Biomedical subjects
Publications and source records attributed to P McCulloch.
This is a detailed description of the technique of 'R2' radical gastrectomy for cancer, used in Japan. Points of anatomical and technical interest which are omitted in currently available published outlines of the operation are emphasised to provide a guide of practical value to Western surgeons who wish to adopt the technique.
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Warfarin inhibits metastasis in the animal model and injection of the Warfarin-dependent coagulation factor complex II, IX, X enhances pulmonary metastasis in the same model. We have studied two possible mechanisms responsible for the observed effect. Mtln3, rat mammary carcinoma cells, radiolabelled with 5-(125) Iodo-2'-deoxyuridine (IUDR) were injected intravenously in female Fisher 344 rats either alone or in combination with factor complex II, IX, X or bovine serum albumin. Following sacrifice at various intervals, measured lung radioactivity was significantly higher (20%) in animals administered cells with the factor complex than in the other two groups (P less than 0.001, ANOVA and Student's t-test). These results indicate increased entrapment of tumour cells in the pulmonary microcirculation. In a second experiment, rat factor complex II, IX, X was prepared, and Mtln3 cells were then injected in female Fisher 344 rats alone or in combination with either human factor complex or rat factor complex. Following sacrifice, the number of pulmonary nodules in animals receiving cells with rat factor complex was similar to that in animals receiving human factor complex, and significantly higher than that in the control (P less than 0.001, ANOVA and Mann-Whitney), indicating that the observed enhancement of pulmonary seeding is unrelated to the xenogeneic properties of the human factor complex.
The ability of LAK cells and/or IL-2 to affect the course of an established T cell response was examined in a delayed-type hypersensitivity (DTH) model. IL-2 greatly increased the magnitude of the response at 24 h, while LAK cells alone had no effect. The administration of LAK cells and IL-2 together also had no effect on the magnitude of the DTH response, demonstrating that LAK cells were able to remove the enhancement seen with IL-2 alone. The presence of LAK cells reduced the serum half-life of IL-2 significantly, but not to an extent able to account for the observed loss of IL-2 induced DTH enhancement. IL-2 administration influenced cell phenotypes in the spleen and draining lymph nodes (DLN), as well as increasing splenic weight; the additional presence of LAK cells markedly altered these effects of IL-2 in the spleen (but not the DLN). Taken together, these results suggest that LAK cells interact with activated T-cells within the immune system and modulate their function.
The immunopharmacological effects of interleukin-2 (IL-2) on the sensitization and effector phases of the delayed-type hypersensitivity (DTH) reaction were studied using contact sensitivity to the haptenizing agent dinitrochlorobenzene (DNCB). When administered at the time of priming to DNCB, IL-2 had no effect on the subsequent magnitude of the response. Interleukin-2 was, however, able to increase the magnitude of the response when given at the time of secondary challenge; the degree of change was directly related to the dose of IL-2. The proportions of T cells in the draining lymph node and spleen of IL-2-treated animals decreased by approximately one-third, but there was no alteration to the balance between CD4+ and CD8+ T cells. The results suggest that the increase in DTH observed was due to a pharmacological effect rather than to an increase in T-cell number.
The predictive value for cancer recurrence of five measurements of haemostatic activity was studied in 89 patients with operable breast cancer. Neither preoperative nor sequential measurements up to 9 months postoperatively of fibrinopeptide A, fibrin fragment B beta 15-42, fibrinogen and serum fibrin(ogen) degradation products nor the fibrin plate lysis assay correlated with early recurrent disease. B beta 15-42 values were higher preoperatively in patients with oestrogen receptor positive tumours (P = 0.017). Mean B beta 15-42 values rose postoperatively (P = 0.003), largely because of an increase in patients with oestrogen receptor negative tumours.
Disturbances of coagulation were measured in breast cancer, colon cancer and benign breast disease using an enzyme immunoassay against total plasma fibrinogen and fibrin degradation products (TDP). Results were compared with measurements of fibrinopeptide A (FPA) and of serum fibrinogen-related antigen (FRA). Plasma TDP before surgery was significantly higher in colon cancer than in breast cancer patients (p = 0.0009) or in benign breast disease (p = 0.0292). A post-operative rise in TDP at 4 months (colon cancer) or 9 months (breast cancer) was associated with early recurrent disease (p less than 0.0173 for colon cancer, p less than 0.1835 for breast cancer). No such association was noted with FPA or FRA measurements. TDP may prove to be of value in detecting activation of coagulation by malignant disease.
Fibrin formation and fibrinolysis were estimated in 89 breast cancer patients by measurement in plasma of Fibrin Fragment B beta 15-42 and Fibrinopeptide A (FPA), serum Fibrin(ogen) Degradation Products (FDPs) and plasminogen activator by Fibrin Plate Lysis Assay. Results were compared with (a) 26 patients with benign breast diseases; and (b) 45 healthy factory workers. FPA, FDP and B beta 15-42 levels were elevated in both breast cancer patients and benign disease patients, but there were no significant differences between these two groups. Cancer stage, patient age and smoking habits did not affect these results, but Oestrogen Receptor (ER) positive patients had higher B beta 15-42 values than ER negative patients (p = 0.017). These results show that fibrin formation is enhanced preoperatively in patients with either benign or malignant breast disease. The fibrinolytic response to activated coagulation may be relatively deficient in breast cancer. The roles of malignancy, stress and other factors in the causation of these abnormalities require further assessment.
Suture implantation of viable exfoliated malignant cells may be responsible for local recurrence (implantation metastasis) of colorectal cancer. In this study, four anastomotic materials (braided polyamide, braided polyglycolic acid, monofilament polypropylene and monofilament stainless steel) were compared with respect to their ability to entrap and transfer free Mtln3 carcinoma cells from the colonic lumen of a rat. The braided materials transferred greater numbers of cells than did the monofilament sutures (P less than 0.001), but significant differences were also observed between polyglycolic acid and polyamide (P less than 0.001) and between polypropylene and stainless steel (P less than 0.05). Secondly, the firm adherence of tumour cells to the suture materials was assessed by an in vitro technique. The Mtln3 cells were found to adhere in significantly greater quantities to the braided sutures than to the monofilaments (P less than 0.001) and this was supported by in vivo tumour growth studies. These findings may have implications for colorectal cancer surgery in man.
Coumarin anticoagulants inhibit metastasis in several animal models, but the mechanism of this effect is uncertain. In order to determine the role of cytotoxic and/or cytostatic actions of coumarins on the tumour cells, we have studied the effects of warfarin on tumour cell growth in a model in which tumour metastasis is inhibited by this drug. Clonogenic assay, growth curve analysis and thymidine labelling index revealed that warfarin had no effects on Mtln3 mammary carcinoma cell growth in vitro at concentrations below 1 mM. The growth rate of subcutaneously implanted Mtln3 tumour deposits in female F344 rats, assessed by weight and by stathmokinetic analysis of the tumour tissue, was identical in warfarin-treated and control animals. Spontaneous metastasis from such tumours to the lungs was, however, significantly reduced in warfarin-treated animals (median 0 pulmonary tumours per animal in warfarin treated, eight tumours per animal in control animals; P less than 0.05, Mann-Whitney). The mean plasma warfarin concentration in warfarin treated rats was 1.63 microM. These results suggest that warfarin treatment of the host animal can inhibit tumour metastasis without having any direct or indirect effect on the growth rate of the tumour cells.
Coumarins inhibit metastasis in a number of animal models, but the mechanism of this effect remains unclear. We have investigated the relationship between the coagulation system and metastasis using a new model system, involving i.v. injection of Mtln3 rat mammary carcinoma cells into Fischer 344 rats, and subsequent estimation of pulmonary seeding. Injection of factors II, VII, IX and X elevated the median number of surface pulmonary seedlings per animal to 182, and injection of factors II, IX and X to 181, compared with a median for control animals of 12 (P less than 0.001). Injection of factor VII alone, or of bovine serum albumin did not significantly affect pulmonary seeding. In a second experiment, arvin defibrination reduced the mean plasma fibrinogen concentration to 76.8 mg dl-1 from a control value of 228 mg dl-1. This degree of defibrination had no significant effects on pulmonary seeding, nor on the enhancing effects of factor complex injection (median numbers of seedlings per animal; control 15, arvin 21, arvin plus factors II, VII, IX and X 170, factors II, VII, IX and X only, 157). Factor complex injections did not detectably shorten thrombotest clotting times. In vitro testing suggested that Mtln3 cells contain little or no conventional factor X activating cancer procoagulant. The complex of coagulation factors II, IX and X appears to contain a component which greatly enhances metastasis in this model. This may explain the previously reported antimetastatic effect of coumarin anticoagulants, which suppress factors II, VII, IX and X. The enhancing effect of the factor complex does not appear to be altered by significant reductions in fibrin forming capacity, and defibrination itself has no effect on metastasis. These findings suggest the possibility that the effect of this factor complex on metastasis may be mediated via mechanisms other than the formation of a fibrin clot.
Warfarin inhibits metastasis in animal models by mechanisms that remain unclear. A better understanding of this phenomenon may clarify processes underlying metastasis in human cancer. We have studied the effects of warfarin on metastasis in a rat model by intravenous injection of Mtln3 mammary carcinoma cells and subsequent counting of pulmonary seedlings. To determine whether warfarin acts principally on the tumour cells or the host, we pretreated either cells or animals with warfarin before intravenous injection of 10(4) Mtln3 cells. Pretreatment of tumour cells had no effect, whilst pretreatment of the host reduced median seedlings from 67 to 4.5 per animal (P less than 0.005). To determine whether warfarin was acting via its anticoagulant action, we reversed warfarin anticoagulation by intravenous injection of coagulation factors II, VII, IX and X. Restoration of coagulation for 12 h immediately after injection of cells completely reversed the warfarin effect (P less than 0.001), but if the injection of factors was delayed for 12 h it had no effect (P = 0.1753). We conclude that warfarin acts principally on the host, not the tumour cell, and that it acts via its effect on coagulation. The restriction of the effect to the first 12 h after tumour cell injection suggests a mechanism involving intravascular processes such as tumour cell survival or endothelial adhesion.
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The National Cancer Institute of Canada Clinical Trials Group conducted a phase II study of spirogermanium given daily for 5 days every 3 weeks to previously untreated patients with malignant melanoma. In 21 evaluable patients one complete response was seen (response rate 5%). Disease progression occurred in the other 20 patients. Toxicity was primarily neurologic and mild or moderate in most patients, though there was one treatment related death. In this schedule spirogermanium has extremely limited activity against malignant melanoma and will not contribute significantly to the systemic therapy of this disease.
In the Nude mouse: 1. Xenografts of human tumours often grew successfully. 2. There was very little growth in allografts of actively-growing normal tissue from Swiss mice. 3. Transplants of mature tissue from the toad failed to grow.
A variant, HCT-8R, of the colon adenocarcinoma cell line HCT-8 was located and cloned. The variant and parent cell line were characterized with respect to morphology, growth characteristics, karyotype, production of Cea, and ability to form tumors in nude mice. The variant cells differed from the parent cells in morphology, marker chromosomes, and ability to form colonies in soft agar and produced more carcinoembryonic antigen. The two cell strains were equally oncogenic in nude mice, although HCT-8R cells produced poorly differentiated tumors while HCT-8 cells produced tumors with both differentiated and poorly differentiated areas. Thus, in nude mice, no correlation was observed between carcinoembryonic antigen production by cells and their oncogenicity.
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