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Biomedical subjects

B N Gray

Publications and source records attributed to B N Gray.

At least 91 records · Page 5Linked to original sources
PubMed1976

Sialoproteinaemia: lack of correlation with inhibition of in vitro lymphoblastosis induced by phytohaemagglutinin or alloantigen.

Elevation of serum-bound sialic acid concentration in different disease states fails to correlate significantly with suppressive serum actions in mixed allogeneic lymphocyte cultures or phyto-haemagglutinin cultures. Heat-decomplemented serum from patients with abnormal levels of bound sialic acid was added to parallel cultures containing similar blood lymphocyte populations derived from normal humans. Wide fluctuations of the rate of incorporation of tritiated thymidine into nucleoprotein indicated presence of suppressive elements other than sialoprotein in the added serum components. Serum with rising sialyl concentration derived from patients with cancer showed slight tendency to augment mixed lymphocyte and phytohaemagglutinin responses. The findings suggest that the previously documented nonspecific suppressive action of serum sialoprotein on human host lymphoblastic response to neuraminidase-treated cancer cells represents a mechanism unique to that culture system rather than a manifestation of a general immunoregulatory function of serum sialoprotein.

Blood Protein Disorders↗
PubMed1975

Immunologic approach to cancer therapy.

The resistance that many cancer patients show to the progress of their disease, attested to by well documented cases of spontaneous regressions as in neuroblastoma, hypernephroma, choriocarcinoma and malignant melanoma, and the long-term dormancy of multiple metastases seen particularly after removal of a primary mass, can be explained only by host defense mechanisms. Attemps at immunotherapy over the years are reviewed and new directions are presented.

Animals↗
PubMed1974

Neuraminidase-mediated augmentation of in vitro immune response of patients with solid tumors.

Host blood lymphocytes undergo accentuated blastic transformation when cultured with tumor cells pretreated with neuraminidase. The effect has been observed in 38 patients with such common solid tumors as bronchus carcinoma, skin melanoma, hypernephroma, or adenocarcinoma of the breast, lung, colon, or rectum. Individual response varied but often exceeded response to allogeneic cells. Three patients with glioblastoma of the brain did not respond. Lymphoblastic transformation was not observed in three of four cultures containing benign tumor or in any cultures containing normal tissue analogues of the malignant tumors. A factor in host blood serum inhibiting lymphoblastic transformation correlated to abnormal elevation of serum-bound sialic acid. This blocking factor differed in specificity from enhancing antibody or serum blocking complexes described by other investigators. Blocking effects were observed when the tumor-cell type of a serum donor differed from the cell type of the culture test tumor. Serum with abnormal elevation of bound sialate from a cancerfree human also non-specifically blocked host response to tumor. The blocking effect could be eliminated by partial enzymatic removal of bound sialic acid from serum glycoproteins.

Adenocarcinoma↗
PubMedDate not supplied

The effect of tumour size on ferromagnetic embolization hyperthermia in a rabbit liver tumour model.

OBJECTIVE: Ferromagnetic Embolization Hyperthermia (FEH) consists of arterially embolizing tumours with ferromagnetic particles to cause hysteretic heating upon subsequent exposure to an alternating magnetic field. The objective was to determine the effect of tumour size during FEH using a rabbit liver tumour model. METHOD: Thirty-three rabbits containing implanted hepatic VX2 carcinomas received a hepatic arterial infusion of ferromagnetic particles suspended in lipiodol. Following hysteretic heating, tumour and normal hepatic tissues were chemically analysed for iron content. Tumours were classed as small if their mass was less than the median mass for the whole group of subjects (2.1 g), and as large if their mass was greater than or equal to the median. To control for variability in tumour iron concentration, 13 small tumours were matched to 13 large tumours by iron concentration, and their heating characteristics compared. RESULTS: The heating rate in large tumours (median = 5.0 degrees C/min) was significantly greater than that in the matched small tumours (median = 2.8 degrees C/min), p = 0.006. Regression analysis determined that the slope of the heating rate vs iron concentration curve for large tumours was 1.5 times greater than that for the matched small tumours, p < 0.001. After cessation of heating in large tumours, there was continued heat dissipation into surrounding tissues, which led to anomalous temperature increases. There was an inverse linear relationship between tumour size and tumour iron concentration for a given dose of particles. CONCLUSION: For a given tumour iron concentration, larger tumours heat at a greater rate than small tumours, due to the poorer tissue cooling and better heat conduction in the necrotic regions of large tumours. This warrants further investigation as this finding could confer a significant advantage on FEH over other hyperthermic modalities in the treatment of hepatic malignancies.

Animals↗
PubMedDate not supplied

Treatment of experimental rabbit liver tumours by selectively targeted hyperthermia.

Experimental rabbit liver tumours were preferentially heated to therapeutic temperatures without compromising the surrounding normal hepatic parenchyma. This was achieved by the use of hepatic arterially infused ferromagnetic microspheres that heat as a result of magnetic hysteresis loss when exposed to an alternating magnetic field. Treatment sessions involving a single 20-min exposure to the alternating field resulted in total suppression of tumour growth at 14 days compared to controls, in which tumour sizes increased dramatically over the same period. Histopathological examination of treated tumour sections showed total tumour destruction in some cases. Separate animal groups used to control for the effects of the embolized microspheres alone and for the effect of the applied magnetic field yielded similar tumour growth responses to a control group with no intervention whatsoever. The achievement of positive temperature differentials between tumour and normal liver and the consequent therapeutic responses encourages further development of this technology for the treatment of liver cancer in humans.

Animals↗
PubMedDate not supplied

Magnetically mediated hyperthermia: current status and future directions.

The use of hyperthermia in the treatment of cancers is appealing because, as a physical therapy, hyperthermia would have far fewer restrictive side effects than chemotherapy and radiotherapy, and it could be used in combination with these therapies. However, the currently available modalities of hyperthermia are often limited by their inability to selectively target tumour tissue and, hence, they carry a high risk of collateral organ damage or they deposit heat in a very localized manner which can result in under-treatment of a tumour. Magnetically mediated hyperthermia (MMH) has the potential to address these shortcomings. MMH consists of the localization of magnetic particles or seeds within tumour tissue followed by exposure to an externally applied alternating magnetic field to cause them to heat. Since this concept was introduced (over 40 years ago), MMH has evolved into four general sub-classes: arterial embolization hyperthermia (AEH), direct injection hyperthermia (DIH), intracellular hyperthermia (IH) and interstitial implant hyperthermia (IIH). It is the purpose of this article to review these four sub-classes in terms of experimental or clinical results, advantages, limitations and current status.

Humans↗
PubMedDate not supplied

Hepatic clearance of arterially infused ferromagnetic particles.

OBJECTIVE: Arterial embolization hyperthermia (AEH) consists of arterially embolizing tumours with ferromagnetic particles that generate hysteretic heating on exposure to an alternating magnetic field. It was the objective of this study to determine if such particles are cleared from the liver. METHOD: A lobe of normal liver in three pigs was arterially embolized with 300 mg of gamma-Fe2O3 particles (150 nm) suspended in lipiodol. The same liver lobe of three other pigs was embolized with 300 mg of ferromagnetic polymer matrix-encapsulated microspheres (32 microm) suspended in 1% tween-water. Samples of liver and blood were obtained before infusion, and at 60 min and 28 days after arterial infusion. At 28 days, samples of lung and other abdominal viscera were also obtained. The tissue samples were chemically analysed for iron content, and submitted to histopathological examination. RESULTS: There was no significant reduction in the hepatic iron concentration in either treatment group 28 days after infusion. Both types of particles illicited an immunogenic response and were extensively phagocytosed in the liver. The particle/lipiodol suspension caused extensive necrosis of liver, while the microsphere/tween-water suspension was well tolerated. Small amounts of both types of ferromagnetic particles embolized in the lungs, but there was no evidence of embolization into other organs. There were no haematological or biochemical changes and all subjects experienced uneventful 28-day survivals. CONCLUSION: This study has shown that, although arterially infused ferromagnetic particles were extensively phagocytosed, there was no significant hepatic clearance 28 days after infusion. It also determined that the suspension of 150 nm ferromagnetic particles in lipiodol was too vaso-occlusive for use in hepatic tissue. However, the suspension of 32 microm microspheres containing ferromagnetic particles in tween-water was safe and well tolerated.

Animals↗
PubMedDate not supplied

Changes in hepatic blood flow during regional hyperthermia.

The influence of liver hyperthermia on hepatic arterial and portal venous blood flow to tumour and normal hepatic tissue was examined in a rabbit VX2 tumour model. Hyperthermia was delivered by 2450 MHz microwave generator to exteriorized livers in 18 rabbits. Blood flow was measured in both portal vein and hepatic artery using radioactive tracer microspheres before, during and 5 min after intense (greater than 43 degrees C) hyperthermia. During hyperthermia a decrease in total liver blood flow was composed primarily of a decrease in hepatic arterial blood flow to tumour tissue. Tumours were supplied almost exclusively by the hepatic artery and thus total tumour blood flow was significantly depressed during heating. The decreased tumour blood flow persisted after the cessation of hyperthermia and was indicative of vascular collapse in the tumour tissue. Temperature differentials in tumour compared to normal tissue ranged from 5 degrees C to 8 degrees C during hyperthermia because of the lower tumour blood flow. The portal vein exerted minimal influence on temperatures attained in the tumour tissue during hyperthermia but would have mediated normal liver tissue heat loss.

Animals↗
PubMedDate not supplied

In vitro and in vivo responses of doxorubicin ion exchange microspheres to hyperthermia.

The utility of microspheres as targeted drug delivery agents is addressed with reference to using heat during formulation and to administration in combination with hyperthermia. It was demonstrated that rate of loading of the drug doxorubicin onto resin microspheres is enhanced under conditions of elevated temperature but this was shown to increase the incidence of microsphere aggregation. Total amount of drug loaded was related to time rather than temperature such that low temperature loading for up to 24 h produced optimum quality injectates. However, release of doxorubicin from microspheres was significantly increased during elevations of temperature to 43 degrees C. Thus, during hyperthermia doxorubicin release can be increased to provide periods of high drug availability targeted to tumour tissue for concomitant thermochemotherapy with microspheres. The therapeutic benefit derived from this combined therapy was assessed in 20 rabbits with VX2 carcinoma implanted in the liver. Hyperthermia was delivered by 2450 MHz microwave applicator to the exteriorized liver at 43 degrees C for 30 min, while chemotherapy was administered by intratumoural injection of doxorubicin microspheres (2.3 mg) into each tumour. Both hyperthermia and chemotherapy alone significantly reduced the size of tumours 10 days following treatment (p less than 0.01). However, in animals treated with both modalities, the size of tumours was significantly less than either treatment alone (p less than 0.05). These results provide a strong rationale for combining hyperthermia with targeted chemotherapy using microspheres.

Animals↗
PubMedDate not supplied

Prevention of myelosuppression does not improve the therapeutic efficacy of chemo-immunotherapy.

This study was designed to investigate whether the prevention of doxorubicin (DOX) induced myelosuppression could further improve the therapeutic efficacy of chemoimmunotherapy with DOX, interleukin-2 (IL-2) and interferon gamma (IFN-gamma). The antitumour activity of systemic IL-2/IFN-gamma immunotherapy in combination with DOX administered either systemically, regionally or on ion-exchange microspheres, was assessed in WAG rats bearing hind limb solid colonic adenocarcinoma implants. Whilst the use of microspheres to transport DOX clearly avoided the myelosuppression, systemic and renal toxicity associated with the use of free DOX, it did not provide any therapeutic advantage over chemo-immunotherapy with free systemic or regional drug.

1,2-Dimethylhydrazine↗
PubMedDate not supplied

Improved efficacy of doxorubicin by simultaneous treatment with interferon-gamma and interleukin-2.

Doxorubicin (DOX) is a potent anticancer agent active against a wide range of human neoplasms, yet, as is characteristic of most chemotherapeutics, the treatment of cancer with DOX alone has met with only limited success. This study was designed to investigate the possibility that the therapeutic potential of DOX could be enhanced by combination with one or more biological response modifiers. Segments (1mm3) of a transplantable colonic adenocarcinoma were implanted into the hind limbs of male WAG rats (200-250g). Serial tumour measurements were taken 3 x weekly throughout the 4 week experimental period by measuring the longest and perpendicular lengths with calibrated calipers. All drug administration was via a chronic indwelling jugular catheter, commencing 12 days after tumour implant, with control animals receiving physiological saline. Treatment of animals with DOX (4.5mg/kg as a 15 minute i.v. infusion), interferon gamma (IFN-gamma) (5 x 10(5) U/kg/day bolus i.v. for 5 days) or interleukin-2 (IL-2) (1 x 10(5)U/rat/day continuous i.v. infusion for 5 days) retarded tumour growth by approximately 30% by the completion of the study period (P < 0.001). The combined administration of IFN-gamma with DOX did not significantly alter the antitumour activity of either DOX or IFN-gamma. Concurrent administration of IL-2 with DOX also showed this treatment to have no therapeutic activity over that achievable with either agent alone. However, treatment of animals with IL-2, IFN-gamma and DOX resulted in a significant increase in tumour growth inhibition compared to DOX with either single cytokine (P < 0.001) and this was achieved without any apparent increases in the gross toxicity of DOX.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMedDate not supplied

Lack of synergy between 5-fluorouracil and interferon-gamma in the treatment of malignancy in the rat.

Numerous in vivo studies have reported synergism between 5-fluorouracil (5-FU) and interferon-gamma (IFN-gamma) but this has not been the case in clinical trials. As the immunomodulatory effects of IFN may be of greater importance in vivo than its direct anti-proliferative activities, it was of interest to determine whether the myelosuppressive effects of high dose 5-FU were responsible for the lack of enhanced activity of the combined drug treatment in the clinical setting. Using an animal model, the anti-tumour activity of three doses of 5-FU (5, 10 and 20 mg/kg/day, continuous intravenous infusion of 7 days) and concurrent IFN-gamma (5 x 10(5) U/kg/day, bolus IV for 5 days) were compared to 5-FU alone. IFN-gamma treatment alone produced a significant anti-tumour response relative to control. No synergism was observed at any dose of 5-FU when combined with IFN-gamma treatment despite white blood cell counts being similar to that in the IFN-gamma group at the lowest dose of 5-FU treatment. Thus, a lack of synergism in vivo is unlikely to be due to myelosuppression resulting in diminished immune response. However, other factors such as tumour type, size and location may be important in determining the final outcome.

Animals↗
PubMedDate not supplied

Reduced toxicity of adriamycin by incorporation into ion exchange microspheres: a therapeutic study using a rat liver tumour model.

A comparison of the systemic toxicity and therapeutic efficacy of adriamycin carrying microspheres with conventional chemotherapeutic use of adriamycin was performed using a rat liver tumour model. The drug-microspheres were administered via the gastro-duodenal artery for delivery to the liver, whilst similar quantities of free adriamycin were given by systemic intravenous or regional intra-arterial routes. Significant leukopenia, thrombocytopenia and mortality were observed in the systemically treated free drug group (P less than 0.05) with a similar trend for for myelosuppression occurring in the intra-arterial free drug group. The adriamycin-microsphere group showed no toxic side-effects despite retarding tumour growth by similar amounts to the other drug modalities. This work demonstrates a large potential for the use of adriamycin carrying ion-exchange microspheres in the treatment of human malignancy.

Adenocarcinoma↗
PubMedDate not supplied

A comparative study of the anticancer efficacy of doxorubicin carrying microspheres and liposomes using a rat liver tumour model.

Due to low efficacy of chemotherapy in the treatment of liver cancer, several methods of drug targeting have been investigated. Liposomes designed to carry cytotoxic drugs to the liver are currently under clinical evaluation. While experimental evidence shows promise, this method of drug delivery has several disadvantages that include short shelf life and poor drug delivery into tumour tissue. An alternative strategy for targeted drug delivery involving use of ion exchange microspheres may overcome these limitations while still reducing systemic toxicity and maintaining therapeutic efficacy. The purpose of this study was to determine the relative antitumour efficacy of these two drugs carrying systems in the treatment of liver cancer. Compared to controls, DOX treatment with free drug, liposomes or microspheres significantly reduced tumour growth by 56% (P < 0.001), 51% (P < 0.01) and 79% (P < 0.001) respectively. Furthermore, the DOX-microsphere treatment was significantly better than either of the other DOX treatments (53%, P < 0.05) or the sham-microsphere treated group (64%, P < 0.05). Thus, drug microspheres can increase the anti-tumour efficacy compared to either free or liposomal drug while simultaneously reducing systemic toxicity.

Animals↗