least three UDP-glucuronyltransferases (UGTs): bilirubin UGT, phenol UGT, and androsterone UGT. Bilirubin and phenol UGT activities are regulated by thyroid hormone, but the effect of thyroid status on hepatic glucuronidation of iodothyronines is unknown. We examined the effects of hypothyroidism induced by treatment of rats with propylthiouracil (PTU) or methimazole (MMI) or by thyroidectomy as well as the effects of T4-induced hyperthyroidism on the hepatic UGT activities for T4, T3, bilirubin, p-nitrophenol (PNP), and androsterone. Bilirubin UGT activity was increased in MMI- or PTU-induced hypothyroid and thyroidectomized rats, and decreased in hyperthyroid animals. T4 and, to a lesser extent, T3 UGT activities were increased in MMI- or PTU-induced hypothyroid rats, and T4 but not T3 glucuronidation also showed a significant increase in thyroidectomized rats. T4 but not T3 UGT activity was slightly decreased in hyperthyroid rats. While PNP UGT activity was decreased in thyroidectomized rats and increased in hyperthyroid animals, it was also markedly increased by MMI and slightly increased by PTU-induced hypothyroidism. In T4-substituted rats, MMI did not affect T4, T3, bilirubin and androsterone UGT activities but again strongly induced PNP UGT activity, indicating that this represented a direct induction of PNP UGT by the drug independent of its thyrostatic action. Androsterone UGT activity was hardly affected by thyroid status. Our results suggest a modest, negative control of the hepatic glucuronidation of thyroid hormone by thyroid status, which may be mediated by changes in bilirubin UGT activity. To our knowledge, this is the first report of the marked induction of a hepatic enzyme by MMI, which is not mediated by its thyroid hormone-lowering effect

Enterohepatic circulation of triiodothyronine (T3) in rats:Importance of the microflora for the liberation and reabsorption of T3 from biliary T3 conjugates

In normal rats, T3 glucuronide (T3G) is themajor biliary T3 metabolite, but excretion of T3 sulfate (T3S) isgreatly increased after inhibition of type I deiodinase, e.g. with6-propyl-2-thiouracil (PTU). In this study, the fate of the T3conjugates excreted with bile was studied to assess the significance of a putative enterohepatic circulation of T3 in rats.Conventional (CV) or intestine-decontaminated (ID) rats received iv [125I]T3G or [125I]T3S, the latter usually after pretreatment with PTU (1 mg/100 g BW). Radioactivity in plasma andbile or feces was analyzed by Sephadex LH-20 chromatographyand HPLC. Within 1 h, 88% of injected T3G was excreted inbile of CV or ID rats, independent of PTU. About 75% of theinjected T3S was excreted within 4 h in PTU-treated rats, incontrast to only 20% in controls. Up to 13 h after iv administration of T3G or T3S (+PTU) to intact ID and CV rats, fecalradioactivity consisted of more than 90% T3 in all CV rats, 95%of T3S in T3S-injected ID rats, and 30% T3 and 67% T3G inT3G-injected ID rats. In overnight-fasted CV rats injected withT3G, total plasma radioactivity rapidly declined until a nadir of0.10% dose/ml at about 2.5 h, but radioactivity reappeared witha broad maximum of 0.12% dose/ml between 5.5-10 h. In thelatter phase, plasma radioactivity consisted of predominantly I"and T3 in a ratio of 2:1. Reabsorption was diminished in fed CVrats and prevented in ID rats. Plasma T3 4-10 h after iv T3Ginjection to overnight-fasted CV rats was 12, 2, and 3 timeshigher than that in bile-diverted rats, fed CV rats, and ID rats,respectively, and similar to that 4 h after the injection of T3itself. Total plasma radioactivity as well as plasma T3 6-13 hafter iv administration T3S in PTU-treated rats were significantly increased in CV us. ID rats, e.g. T3 0.016% us. 0.005%dose/ml. These results demonstrate a significant enterohepaticcirculation of T3 in rats in which bacterial hydrolysis of T3conjugates excreted with bile plays an important role. {Endocrinology 125: 2822-2830,1989

A membrane cofactor protein transgenic mouse model for the study of discordant xenograft rejection.

BACKGROUND: In recent years, interest has been revived in the possibility of transplanting organs into humans from a phylogenetically disparate species such as the pig (xenotransplantation). Such discordant xenografts, however, are subject to hyperacute rejection (HAR) and activation of host complement plays a major role in this rejection. This problem may be solved through the use of transgenic technology by providing the grafted tissue with molecules that down-regulate the action of host complement. RESULTS: Transgenesis with a yeast artificial chromosome (YAC) was used to produce transgenic mice with the complete genomic gene of the human complement regulator membrane cofactor protein (MCP). Transgenic mice were obtained that exhibit full regulation of MCP as normally observed in humans. Hearts from these mice were shown to be significantly protected from HAR caused by human serum in an in vivo experimental procedure. CONCLUSIONS: We conclude that MCP can protect discordant xenografts from HAR caused by human serum and that transgenic mice can be used effectively as in vivo models for the study of the role of human complement regulatory molecules in xenotransplantation

Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2

In mycophenolate mofetil (MMF)-treated organ transplant recipients, lower mycophenolic acid (MPA) plasma concentrations have been found in cyclosporine (CsA) compared with tacrolimus (Tac)-based immunosuppressive regimens. We previously demonstrated that CsA decreases exposure to MPA and increases exposure to its metabolite MPA-glucuronide (MPAG), possibly by interfering with the biliary excretion of MPAG. To elucidate the role of the multidrug resistance-associated protein (Mrp)-2 in the interaction between MMF and CsA, we treated three groups of 10 Mrp2-deficient rats (TR- rat) for 6 days with either vehicle, CsA (8 mg/kg) or Tac (4 mg/kg) by oral gavage. Hereafter, co-administration with MMF (20 mg/kg) was started in all groups and continued through day 14. The 24-h MPA/MPAG area under the concentration-time curve (AUC) was determined after single (day 7) and multiple MMF doses (day 14). On both study days, there were no significant differences in the mean MPA and MPAG AUC between CsA and Tac-treated animals. We conclude that the pharmacokinetics of MMF are comparable in Mrp2-deficient rats receiving either CsA or Tac as co-medication. This finding suggests that CsA-mediated inhibition of the biliary excretion of MPAG by the Mrp2 transporter is the mechanism responsible for the interaction between CsA and MM

Red blood cells inhibit tumour cell adhesion to the peritoneum

Background: Perioperative blood transfusion has been associated with increased tumour recurrence and poor prognosis in colorectal cancer. Blood loss in the peritoneal cavity might be a tumour-promoting factor for local recurrence. The aim of this study was to investigate whether blood in the peritoneal cavity affects local tumour recurrence. Methods: In an established in vivo rat model the effect of 1.5 ml syngeneic whole blood on tumour cell adhesion and tumour growth was investigated. In the same model the effect of 1.5 ml pure red blood cell (RBC) concentrate and 1.5 ml RBC-derived substances on tumour cell adhesion was studied. In an established in vitro model the effect of increasing numbers of RBCs (0-250 x 10 6) on tumour cell adhesion and tumour growth was assessed. Results: Both the presence of blood and RBC concentrate in the peritoneal cavity prevented tumour cell adhesion in vivo (overall P ≤ 0.001 and P ≤ 0.05 respectively), rather than promoting adherence. RBC concentrate and RBC-derived substances had a comparable inhibitory effect on tumour cell adhesion. In in vitro studies RBCs inhibited tumour cell adhesion but not tumour growth. Conclusion: RBC-derived factors prevent tumour cell adhesion to the peritoneum, and consequently tumour recurrence