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Biomedical subjects

A Gabizon

Publications and source records attributed to A Gabizon.

46 records · Page 3Linked to original sources
PubMed1985

Superior therapeutic activity of liposome-associated adriamycin in a murine metastatic tumour model.

We have examined the anti-tumour activity of liposome-entrapped Adriamycin in a murine metastatic tumour model produced by i.v. inoculation of J-6456 lymphoma cells and affecting predominantly the liver. Sonicated liposomes containing phosphatidylcholine, a negatively-charged phospholipid and cholesterol were used in these experiments. Liposome-entrapped Adriamycin was more effective than free Adriamycin at equivalent doses of the drug. The superior therapeutic effect of the liposome-associated drug was manifest, either with a single i.v. treatment using a dose bordering the toxicity threshold of free Adriamycin or with a multi-injection schedule using smaller doses. Based on the growth kinetics data of the J-6456 lymphoma, our results indicate that tumour cell killing was enhanced by a factor of approximately 100 using the liposome associated form of Adriamycin. Histopathologic studies in mice bearing well-established metastases of the J-6456 lymphoma in liver and spleen indicated that the extent and duration of pathologic remission were significantly improved in mice receiving the liposome-entrapped drug as compared to mice receiving free drug. No significant differences in the anti-tumour effect of liposome entrapped Adriamycin were observed replacing phosphatidylserine by phosphatidylglycerol and reducing the cholesterol:phospholipid molar ratio from 100% to 25%. In contrast to the metastatic tumour model, liposome-entrapped Adriamycin was significantly less effective than free Adriamycin on the local i.m. growth of the J-6456 tumour. Altogether the survival and histopathological data presented suggest that, with regard to a group of neoplastic conditions with a predominant pattern of liver dissemination, a substantial increase in the therapeutic index of Adriamycin can be achieved in a selective manner with the use of liposomes.

Animals↗
PubMed1983

Enhancement of adriamycin delivery to liver metastatic cells with increased tumoricidal effect using liposomes as drug carriers.

We have investigated the tissue distribution of liposome-entrapped Adriamycin (ADM) in mice with metastatic spread to the liver and spleen after inoculation of J-6456 lymphoma cells. Sonicated phosphatidylserine:phosphatidylcholine:cholesterol liposomes were used as carriers of ADM, based on previous studies on the drug entrapment, stability, and tissue distribution of ADM-containing liposomes of various compositions (A. Gabizon, A. Dagan, D. Goren, Y. Barenholz, and Z. Fuks. Cancer Res., 42: 4734-4739, 1982). Increased hepatic and splenic levels of ADM were found in tumor-bearing mice when the drug was injected in the liposome-entrapped form. Concomitantly, decreased cardiac uptake of ADM was observed in tumor-bearing mice treated with liposome-entrapped ADM. In order to measure the concentration of ADM directly in metastatic cells, J-6456 lymphoma cells were isolated from the liver by Percoll density gradients. It was found that the ADM levels were significantly augmented in tumor cells from mice given injections of liposome-entrapped ADM as compared to those given injections of free ADM at all time intervals checked after drug injection. In addition, the in vitro and in vivo growth ability of these isolated metastatic cells was significantly more impaired when they were obtained from mice receiving liposome-entrapped ADM as compared to mice which received free ADM. The histopathological damage to the normal liver parenchyma of mice treated with liposome-entrapped ADM was mild and confined to discrete foci and was not significantly different from that observed in mice treated with free ADM. These results indicate that liposome delivery may provide an efficient means of improving the therapeutic efficiency of ADM in certain forms of metastatic liver disease, while diminishing the potential hazard of cardiotoxicity.

Animals↗
PubMed1980

Enhancement of growth of a radiation-induced lymphoma by T cells from normal mice.

The effect of lymphocytes from normal mice on the growth of a syngeneic, radiation-induced, T-cell-derived lymphoma was investigated. Thymus and spleen cells enhanced the growth of admixed lymphoma cells in a reproducible manner. Growth enhancement was manifested by the earlier appearance and higher final incidence of tumours. Lymphocytes also enhanced the growth of radiation-damaged lymphoma cells. The enhancing activity of spleen cells was predominantly a property of T cells, since it was abolished by treatment with anti-theta serum plus complement and significantly less in spleen cells of nude mice. Tumour-enhancing thymocytes seem to belong to the immature thymic subpopulation, as indicated by their binding to peanut agglutinin.

Animals↗
PubMed1980

Contrasting effects of activated and nonactivated macrophages and macrophages from tumor-bearing mice on tumor growth in vivo.

The effect of macrophages from normal and tumor-bearing mice on tumor growth was investigated with the use of an in vivo neutralization test. Macrophages from unstimulated and thioglycollate-stimulated peritoneal cavities (nonactivated macrophages) of normal mice enhanced growth of various syngeneic tumors [a 3-methylcholanthrene-induced transplantable fibrosarcoma from inbred C3HeB mice, a spontaneously originated transplantable melanoma (B16) from inbred C57BL/6 mice, and a radiation-induced lymphoma from inbred BALB/c mice]. This enhancing effect was not destroyed by irradiation of macrophages and was apparently mediated by macrophage secretory products. The effect appeared to be unrelated to immunosuppression and may have reflected direct stimulation of tumor cells. In contrast, Corynebacterium parvum-activated macrophages markedly inhibited tumor growth. Peritoneal macrophages from fibrosarcoma-bearing mice, which possessed tumor-inhibitory T-lymphocytes, enhanced tumor growth and abolished the effects of the tumor-inhibitory lymphocytes. Clearly, under certain conditions nonactivated macrophages interfered with the mechanisms of T-cell-mediated antitumor resistance in tumor-bearing mice.

Animals↗
PubMed1980

Regulatory action of THF on T-cell reactivity to mitogens.

The effect of in vivo treatment with THF (thymus humoral factor) on the response of mouse lymphocytes to mitogens was investigated. Different preparations of THF were tested by daily i.m. injections into normal mice. Spleen, peripheral lymph node and thymus cells were tested for reactivity to several mitogens at various intervals after initiation of treatment. Our results indicate that the administration of THF to normal mice causes an inhibitory trend in the response of spleen cells to T-cell mitogens. It was found that the response of spleen cells to phytohemagglutinin (PHA) and concanavalin A (Con A) was strongly depressed after 7 days of treatment with 50 micrograms of THF. This was followed by a recovery of the response to normal levels after 14 days of treatment. The response of spleen cells to lipopolysaccharide (LPS) a B-cell mitogen, did not change throughout 14 days of treatmnent with THF. Lymph node cells of THF-treated mice behaved qualitatively in a similar manner to spleen cells, while thymus cells from THF-treated mice showed a significantly increased response to Con A. In contrast to normal mice, the injection of THF into mice with an impaired reactivity to PHA, such as thymectomized mice and tumor-bearing mice, caused an augmentation of the mitogenic response of spleen cells. These results suggest that in vivo administration of THF causes regulatory changes in the lymphocyte reactivity to T-cell mitogens.

Animals↗
PubMed1979

Enhancement of tumor growth by peritoneal macrophages of normal and tumor-bearing mice.

The effect of peritoneal macrophages on tumor growth was investigated in an in vivo transfer assay (Winn test). A significant acceleration of tumor appearance was observed in animals injected with tumor cells together with peritoneal exudate cells (PEC) from normal mice, as compared to animals injected with tumor cells alone. Macrophages were shown to be the cells responsible for tumor enhancement. PEC from tumor-bearing mice also caused a strong tumor-enhancing effect in the Winn test. These results indicate that non-activated macrophages can enhance tumor growth in in vivo transfers and raise the question of whether a similar effect takes place in the primary host of a tumor.

Animals↗
PubMed1976

Kinetics of the response of spleen cells from tumor-bearing animals in an in vivo tumor neutralization assay.

The behavior of spleen cells from tumor-bearing mice, vis-à-vis isologous tumor cells, was investigated by means of an in vivo adoptive neutralization test. C3H/eB mice were challenged with tumor cells from a chemically induced fibrosarcoma. Spleens from these animals were removed at weekly intervals following tumor inoculation, mixed with tumor cells, and tested for their influence on tumor growth in syngeneic recipient mice. Two phases in the reactivity of spleen cells from tumor-bearing mice were clearly distinguishable. In a first stage of tumor growth, these mice yielded specific tumor-inhibitory cells conferring protection. Subsequently, the protective activity declined leading to a second phase characterized by tumor enhancement. Both protective and enhancing activities were shown to be mainly dependent on the presence of T cells.

Animals↗
PubMedDate not supplied

Targeting folate receptor with folate linked to extremities of poly(ethylene glycol)-grafted liposomes: in vitro studies.

Conjugates of three components, folic acid-poly(ethylene glycol)-distearoylphosphatidylethanolamine (FA-PEG-DSPE), derived from PEG with molecular masses of 2000 and 3350 Da were synthesized by a carbodiimide-mediated coupling of FA to H2N-PEG-DSPE. The conjugates were characterized by 1H NMR, MALDI-TOF, and HPLC analysis of enzymatic cleavage with carboxypeptidase G. As a prototype of a folate receptor (FR)-targeted system, the conjugates were formulated at 0.5 mol % phospholipid in hydrogenated phosphatidylcholine/cholesterol liposomes with or without additional methoxyPEG2000-DSPE. In vitro binding studies were performed with sublines of M109 (murine lung carcinoma) and KB (human epidermal carcinoma) cells each containing high and low densities of FR. FA-PEG-DSPE significantly enhanced liposome binding to tumor cells. The best binding was observed when FA-PEG liposomes contained no additional mPEG-lipid. In fact, our experiments showed that the presence of mPEG on liposomal surfaces significantly inhibited FA-PEG-liposome binding to FR. Increasing the molecular mass of the PEG tether from 2000 to 3350 Da improved the FR binding, particularly in the case of mPEG-coated liposomes. The FA-PEG liposomes bound to M109-HiFR cells very avidly as demonstrated by the inability of free FA (used in a 700-fold excess either at the beginning or at the end of the incubation) to prevent the cell binding. This is in contrast to the 5-10-fold lower cell binding activity of mPEG-FA compared to that of free FA, and likely to be related to the multivalent nature of the liposome-bound FA. Only 22% of FA-PEG3350 and 32% of FA-PEG3350/mPEG cell-associated liposomes could be removed by exposure to pH 3, conditions that dissociate FA-FR, suggesting that more than two-thirds of the bound liposomes were internalized during incubation for 24 h at 37 degrees C. FA-targeted liposomes also show enhanced nonspecific binding to extracellular tissue culture components, a phenomenon especially relevant in short incubation time experiments.

Binding, Competitive↗
PubMedDate not supplied

Investigations on the antitumor efficacy of liposome-associated doxorubicin in murine tumor models.

In this report we review our preclinical studies on the antitumor efficacy of L-DXR, using negatively charged sonicated vesicles. Animal studies indicate that various L-DXR formulations are more active than F-DXR on tumors infiltrating the liver and spleen, organs where liposomes are accumulated, and are equally effective on bone marrow-residing leukemic cells. In contrast, F-DXR was more effective than L-DXR when i.v.-administered, mg-equivalent doses were tested against ascitic and subcutaneously implanted tumors. Intraperitoneal administration of L-DXR was significantly more effective and approximately twofold less toxic than F-DXR in the treatment of an ascitic tumor. The antitumor effect correlated well with differences in drug levels in the relevant anatomic areas. These observations stress the site-specific activity of L-DXR and its dependence on biodistribution factor.

Animals↗