Dick L. Westbroek

Enhanced growth of artificial tumor metastases following blood transfusion: The effect of erythrocytes, leukocytes and plasma transfusion

Clinical and experimental investigations have shown that allogeneic blood transfusions may modulate the growth of tumors. Dependent on the tumor model used in animal studies, the effects observed ranged from inhibition to stimulation of tumor growth. We have demonstrated previously that allogeneic blood transfusions gave rise to enhanced growth of a transplantable sarcoma (LS 175) in BN rats. In the experiments reported here the effect of transfusion of different allogeneic blood constituents on the growth of artificial LS 175 lung metastases was investigated. Erythrocytes and leukocytes were found to promote tumor growth to a similar degree as whole blood transfusions, plasma transfusions had no effect.

Effect of Viable Isolated Hepatocytes or Hepatocyte Fractions on Survival Rate following Galactosamine-Induced Acute Liver Failure

Administration of galactosamine to rats results in an acute liver failure. The dose-effect relation appeared to be highly strain-dependent. Intraperitoneal injection of 1,000 mg/kg galactosamine resulted in a 90% lethal acute liver failure in Wag/Rij rats. Transplantation of viable isolated hepatocytes, administration of homogenate or cytosol of normal or regenerating liver tissue, or administration of cell-free liver cell culture supernatant did not improve the survival rate in this model of acute liver failure. These findings, which are in striking contrast with the data reported in the literature, are discussed in relation to the specific properties of this type of experimental model for acute hepatic failure.

Effect of stress and dietary fatty acids on allograft survival in the rat.

To determine the immunosuppressive effect of stress and a diet rich on linoleic acid on vascularized organ graft survival in the rat, a series of allogeneic heart and kidney grafts were carried out. Restraint stress resulted in a significant prolongation of the survival time. Although 5 days of postoperative stress gave the best results, 3 h of stress given on the first postoperative day already gave a marked prolongation of the survival time of kidney allografts. The beneficial effect of stress on heart survival was abolished when prior adrenalectomy was carried out. A diet high on polyunsaturated fatty acids gave significant prolongation of the survival times of kidney-grafted rats. A diet hgh on saturated fatty acids did not result in a statistical significant prolongation of the survival time, although the difference with the polyunsaturated fatty acid group was very small and not statistically significant. It was concluded that stress and diets high in certain types of fatty acids depress the immune response in rats, possibly via a mechanism which has some common pathways. The adrenal glands could play an important role in this immune inhibition.

Clinical and immunological evaluation of 20 patients with advanced colorectal cancer treated with high dose recombinant leukocyte interferon-αA (rIFNαA)

SummaryA total of 20 patients with advanced colorectal cancer received recombinant leukocyte interferon-αA (rIFNαA) either chronically (group I: twice a week up to 20×106 IU/m2 i.m.) or cyclically (group II: 1–4 periods of 8 consecutive days up to 20×106 IU/m2 i.m. daily at 20-days intervals) over a period of 12 weeks. There was 1 partial response, 1 mixed response and 1 patient with stable disease, whilst 17 patients had progressive disease. Median survival was 15.5 months. Survival was significantly shorter when the extent of hepatic disease was >25% (P=0.05), extrahepatic disease was extensive (P<0.005), alkaline phosphatase level was >2× normal (P<0.02), or performance status was <100% (P<0.001). Toxicity consisting mainly of fever, fatigue, anorexia and weight loss was serious in group I and minimal in group II. Administration of rIFNαA led to a “short lived” augmentation of natural killer (NK) cell activity. In the cyclically treated group this was a recurrent phenomenon whereas a marked lasting depression of NK cell activity was seen in chronically treated patients. Interferon-γ production capacity was significantly stimulated during rIFNαA therapy. The differences in toxicity and immunostimulatory effects between the two schedules may be of importance in the design of further studies.

Growth of an implanted fibrosarcoma in rats is associated with high levels of plasma prostaglandin-E2 and thromboxane-B2

Growth of BN175, a malignant fibrosarcoma, was correlated with high plasma TXB2 and PGE2 levels. This statistically significant increase was first detected 17 days after inoculation of the tumor, at which time the tumors were 20 mms in diameter. A further increase in tumor size was associated with still higher PGE2 and TXB2 values. At the same time, progressive alterations in platelet function, as measured by ADP-induced platelet aggregation, were observed. 6-keto-PGF1 alpha levels remained normal throughout the whole experiment. It was concluded that tumor growth was associated with changes in PG synthesis and platelet function, although it remains unclear whether these changes were caused by some host immunological response towards the tumor or were predominantly the result of tumor PG-synthesis.

Reductive Effect of Phenobarbital on Graft Survival in Prednisolone-Treated Rats

This study was meant to elucidate in an animal model the results found in a clinical retrospective study, where a higher incidence of graft failure occurred when anticonvulsant therapy was given to pa

Influence of the linoleic acid content of the diet on tumor growth in transplantable rat tumor models

Diets high (17.7 cal%) and low (3.3 cal%) in linoleic acid were given to groups of Brown Norway female rats before and after inoculation of syngeneic tumor models with different characteristics, with regard to tumor spread, malignancy, immunogenicity, growth rate, rat strain, and histopathological features. Despite the differences in characteristics, in most tumor models, tumor growth was identical in both experimental groups. However, in 2 tumor models, an adrenal cortical carcinoma and a myeloid leukemia, differences in growth were noted. In rats given the diet low in linoleic acid, growth of the cortical carcinoma was significantly increased, whereas the opposite effect was seen in rats with myeloid leukemia.

Diets Rich in Fish Oil Cannot Control Tumor Cell Metastasis

Rats fed diets containing different amounts of polyunsaturated fatty acids either of the n-3 or n-6 type, received cultured, syngeneic mammary tumor (BN472) cells intravenously. Animals were sacrificed 2 weeks after tumor inoculation, and the number of pulmonary tumor foci was counted. No significant differences in the number of metastatic foci were observed between the dietary groups. Prostaglandin measurements in the supernatant of tumor cells cultured in vitro showed that the tumor cells could produce thromboxane A2. Many investigators connected this tumor synthesis capacity with tumor metastatic activity. Yet in our study, diets rich in menhaden oil, with the known capacity to inhibit thromboxane synthesis, could not control tumor metastasis in this particular tumor model.

Is the 7,12-Dimethylbenz[a]anthracene-Induced Rat Mammary Tumor Model Suitable as a Preclinical Model to Study Mammary Tumor Malignancy?

To study the biological characteristics of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in rats, 20 Sprague Dawley female rats received a single oral dose of 5 mg of this carcinogen. During the 35-week observation time 78 primary tumors were removed. While in most cases the primary tumor could be removed completely, 7 out of 20 animals eventually had to be sacrificed for inoperable local recurrence of the primary tumor. Notwithstanding, the long period of time given for tumor metastases to develop (mean time between tumor removal and termination was 18.5 weeks), tumor spread either to lungs or regional lymph nodes could not be established. This relatively benign behavior of the tumor was in contrast with the morphological characteristics of the tumor, which uniformly showed the features of adenocarcinomas. The difference in biological behavior between DMBA-induced mammary tumors in rats and malignant mammary tumors in humans suggests that as a model this system is of limited value for investigations of mechanisms of malignant behavior of human tumors.

Abrogation of the tumor promoting effect of allogeneic blood transfusion by polyadenylic-polyuridylic acid (poly A-poly U)

SummaryStudies from several centers have shown an immunosuppressive effect of surgical procedures, whilst others have shown blood transfusion in association with cancer surgery to have an adverse effect on ultimate prognosis. We have previously demonstrated enhanced growth of tumor metastases, in rats following allogeneic blood transfusion and surgery. Polyadenylic-polyuridylic acid (poly A-poly U) has been reported to stimulate immune responses. In this report, we have investigated the effectiveness of poly A-poly U as an adjuvant to blood transfusion and surgical procedures in BN rats bearing artificial lung metastases. Significantly reduced tumor growth was observed, following poly A-poly U adjuvant treatment. These results lead to serious contemplation of the use of this drug as adjuvant therapy in blood transfused and surgically treated patients.