A. J. Cooper

Enhanced growth of tumour cells in healing colonie anastomoses and laparotomy wounds

In the past, it has been noted that experimental tumour cells innoculated into the peritoneal cavity or into the lumen of the bowel will grow at a recently formed colonic anastomosis. However, it has previously been unclear whether the healing process enhances tumour growth or whether the presence of a suture line merely allows the tumour cells to gain access to the tissues. In the present study, using the hooded Lister rat, we have confirmed these findings by showing that growth of the syngeneic MC28 sarcoma and OES5 breast carcinoma occurs preferentially at colonic anastomoses and laparotomy wounds after intraperitoneal injection, and at colonic anastomoses after intraluminal injection. In previous studies using the MC28 sarcoma and the OES5 breast carcinoma injected by the intracardiac route (so that tumour cells reach normal and healing tissues in approximately equal numbers) we have shown that tumour growth is enhanced in healing wounds but not in the surrounding normal tissues when cells reach a healing colonic anastomosis or laparotomy wound within 2 h of its formation. Furthermore, by studying the distribution of radiolabelled tumour cells after intracardiac injection, we have calculated that the probability of a tumour cell leading to a deposit in a healing anastomosis or laparotomy wound is increased 1,000 fold compared to normal tissue. No previous studies have combined the data for intracardiac, intraluminal and intraperitoneal injection of tumour cells using the same animal model. We conclude that the same phenomenon of tumour growth enhancement in colonic anastomoses and laparotomy wounds reported after intracardiac injection of tumour cells may well be enhancing tumour growth after intraperitoneal and intraluminal injection. If these results can be extrapolated to man, then tumour cells spilled at surgery for colorectal cancer (or indeed any other cancer) may well encounter an environment which favours their growth and so the healing process itself may contribute to the genesis of local recurrence of malignant disease.

Facilitation by partial hepatectomy of tumor growth within the rat liver following intraportal injection of syngeneic tumor cells

The effects of both mechanical trauma and regeneration on the growth of intraportally injected tumor in the rat liver were investigated using two-thirds partial hepatectomy (PH). Tumor grew at the excision scar when PH was performed less than 2 days before tumor injection (34/34 animals). However, when the PH was performed 4–7 days before injection, tumor developed within the regenerating lobe, but not at the scar (50/51). Injecting the same cell dose into rats with intact livers caused few tumors to develop in 12/30 animals. Intraportally injected51Cr-labelled tumor cells distributed uniformly in the liver irrespective of the time after PH. Patterns of tumor take seen at different times after PH were not due to selective trapping of the injected cells. Liver extracts showed that epidermal growth factor-like activity was unaltered by PH, while heparin-binding growth factor activity peaked at 2 days post-PH, before the incidence of tumor growth in the parenchyma increased. We observed two peaks of DNA synthesis at days 1 and 4 post-PH by pulse labeling with [125I]deoxyuridine and bromodeoxyuridine. Bromodeoxyuridine immunohistochemistry showed the first peak to be confined to hepatocytes. The second peak involved non-hepatocytes and coincided with the beginning of enhanced tumor take in the regenerating lobe.

Effect of γ-linolenic acid on cellular uptake of structurally related anthracyclines in human drug sensitive and multidrug resistant bladder and breast cancer cell lines

This study investigated the effect on drug uptake in multidrug resistant cells by the incorporation of the essential fatty acid γ-linolenic acid (GLA). The cell lines used were the MCF-7/R resistant human breast cancer and MGH-U1/R bladder cancer. Uptake of drug (doxorubicin, epirubicin, mitoxantrone and idarubicin) after the incorporation of GLA was investigated quantitatively by flow cytometry and qualitatively by confocal microscopy. There was no observable overall increase in drug uptake due to GLA incorporation into the cells as shown by flow cytometry. However, an increase in uptake of the chemotherapeutic agent idarubicin was observed in GLA-treated resistant cells compared with untreated cells using the confocal microscope. This overall increase in cellular drug uptake was not accompanied by a change in cellular drug distribution. Only one drug, mitoxantrone, displayed a change in intracellular drug distribution due to GLA incorporation into MCF-7/R cells. This suggests that essential fatty acid incorporation into the cellular membranes of some resistant cells may cause a shift in the intracellular distribution of certain chemotherapeutic drugs.

Effect of 1-γlinolenyl-3-eicosapentaenoyl propane diol on the growth of human pancreatic carcinoma in vitro and in vivo

Abstract Essential fatty acids such as gammalinolenic (GLA) and eicosapentaenoic (EPA) acids have been proposed as anticancer drugs. The aim of this study was to test the effect of a lipid emulsion containing both GLA and EPA in a novel chemical formulation of 1-γlinolenyl-3-eicosapentaenoyl propane diol on the growth of human pancreatic carcinoma in vitro and in nude mice. This compound had a dose-dependent growth-inhibitory effect on human pancreatic cancer cell lines MIA PaCa-2 and Panc-1 in vitro. The concentration necessary for 50% growth inhibition was 25 μmol/l for MIA PaCa-2 and 68 μmol/l for Panc-1 (95% CI 20–29 and 59-77 μmol/l respectively). Nude mice bearing subcutaneous pancreatic tumours produced with the MIA PaCa-2 cell line were treated with the maximum tolerated dose (6.75 mg GLA and 7.3 mg EPA per g of body weight) administered over 10 days by daily intravenous (i.v.) bolus injections. No antitumour effect or major alteration in tumour lipid fatty acid composition was seen in comparison with control animals. Concurrent treatment with parenteral iron (iron saccharate, 5 μg/gram body weight daily) did not make a significant difference. Further improvements in fatty acid delivery mechanisms are necessary before they can become useful anticancer agents.

Effect of a Microwave Coagulator on Implanted Liver Neoplasms in Rats

An experimental study was conducted to determine the applicability of a microwave (MW) source for coagulation and dissection of metastatic tumour and liver parenchyma. Twenty PVG rats were studied after implantation of MC28 tumour cells into the liver. Eleven days later they underwent sham laparotomy (control) MW coagulation of the tumour deposit, local resection of the tumour deposit with 2 mm clearance or resection of the tumour with MW coagulation of the resection zone. The control animals all died with blood-stained ascites and heavy tumour burden in the liver. After MW coagulation, tumours disappeared in all but one rat. Local resection also led to tumour clearance in 4 of 5 rats. MW coagulation of the resection zone allowed rapid bloodless resection, and no tumour recurrence was observed after 40–89 days. We conclude that MW coagulation is a potentially useful tool for ablation of hepatic metastasis and as an adjunct to hepatic resection.