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At least 145 records · Page 8Linked to original sources
PubMed1993

The dissociation of tumor-induced weight loss from hypoglycemia in a transplantable pluripotent rat islet tumor results in the segregation of stable alpha- and beta-cell tumor phenotypes.

We previously established pluripotent transformed rat islet cell lines, MSL-cells, of which certain clones have been used to study processes of islet beta-cell maturation, including the transcriptional activation of the insulin gene induced by in vivo passage. Thus, successive sc transplantation in NEDH rats resulted in stable hypoglycemic insulinoma tumor lines, such as MSL-G2-IN. Occasionally, hypoglycemia as well as severe weight loss were observed in the early tumor passages of MSL-G and the subclone, NHI-5B, which carry the transfected neomycin and human insulin genes as unique clonal markers. By selective transplantation, it was possible to segregate stable anorectic normoglycemic tumor lines, MSL-G-AN and NHI-5B-AN, from both clones. These tumors cause an abrupt onset of anorexia when they reach a size of 400-500 mg (< 0.3% of total body weight), and the observed weight loss parallels that of starved rats until death results from cachexia. After tumor resection, animals immediately resume normal feeding behavior. Comparative studies of hormone release and mRNA content in anorectic lines, MSL-G-AN and NHI-5B-AN, vs. those in the insulinoma line, MSL-G2-IN, revealed selective glucagon gene expression in both of the anorectic tumors, whereas insulin and islet amyloid polypeptide gene expression were confined to the insulinoma. Both tumor phenotypes produced cholecystokinin and gastrin in variable small amounts, making it unlikely that these hormones contribute to the anorectic phenotype. Tumor necrosis factor (cachectin) was not produced by any of the tumors. Proglucagon was processed as in the fetal islet to products representative of both pancreatic alpha-cell and intestinal L-cell phenotypes, with glucagon and Glp-1 (7-36)amide as the major extractable products. In contrast to the administration of cholecystokinin, neither glucagon, Glp-1 (7-36)amide, nor their combination, affected feeding behavior in fasted mice, suggesting the presence of a hitherto unidentified anorectic substance released from the glucagonoma. We conclude 1) that glucagonomas and insulinomas can be derived from a common clonal origin of pluripotent MSL cells, thus supporting the existence of a cell lineage relationship between islet alpha- and beta-cell during ontogeny; and 2) that our glucagonomas release an anorexigenic substance(s) of unknown nature that causes a severe weight loss comparable to that reported in animals carrying tumor necrosis factor-producing experimental tumors.

Adenoma, Islet Cell↗
PubMed2006

Lowering of tumor interstitial fluid pressure reduces tumor cell proliferation in a xenograft tumor model.

High tumor interstitial fluid pressure (TIFP) is a characteristic of most solid tumors. TIFP may hamper adequate uptake of macromolecular therapeutics in tumor tissue. In addition, TIFP generates mechanical forces affecting the tumor cortex, which might influence the growth parameters of tumor cells. This seems likely as, in other tissues (namely, blood vessels or the skin), mechanical stretch is known to trigger proliferation. Therefore, we hypothesize that TIFP-induced stretch modulates proliferation-associated parameters. Solid epithelial tumors (A431 and A549) were grown in Naval Medical Research Institute nude mice, generating a TIFP of about 10 mm Hg (A431) or 5 mm Hg (A549). Tumor drainage of the central cystic area led to a rapid decline of TIFP, together with visible relaxation of the tumor cortex. It was found by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blot analysis that TIFP lowering yields a decreased phosphorylation of proliferation-associated p44/42 mitogen-activated protein kinase and tumor relaxation. In confirmation, immunohistochemical staining showed a decrease of tumor-associated proliferation marker Ki-67 after TIFP lowering. These data suggest that the mechanical stretch induced by TIFP is a positive modulator of tumor proliferation.

Animals↗
PubMed2003

Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells.

Cross-presentation of cell-bound Ags from established, solid tumors to CD8 cells is efficient and likely to have a role in determining host response to tumor. A number of investigators have predicted that when tumor Ags are derived from apoptotic cells either no response, due to Ag "sequestration," or CD8 cross-tolerance would ensue. Because the crucial issue of whether this happens in vivo has never been addressed, we induced apoptosis of established hemagglutinin (HA)-transfected AB1 tumors in BALB/c mice using the apoptosis-inducing reagent gemcitabine. This shrank the tumor by approximately 80%. This induction of apoptosis increased cross-presentation of HA to CD8 cells yet neither gross deletion nor functional tolerance of HA-specific CD8 cells were observed, based on tetramer analysis, proliferation of specific CD8 T cells, and in vivo CTL activity. Interestingly, apoptosis primed the host for a strong antitumor response to a second, virus-generated HA-specific signal in that administration of an HA-expressing virus after gemcitabine administration markedly decreased tumor growth compared with viral administration without gemcitabine. Thus tumor cell apoptosis in vivo neither sequesters tumor Ags nor cross-tolerizes tumor-specific CD8 cells. This observation has fundamental consequences for the development of tumor immunotherapy protocols and for understanding T cell reactivity to tumors and the in vivo immune responses to apoptotic cells.

Animals↗
PubMed1993

Tumor response to ionizing radiation and combined 2-deoxy-D-glucose application in EATC tumor bearing mice: monitoring of tumor size and microscopic observations.

The present study deals with the changes induced by two fractionation schedules (5 x 9 Gy and 10 x 4.5 Gy; 30 MeV-electrons) of ionizing radiations and 2-deoxy-D-glucose (2-DG) application on EATC tumor bearing swiss albino mice. The monitoring of tumor response was carried out by means of caliper measurement on the macroscopic level and by histopathological examination of tumor preparations stained with hematoxiline and eosine on the microscopic level. The tumor material was assessed at suitable intervals after treatment by killing the animals. The tumor response was analysed in the histological preparations and the thickness of the tumor band was determined quantitatively by an ocular micrometric technique. Tumor damage was most extensive in the combined treated animals (5 x 9 Gy + 2-DG). Only in this group local tumor control was achievable. The histological analysis of tumor preparations revealed additional data about treatment-induced changes in the tumor compared to the measurement of the tumor volume with mechanical calipers. We also found that the treatment outcome could be predicted from the histopathological analysis. It is concluded that studies involving histopathological examinations may give some insight into the way cancer is controlled by radiotherapy and may be of value in prognosis and selection of treatment in patients.

Animals↗
PubMed1997

The anti-tumor effects of IL-12 involve enhanced IFN-gamma production by anti-tumor T cells, their accumulation to tumor sites and in situ IFN-gamma production.

We investigated cellular and molecular mechanisms underlying the anti-tumor effects of IL-12. Intraperitoneal injections of rIL-12 into later stages of tumor-bearing mice induced not only a striking reversal of suppressed IFN-gamma-production by splenic T cells, but also complete regression of s.c. growing tumors. A massive infiltration of lymphoid cells was found following IL-12 treatment. Whereas fresh spleen cells obtained from IL-12-treated tumor-bearing mice failed to express IFN-gamma mRNA, significant levels of IFN-gamma mRNA were detected in the tumor mass of the same mice. The systemic administration of anti-IFN-gamma antibody (Ab) prior to IL-12 injection abrogated the anti-tumor effect of IL-12 although this Ab did neither inhibit accumulation of lymphoid cells to tumor sites nor in situ IFN-gamma expression. Importantly, while high levels of inducible nitric oxide synthase (iNOS) mRNA expression was induced in tumor masses after IL-12 treatment, its expression was completely inhibited by pretreatment with anti-IFN-gamma Ab. Thus, induction of tumor regression by IL-12 is ascribed to a series of events: a striking reversal of suppressed IFN-gamma production by anti-tumor T cells, their accumulation and IFN-gamma production at tumor sites, and manifestation of IFN-gamma activity as exemplified by iNOS expression.

Animals↗
PubMed1998

Tumor necrosis factor alpha-mediated tumor regression by the in vivo transfer of genes into the artery that leads to tumors.

We report that tumor necrosis factor (TNF) alpha induced a strong antitumor immune reaction when it was produced in arteries leading to tumors by gene transfer in vivo. We used a mouse model carrying a sarcoma-180 tumor in the right footpad and injected the fusogenic liposomes encapsulating the human TNF-alpha gene into the right femoral artery. Under this condition, human TNF-alpha was detected only in the artery leading to the tumor and in the tumor. There was a significant regression in tumor growth when the TNF-alpha gene was delivered into the right femoral artery, with 4 of 11 mice completely cured. No regression was observed when the TNF-alpha gene was delivered into the left femoral artery or into the tumor or when the luciferase gene was administered. Tumor regression was inhibited by the injection of anti-TNF-alpha, anti-CD4, or anti-CD8 monoclonal antibody, and CD8+ T cells accumulated in the tumors of TNF-alpha-treated mice. These results suggest that TNF-alpha expressed locally in the arteries leading to tumors efficiently suppresses tumor growth through reinforcement of an antitumor immune reaction. The significance of this phenomenon for cancer gene therapy was discussed.

Animals↗
PubMed1997

Evaluation of cellular uptake, tumor retention, radiation response, and tumor pathophysiology in experimental solid tumors after an intratumoral infusion of colloidal 32P.

BACKGROUND: Order et al. successfully deposited > 85% of radionuclides in pancreatic carcinoma patients using an intratumoral (i. t.) infusion of macroaggregated albumin (MAA) prior to the i. t. infusion of colloidal 32P (32P-CP), apparently due to MAA-induced transient blockade. However, no studies regarding physiologic response and the inhibitory tumor growth of solid tumors after treatment with 32P-CP with or without MAA have been performed. METHODS: First, the authors determined the cellular uptake of 32P-CP in 10 cell lines. They then evaluated the relationship between tumor retention and radiation response in vivo. Third, they evaluated the changes in physiologic parameters such as tumor interstitial fluid pressure (TIFP) and tumor blood flow (TBF) after an i. t. infusion of MAA. RESULTS: In the plateau growth phase of both H4IIE and LS174T tumors, maximal uptake occurred at approximately 100 minutes after treatment with 10 microCi of 32P-CP, but uptake in LS174T was approximately 2 times higher than that in H4IIE. In animal experiments, 32P-CP alone significantly inhibited the tumor growth of H4IIE. However, additional i. t. infusion of MAA did not improve the growth delay induced by 32P-CP, mainly due to insignificant differences in retention of radioactivity when using 32P-CP with or without MAA. It was speculated that when the outflow of the tumor vasculature was obstructed by clamping (or an i. t. infusion of MAA), it would reduce TBF and increase TIFP. However, neither increased TIFP nor decreased TBF was observed when MAA was given i. t. to tumors. CONCLUSIONS: The authors concluded that an MAA-induced transient blockade of tumor vasculature after an i. t. infusion of MAA did not occur in experimental solid tumors.

Albumins↗
PubMed1982

Interference of anti-tumor and immunosuppressive effects of cyclophosphamide in tumor-bearing rats. Analysis of factors determining resistance or susceptibility to a subsequent tumor challenge.

Adult rats were given 10(5) or 10(6) Yoshida ascites sarcoma (YAS) cells IP and were treated with cyclophosphamide (CY) given IP in single doses of 20 mg/kg or 100 mg/kg, 2 or 5 days after YAS inoculation. Both the curative effect of CY and subsequent resistance to tumor challenge in rats that survived depended on the dose of injected tumor cells and on the dose and time of administration of CY. These three factors determined whether the host's immune response to tumor antigens would develop and contribute to the overall anti-tumor effects of the chemotherapy. The curative effects of CY were significantly less pronounced in T-cell-deficient than in normal rats. Anti-tumor and immunosuppressive activities of CY exerted opposite influences on the ultimate result of the chemotherapy. Adverse immunosuppressive effects prevailed when the drug was administered early (2 days) after YAS inoculation. In this case the chemotherapy was less efficient and the surviving rats were susceptible to a subsequent tumor challenge. Further analysis showed that the injection of CY 2 days after inoculation of YAS antigens induced strong and specific immunologic tolerance to the tumor. In contrast, when a sufficient amount of tumor antigens (higher dose of tumor cells injected and CY injection delayed) elicited an anti-YAS immune response that was not suppressed by early injection of CY (CY administered 5 days after the tumor) effective eradication of tumor cells and anti-YAS resistance in cured animals were observed.

Animals↗
PubMedDate not supplied

Influence of tumor transplantation methods on tumor growth rate and metastatic potential of solitary tumors derived from metastases.

This study was performed to determine whether the growth rate and metastatic potential of tumors generated by spontaneous lung metastases is influenced by transplantation methods. Three different tumors syngeneic to C3Hf/Kam mice were studied: the SA-NH and SA-4020 sarcomas and the hepatocarcinoma HCA-I. Solitary tumors in the legs of mice were generated by a single metastatic nodule taken at random from lung metastases, by a single metastatic nodule taken from each mouse with the highest number of metastases, by a mixture of cells from lung metastases taken randomly, or by a mixture of cells from primary leg tumors. These transplantation procedures were repeated for two to four isotransplant generations. Repeated isotransplants of primary tumors showed little if any change in the growth rate and metastatic spread. In contrast, primary tumors derived from spontaneous metastases frequently exhibited a decrease in their growth rate and an increase in metastatic potential. This was particularly frequent when tumors were established from single metastatic nodules taken randomly from the lung, or taken from lungs that contained the largest number of metastatic nodules. The magnitude of this change varied greatly among the three tumors studied. Increased metastatic formation in the lung was also frequently associated with slower growth of the primary tumors. Thus, transplantation methods used for establishing primary tumors have an important influence on the metastatic potential of tumor transplants.

Animals↗
PubMed1987

A gelatin sponge model for studying tumor growth: quantitation of tumor cells and leukocytes in the CHO tumor.

A gelatin sponge model system for tumor cell inoculation and retrieval of tumor-associated leukocytes is described. Gelatin sponges pre-implanted in nude mice harboring tumorigenic Chinese hamster ovary cells (line CHO) were examined at 2 and 11 days after injection of tumor cells for tumor cell content and leukocyte accumulation after digesting the sponge matrix in collagenase solution. The data indicate a progressive influx of host cells consisting primarily of macrophages, neutrophils and lymphocytes. The total number of viable tumor cells as well as the fraction of surviving tumor cells with clonogenic potential also increased with tumor age. Blank sponges not harboring tumor cells elicited an inflammatory response in the animals which did not change appreciably with length of sponge residence. However, when the sponges were harboring tumor cells, the accumulation of host leukocytes far exceeded that which occurred in blank sponges. This observation suggests a host response directed toward the tumor which is absent in animals bearing blank sponges. Apart from providing anchorage for injected cells, the gelatin sponge, by virtue of its digestibility in collagenase, makes possible the easy retrieval and precise quantitation of tumor-associated host cells.

Animals↗
PubMed2001

Downregulation of a tumor promotion immune response via induction of oral tolerance towards tumor-associated-antigens: can we 'eat the tumor'?

The mechanism by which hepatocellular carcinoma (HCC) develops and the role of the hepatitis B virus (HBV) in inducing tumors, are not yet well understood. Patients persistently infected with HBV tend to have a defective immune response against the virus, which fails to clear the virus and also induces liver injury. This defective response may also have an inducible effect on the virus and on cells that express HBV antigens, as well as play a role in the growth of neoplasm. It is possible that one of the mechanisms of tumor growth is related to a deviant immune response towards viral or tumor associated antigens. We describe two responses against the tumor. A 'good' response that would suppress the tumor and a 'bad' response that would promote it and theorize that the net balance between 'bad' and 'good' responses of the immune system towards a cancerous cell and/or antigen will predict whether a tumor grows or is suppressed. Oral tolerance involves the induction of immunological hyporesponsiveness towards specific antigens. It was shown that oral tolerance induces antigen-specific immune suppression towards tumor-associated-antigens by feeding of HBV or other tumor proteins. We hypothesize that induction of immune tolerance towards tumor-associated antigens will suppress the immune response towards these antigens, thus reducing the 'bad' response. The proposed new treatment strategy would redirect the focus from augmenting anti-tumor immune responses to inducing host tolerance towards the tumor.

Adaptation, Physiological↗
PubMed1975

Tumor-secific immunity to chemically induced tumors. Evidence for immunologic specificity and shared antigenicity in lymphocyte responses to soluble tumor antigens.

Experiments were designed to explore the apparent paradox that methylcholanthrene-induced tumors of mice evoke tumor-unique transplantation immunity but reveal almost complete cross-reacting antigenicity in tests of lymphocyte behavior in vitro. The approach involved use of tumor membranes solubilized in 3 M KCl, employed both as the stimulating antigen source in a new in vitro proliferation assay of lymphocyte recognition, and as immunogens in vivo. The kinetics of the assay resembled those of in vitro tests of mitogen or specific antigen stimulation in other systems. Lymphoid cell proliferation was assessed in peripheral blood leukocytes, lymph nodes (LN), and spleen over the course of tumor bearing, and in animals immunized by tumor amputation or with the solubilized antigens. The pattern of spread of reactivity was from regional LN to spleen, peripheral blood, and nonregional nodes in each circumstance. An unexplained low antigen dose inhibitory phenomenon was encountered in spontaneously proliferating cell subpopulations taken from some tumor-bearing animals. In vitro responses to some but not all solubilized antigens made from multiple syngeneic tumors were detected in each circumstance. The soluble antigens also induced shared resistance to some tumors. The patterns of spread of responsiveness to syngeneic tumor antigens, the time-course, and relative intensity were most compatible with independent clonal responses to multiple tumor-borne antigens, some but not all of which are shared in any family of syngeneic tumors.

Animals↗
PubMed1997

The morphologic spectrum of ovarian metastases of appendiceal adenocarcinomas: a clinicopathologic and immunohistochemical analysis of tumors often misinterpreted as primary ovarian tumors or metastatic tumors from other gastrointestinal sites.

Twenty cases of ovarian metastases derived from appendiceal adenocarcinomas were analyzed. The most common presentation was a pelvic mass. The appendiceal and ovarian tumors were diagnosed concurrently in 15 cases; in the remaining five, the ovarian tumors were diagnosed before the appendiceal tumor. The appendiceal adenocarcinomas demonstrated four morphologic patterns: 1) signet ring cell type, with or without glandular or goblet cell differentiation (14 cases); 2) mixed signet ring cell and intestinal type (two cases); 3) intestinal type (two cases); and 4) typical colorectal type (two cases). The ovarian tumors were bilateral in 16 cases and were histologically similar to the associated appendiceal tumor in each case. Ovarian metastases that demonstrate signet ring cell, glandular, and goblet cell differentiation mimic metastases from gastric adenocarcinoma. Those that are derived from well-differentiated mucinous appendiceal adenocarcinomas mimic primary ovarian mucinous tumors and metastases from the pancreas and biliary tract. Metastases of appendiceal adenocarcinomas of colorectal type simulate both metastatic colorectal carcinoma and primary ovarian endometrioid carcinomas. The appendiceal and ovarian tumors were immunophenotypically identical in each case. Approximately 50% of the appendiceal and ovarian tumors were positive for cytokeratin 7 (CK 7), and all were positive for cytokeratin 20 (CK 20). CK 20 positivity of the ovarian tumors is consistent with gastrointestinal origin; CK 7 positivity does not confirm ovarian origin, because appendiceal carcinomas are positive in 50% of cases. Metastatic appendiceal adenocarcinoma should be considered in the differential diagnosis of mucinous ovarian tumors with signet ring cell, goblet cell, or intestinal type differentiation, especially when these tumors are associated with extraovarian disease and are bilateral.

Adenocarcinoma↗
PubMed2000

Benign tumors and tumor-like lesions of the adult kidney. Part II: Benign mesenchymal and mixed neoplasms, and tumor-like lesions.

In this review article the benign tumors and tumor-like lesions of the adult kidney are discussed. The incidence of benign renal tumors is low, especially when compared to renal cell carcinomas, as most are detected incidentally or at autopsy. Some of these tumors, as their names imply, are unique to the kidney, e.g., renal adenoma, metanephric adenoma, renal oncocytoma, nephrogenic adenofibroma, mesoblastic nephroma, capsuloma, juxtaglomerular cell tumor, renomedullary interstitial cell tumor (medullary fibroma), cystic nephroma, cystic partially differentiated nephroblastoma, and cystic hamartoma of the renal pelvis, while others, such as angiomyolipoma, leiomyoma, hemangioma, lipoma, etc., are not unique to the kidney and show similar morphologic features in the other sites they affect. Of the tumor-like lesions, xanthogranulomatous pyelonephritis, malakoplakia, and renal cysts are the most common. The other entities, such as fibroepithelial polyp, are rare, most having been the topic of case reports. In Part I of this paper the benign epithelial tumors of the kidney were previously discussed. This paper (Part II) is devoted to the benign mesenchymal tumors, mixed mesenchymal and epithelial tumors, and the tumor-like lesions.

Adenoma↗
PubMed2006

The tumor antigen repertoire identified in tumor-bearing neu transgenic mice predicts human tumor antigens.

FVB/N mice transgenic for nontransforming rat neu develop spontaneous breast cancers that are neu positive and estrogen receptor negative, mimicking premenopausal human breast cancer. These animals have been widely used as a model for immunobased therapies targeting HER-2/neu. In this study, we used serological analysis of recombinant cDNA expression libraries to characterize the antigenic repertoire of neu transgenic (neu-tg) mice and questioned the ability of this murine model to predict potential human tumor antigens. After screening 3 x 10(6) clones from 3 different cDNA libraries, 15 tumor antigens were identified, including cytokeratin 2-8, glutamyl-prolyl-tRNA synthetase, complement C3, galectin 8, and serine/threonine-rich protein kinase 1. Multiple proteins involved in the Rho/Rho-associated, coiled coil-containing protein kinase (Rock) signal transduction pathway were found to be immunogenic, including Rock1, Rho/Rac guanine nucleotide exchange factor 2, and schistosoma mansoni adult worm antigen preparation 70. All of the identified antigens are self-proteins that are expressed in normal tissues in addition to breast tumors and the majority of the antigens are intracellular proteins. More than half of the mouse tumor antigens have human homologues that have been reported previously as tumor antigens. Finally, the tumor-specific antibody immunity and marked immune cell infiltration that was observed in mice with spontaneous tumors were not observed in mice with transplanted tumors. Our results indicate that neu-tg mice bearing spontaneous tumors develop humoral immunity to their tumors similar to cancer patients and that tumor antigens identified in transgenic mouse may predict immunogenic human homologues.

Animals↗
PubMed1990

Leaky tumor vessels: consequences for tumor stroma generation and for solid tumor therapy.

Our results may be summarized as follows: 1) The tumor microvasculature is hyperpermeable to macromolecular tracers, as compared with the vessels supplying many normal tissues. 2) In the case of the several solid transplantable animal tumors studied, leaky vessels are well-differentiated venules and small veins, lined by a continuous endothelium with mostly closed interendothelial junctions. Leaky vessels are concentrated at the tumor-host interface and in bands of stroma interspersed between tumor nodules; in contrast, tumor-penetrating vessels exhibit little or no leakage of macromolecules. 3) The mechanisms of vascular leakage have yet to be established but apparently cannot be attributed to vessel immaturity, structural defects, interendothelial cell gaps, vessel injury or development of a specialized (e.g., fenestrated or sinusoidal) endothelium. 4) Macromolecules that extravasate from leaky vessels also accumulate in tumors at higher concentrations than in the blood or control tissues. Increased tracer accumulation in tumors is attributable to increased tracer influx and possibly also to reduced tracer clearance (perhaps resulting from the absence or obstruction of lymphatics). However, the high molecular weight FITC-D tracers that extravasate into solid tumors remain largely confined to tumor stroma, do not extend far from the vessels from which they leaked, and make little contact with malignant cells. 5) In contrast, smaller tracers (e.g., 3 kD FITC-D) extravasate from tumor-penetrating vessels, from the capillaries of normal tissues, as well as from hyperpermeable vessels, and, unlike larger FITC-D, diffuse readily throughout solid tumors.

Animals↗
PubMed1990

Comparative studies of the long-term growth of lymphocytes from tumor infiltrates, tumor-draining lymph nodes, and peripheral blood by repeated in vitro stimulation with autologous tumor.

Tumor-infiltrating lymphocytes (TILs) have been grown from a variety of human tumors. TILs from some patients with melanoma demonstrate lytic activity specific for autologous tumor, and can mediate tumor regression when adoptively transferred to select cancer patients. In this study, we have compared the in vitro properties of lymphocytes from peripheral blood (PBLs), from draining lymph nodes (DLNs), and from tumors (TILs) grown simultaneously from 10 patients: 2 with melanoma, 4 with breast cancer, 1 with gastric cancer, 1 with renal cancer, 1 with sarcoma and 1 with lung cancer. PBLs, TILs, and DLNs were cultured in RPMI 1640 + 10% human AB serum, 20% LAK cell culture supernatant, and 1,000 u/ml of recombinant interleukin-2. Half of each culture was restimulated with irradiated autologous tumor every 14 days. In all groups, tumor feeding enhanced lymphocyte proliferation, although TILs and DLNs consistently proliferated longer and more rapidly than PBLs. Eight of 10 early cultures of TILs and DLNs contained greater or equal proportions of CD8+ cells compared with CD4+ cells, but in long-term cultures an inversion of that ratio was seen (CD4+ greater than CD8+). In short-term chromium release assays, specific lysis of autologous tumor was seen in tumor-fed TILs and DLNs from one patient with melanoma, DLNs from one patient with breast cancer, and TILs from one patient with lung cancer. Other cultures had nonspecific lytic activity. Specific cytotoxicity against autologous tumor sometimes became apparent only after prolonged culture and repeated restimulation with autologous tumor. DLNs have in vitro properties similar to TILs and may be a useful immune reagent for cancer therapy.

Adolescent↗
PubMed1987

Tumor-specific idiotype vaccines. II. Analysis of the tumor-related network response induced by the tumor and by internal image antigens (Ab2 beta).

In this study the tumor-specific immuneresponse induced by irradiated tumor cells (L1210/GZL) and by anti-idiotype antibodies was analyzed. The anti-idiotype antibodies (Ab2) were made against the paratope of a monoclonal antitumor antibody (11C1) that recognizes a tumor-associated antigen which cross-reacts with the mouse mammary tumor virus-encoded envelope glycoprotein 52. Two Ab2, 2F10 and 3A4, induced idiotypes expressed by the monoclonal antitumor antibodies 11C1 and 2B2. Cytotoxic T cells, generated by immunization with irradiated tumor cells, lyse 2F10 and 3A4 hybridoma cells. Furthermore, immunization with Ab2 induces tumor-specific cytotoxic T lymphocytes. The frequency of tumor-reactive cytotoxic T lymphocyte was found to be similar in mice immunized with Ab2 or irradiated tumor cells when examined at the precursor level. However, only 2F10 induces protective immunity against the growth of L1210/GZL tumor cells. The depletion of a L3T4+ T cell population from 2F10 immune mice was found to increase the effectiveness of transferred T cells to induce inhibition of tumor growth. The inability of 3A4 to induce antitumor immunity could be correlated with the presence of a population of Lyt2+ regulatory T cells. Collectively, these results demonstrate the existence of a regulatory network controlling the expression of effective tumor immunity. Our results demonstrate that selection of binding site-related Ab2 may not be a sufficient criteria for the development of an idiotype vaccine. A better understanding of the regulatory interactions induced by anti-idiotypes is needed for the design of effective antitumor immunotherapy.

Animals↗