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PubMed1987

Tumor therapy of neoplastic diseases with tumor cells and neuraminidase: experimental studies on chessboard vaccination in transplantation tumors.

The therapeutic effect of intradermal (i.d.) injection of tumor cells mixed with VCN on growth of spontaneous metastases in transplantable tumors in mice (3-Lewis lung adenocarcinoma; B16-melanoma) and rats (R-3230 mammary adenocarcinoma) was investigated. Intradermal injection was done in a chessboard-like manner; increasing numbers (10(5), 10(6) and 10(7)) of Mitomycin-treated tumor cells (M-TC) were each mixed with increasing amounts (10, 50 and 100 mU) of Vibrio cholerae Neuraminidase (VCN). These different mixtures were injected i.d. at different sites one day after resection of the primary tumor graft to mice and rats, suffering from minimal residual disease. The therapeutic effect of this so-called chessboard vaccination on minimal residual disease was compared to that of the subcutaneous or i.d. injection of VCN-treated M-TC (10(5), 10(6), 10(7) or 10(8) cells) or of single mixtures of M-TC and VCN. The results show that compared to VCN-treated M-TC or single mixtures of M-TC and VCN, chessboard vaccination is the only procedure that is therapeutically effective on metastasation of Lewis lung adenocarcinoma. The therapeutic effect could be abrogated by heat-inactivation of VCN. Incomplete chessboard vaccinations (10(5), 10(6), 10(7) tumor cells, each mixed with 5 mU VCN only) were likewise ineffective. However, treatment with incomplete chessboard vaccinations in combination with a low dose of cyclophosphamide (which is not immunosuppressive, but partly inhibits tumor growth) had a synergistic therapeutic effect on minimal residual disease of Lewis lung adenocarcinoma. In contrast, growth of metastases of B16-melanoma and R-3230 adenocarcinoma could not significantly be influenced by any of those treatments. The DTH response of tumor bearing animals against i.d. applied tumor cells was neither significantly enhanced by the admixture of enzymatically active VCN nor did the DTH response seem to be predictive for a tumor-therapeutic effect. Thomsen-Friedenreich antigens could serologically be detected on untreated cells of Lewis lung adenocarcinoma, B16-melanoma and R-3230 adenocarcinoma. Exposure of Thomsen-Friedenreich antigens after treatment with VCN was enhanced on cells of all tumors except Lewis lung adenocarcinoma. As chessboard vaccination only proved to be successful in Lewis lung adenocarcinoma, but not in the other tumors, it can be concluded that the exposure of Thomsen-Friedenreich antigen plays no decisive role in tumor therapy with tumor cells and VCN. Chessboard vaccination was tolerated without any side effects. Tumor enhancement was not observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed2006

From krukenberg to today: the ever present problems posed by metastatic tumors in the ovary: part I. Historical perspective, general principles, mucinous tumors including the krukenberg tumor.

This review considers historical aspects of metastatic tumors to the ovary, general principles that aid in their evaluation, and metastatic mucinous tumors, including the Krukenberg tumor. The historical timeline on the Krukenberg tumor dates back to the legendary Sir James Paget and the story is followed through the well-known, albeit flawed, contribution of Friedrich Krukenberg and others who have contributed important papers over the years, including the overlooked contribution of the French investigator Gauthier-Villars. Knowledge of metastatic colorectal carcinoma is traced back to the famed British surgeon Sir John Bland-Sutton and followed through to more recent contributions, including the important one of Lash and Hart. Contributions on mucinous tumors conclude the historical perspective, note being made of the recent evidence suggesting that the long held contention of Dr Robert E. Scully that ovarian mucinous tumors in patients with pseudomyxoma peritonei usually originate from the appendix is correct. The section on general principles highlights the many clinical, gross, microscopic, and special techniques such as immunohistochemistry that may aid in determining that an ovarian tumor is metastatic with emphasis on the first 3 mentioned aspects. Problematic features such as a tendency for metastatic tumors to be cystic, even when the primary tumors are not, and for many metastatic tumors to mature in the ovary (so-called maturation phenomenon), are emphasized. Of the many helpful findings that resolve the problem, the characteristic features of surface implants are highlighted. The contribution on the Krukenberg tumor reviews the varied microscopy of this tumor pointing out that the well-known pattern of signet-ring cells in a cellular stroma, albeit characteristic, is often not striking and frequently overshadowed by other microscopic features. The latter include, in many cases, a rather unique microcystic pattern. The final portion of the essay reviews mucinous tumors of non-Krukenberg type, beginning with those that originate from the appendix. The appendiceal neoplasms have distinctive features in most cases being particularly well differentiated, and this is also seen in their ovarian metastases. Other mucinous tumors that commonly simulate closely metastatic neoplasms, include those from the pancreas in particular, but also diverse other sites, are then reviewed.

Adenocarcinoma, Mucinous↗
PubMed1977

Character of the tumors developing in young hamsters by the mixed cell transplantation of para-adeno-virus 12 and SV40 tumors-the similarity to the tumors induced by para-adenovirus 7.

Two mixtures of either allogeneic PARA-adenovirus 12 tumor cells or adenovirus (Adeno) 12 tumor cells and SV40 tumor cells in an equal number of 1 multiplied by 10(7) cells were transplanted subcutaneously at two sites of 10 young hamsters. The former two tumor cells were transplantable in nearly half of the transplants and the latter tumor cells in all of the transplants. By the mixture of PARA-Adeno 12 and SV40 tumor cells, 10 tumors were grown, 7 of which were mixed with Adeno and SV40 types and 3 were solely SV40 type. The other 10 tumors produced by the mixture of Adeno 12 and SV40 tumor cells revealed SV40 type only. Morphologically, Adeno type resembled the tumor induced by Adeno, and SV40 type by SV40. The results suggest that the existence of SV40 genetic information in Adeno type tumor cells is indispensable to the formation of mixed tumor in allogeneic tumor cell system. The similarity between the tumors developed by the mixed cell transplantation and those induced by PARA-adeno 7 was discussed both viro-immunologically and morphologically.

Adenoviridae↗
PubMedDate not supplied

Creation of a stable mammary tumor cell line that maintains fertility-cycle tumor biology of the parent tumor.

A mammary tumor cell line, designated MTCL, was successfully established from a mouse primary mammary tumor (MTP). The MTCL cells retain cytokeratin and both estrogen receptor (ER) and progesterone receptor (PR) in vitro. In vitro exposure of MTCL cells to progesterone causes a decrease in the cellular (3)H-thymidine uptake, indicating an inhibition by progesterone on MTCL cellular deoxyribonucleic acid synthesis, whereas exposure of the cells to a high dose of estrogen (15 pg/ml) for 48 h causes an increase of (3)H-thymidine uptake. We inoculated both MTP or MTCL tumor cells into normal cycling female C(3)HeB/FeJ mice and demonstrated that the post-resection metastatic recurrence of MTCL tumors, like the original MTP tumors, depends on the time of tumor resection within the mouse estrous-cycle stage. Both MTCL and MTP tumors have similar histological appearances with the exception of less extensive tumor necrosis and higher vascularity in MTCL tumors. Equivalent levels of sex hormone receptors (ER alpha, ER beta, and PR), epithelial growth hormone receptors (Her2/neu, EGFR1), tumor suppressors (BRCA1, P53), and cell apoptosis-relevant protein (bcl-xl) were found in these in vivo tumors by immunohistochemistry. Cyclin E protein, however, was significantly higher in MTP tumors compared with MTCL tumors. Our results indicate that MTCL cells retain many of the biologic features of the original MTP primary tumor cells, and to our knowledge, it is the first in vitro cell line that has been shown to maintain the estrous-cycle dependence of in vivo cancer metastasis.

Animals↗
PubMed2002

Response of the immune system of mammary tumor-bearing rats to cyclophosphamide and soluble low-molecular-mass tumor-associated antigens: rate of lymphoid infiltration and distribution of T lymphocytes in tumors.

We have shown previously that soluble low-molecular-mass tumor-associated antigens (sTAA) promote the anti-tumor effect of the anticancer drug cyclophosphamide (CPA) on rat mammary carcinogenesis. In this study, we analyzed the possible mechanism underlying this phenomenon. Studies were performed on tumors obtained from the following groups of mammary tumor-bearing rats: i) control rats, ii) rats treated with sTAA, iii) rats treated with CPA, iv) rats treated with CPA and sTAA. All analyzed tumors represented different types of invasive duct carcinomas. The rate of lymphoid infiltration and T cell content (CD4+ and CD8+ cells) of tumors were analyzed immunohistochemically. In parallel, mitotic index was evaluated in tumor cells. In tumor-bearing rats, high lymphoid proliferation was found at the periphery of tumors, and to a lesser extent deep inside the tumors. In control tumors, CD4+ T cell content was very low whereas CD8+ cells were highly abundant, especially at the tumor periphery. Treatment with sTAA significantly increased the total number of lymph cells and the number of CD8+ lymphocytes inside the tumors. Cytoplasmic vacuolization, decreased mitotic index and various degrees of fibrosis were the most distinct changes in tumors treated with CPA alone. CPA also sharply decreased the activity of all lymph cells studied, especially of CD4+ lymphocytes which could no longer be observed following this treatment. The combined treatment of CPA and sTAA increased the number of lymph cells, although they did not reach control levels. Inhibition of mainly CD4+ lymphocyte synthesis of CPA was confirmed by the low CD4/CD8 ratio, which increased slightly after the combined treatment with CPA and sTAA. Findings in the present study demonstrate that vaccination with sTAA actively promotes the generation of the host's antitumor immune response.

Animals↗
PubMed1988

Role of tumor cytoskeleton and membrane glycoprotein IRGpIIb/IIIa in platelet adhesion to tumor cell membrane and tumor cell-induced platelet aggregation.

Components of the tumor cell cytoskeleton (i.e., microtubules, microfilaments, and intermediate filaments) have been reported to affect metastatic ability, since disruption of these components leads to a decrease in metastasis. One mechanism of metastasis which has not been previously considered is the decreased interaction of tumor cells with platelets. We present evidence that disruption of the tumor cell cytoskeleton decreases the ability of tumor cells to aggregate homologous platelets. This effect is dependent upon the disruption of microfilaments/intermediate filaments but not disruption of microtubules. In addition, tumor cell platelet interactions require the lateral mobility of specific receptors (i.e., clustering) on the tumor cell plasma membrane. A membrane glycoprotein immunologically related to the platelet glycoprotein IIb/IIIa complex was identified on Walker 256 carcinosarcoma cells using specific polyclonal and monoclonal antibodies and Northern blot analysis using complementary DNA probes for IIb and IIIa. Mobility of this receptor is dependent upon tumor cell microfilaments/intermediate filaments, but not microtubules. Furthermore, treatment of tumor cells with specific antibodies to the platelet glycoprotein IIb/IIIa complex inhibits tumor cell-platelet interaction at the macroscopic level (i.e., aggregation) and at the ultrastructural level (i.e., platelet adhesion to the tumor cell surface). These results suggest that this immunologically related glycoprotein IIb/IIIa is a receptor for platelet binding to the tumor cell surface, an event which precedes overt platelet aggregation and is dependent upon an intact tumor cell microfilament and intermediate filament network. Therefore, the decreased metastasis observed by others following disruption of the tumor cell cytoskeleton may be due, in part, to a decreased tumor cell-platelet interaction.

Animals↗
PubMed1987

Studies on the anti-tumor efficacy of systemically administered recombinant tumor necrosis factor against several murine tumors in vivo.

The anti-tumor activity of recombinant human tumor necrosis factor (rHTNF) was examined against four newly induced murine sarcomas (MCA-101, -102, -105, and -106) and a murine adenocarcinoma (MCA-38) transplanted s.c. into C57BL/6 mice. The serum half-life after a single i.v. injection of rHTNF was determined to be 30 +/- 2 min. Tumor-bearing mice were more susceptible to the toxic side effects of rHTNF than were normal mice. Forty-eight percent (41/86) of tumor bearing animals that received 10 micrograms rHTNF died within 48 hr after treatment compared with no deaths in 28 normal animals receiving this dose. Treatment of mice bearing either the MCA-101, -102, -105, or -106 sarcoma or the MCA-38 adenocarcinoma with rHTNF resulted in a marked necrosis of the central portion of each tumor within 24 hr. Animals bearing the weakly immunogenic tumors MCA-105, -106, and -38 experienced a reduction in average tumor area of 47% +/- 5, 46% +/- 6, and 37% +/- 11, respectively, by 3 to 4 days after treatment with rHTNF compared with pre-treatment values (p less than 0.001); increases of 79% +/- 11, 74% +/- 10, and 41% +/- 6 were seen in excipient-treated control animals over the same period. In contrast, animals bearing the non-immunogenic tumors MCA-101 and -102 experienced little if any decrease in tumor area at the doses of rHTNF used. rHTNF failed to mediate cures in animals bearing MCA-38, -101, or -102. In contrast, 67 and 28% of animals bearing MCA-105 and -106, respectively, which received 6 to 10 micrograms rHTNF were cured. Likewise, animals bearing MCA-105 and -106 sarcomas treated with 6 to 10 micrograms rHTNF had significantly increased survival compared with excipient-treated control animals. In contrast, no significant difference in mean survival was observed between excipient and rHTNF treated animals bearing MCA-38, -101, or -102. Histologically, the necrotic response of immunogenic MCA-106 and non-immunogenic MCA-102 tumors to systemically administered rHTNF was very similar. These two tumors differed morphologically, however, by the greater degree of chronic inflammation that was present at the periphery of the MCA-106 tumor in comparison with the MCA-102. By 72 hr after rHTNF administration, the sites of regressed MCA-106 tumors were replaced by a heterogeneous population of inflammatory cells and tumor cell "ghosts".(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1987

The generation of tumor-specific in vivo protective immunity in the tumor mass from mice rendered tolerant to tumor antigens.

C3H/He mice were inoculated i.v. with 10(6) heavily X-irradiated syngeneic X5563 plasmacytoma cells 3 times at 4 day intervals. When these mice received an appropriate immunization procedure consisting of i.d. inoculation of viable tumor cells plus the surgical resection of the tumor which enables i.v. nonpresensitized mice to produce anti-X5563 immunity, they failed to develop tumor-specific immunity. This was demonstrated by the abrogation in potential of spleen and lymph node cells to generate in vivo protective immunity. In contrast, the tumor mass from X5563 tumor-bearing mice which had received the i.v. presensitization contained comparable anti-X5563 tumor neutralizing activity to that obtained from the tumor mass from nonpresensitized, X5563 tumor-bearing mice. Such an in vivo protective immunity was revealed to be mediated by tumor-specific T cells. These results demonstrate the differential generation and antitumor capability of tumor infiltrating T cells and T cells in lymphoid organs from mice which are in the tumor-specific tolerant state. The results are discussed in the context of potential utilization of tumor infiltrating in vivo protective T cells to enhance the local tumor-specific immunity in tumor-specific tolerant mice.

Animals↗
PubMedDate not supplied

Curative potential of GM-CSF-secreting tumor cell vaccines on established orthotopic liver tumors: mechanisms for the superior antitumor activity of live tumor cell vaccines.

In preclinical studies, tumor cells genetically engineered to secrete cytokines, hereafter referred to as tumor cell vaccines, can often generate systemic antitumor immunity. This study investigated the therapeutic effects of live or irradiated tumor cell vaccines that secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) on established orthotopic liver tumors. Experimental results indicated that two doses (3 x 10(7) cells per dose) of irradiated tumor cell vaccines were therapeutically ineffective, whereas one dose (3 x 10(6) cells) of live tumor cell vaccines caused complete tumor regression. In vivo depletion of CD8+ T cells, but not natural killer cells, restored tumor formation in the live vaccine-treated animals. Additionally, the treatment of cells with live vaccine induced markedly higher levels of cytotoxic T lymphocyte activity than the irradiated vaccines in the draining lymph nodes. The higher levels of cytokine and antigen loads could partly explain the superior antitumor activity of live tumor cell vaccines, but other unidentified mechanisms could also play a role in the early T cell activation in the lymph nodes. A protocol using multiple and higher dosages of irradiated tumor cell vaccines also caused significant regression of liver tumors. These results suggest that the GM-CSF-secreting tumor cell vaccines are highly promising for orthotopic liver tumors if higher levels of immune responses are elicited during early tumor development.

Animals↗
PubMed1989

The effects of tumor mass, tumor age, and external beam radiation on tumor-specific antibody uptake.

The effects of external beam radiation on tumor uptake of radiolabeled monoclonal antibody were investigated. Nude mice bearing carcinoembryonic antigen (CEA)-producing subcutaneous human tumor xenografts (LS174T) were irradiated (60Co) with a single fraction of 0, 2 or 20 Gy, 6 or 11 days after tumor inoculation. An Indium-111 labeled anti-CEA monoclonal antibody (T84.66) was injected 1-2 hrs after irradiation. Biodistribution studies performed at 48 hrs showed a statistically significant (p less than 0.01) inverse correlation between tumor mass and tumor antibody uptake. Tumor age was also a significant factor with 11 day old tumors having significantly less uptake (p less than 0.0001) compared to 6 day old tumors for a given mass. Radiation increased tumor antibody uptake only in those tumors where growth inhibition also occurred. Multiple regression analysis showed that this inverse correlation between tumor mass and antibody uptake was the same for irradiated and nonirradiated tumors. We conclude that, in this model system, radiation does not act independently to enhance tumor antibody deposition. Radiation's primary effect is to reduce tumor mass, with mass reduction then resulting in an increase in antibody uptake. The clinical implications of this study are discussed.

Animals↗
PubMed2001

A role of interferon-gamma (IFN-gamma) in tumor immunity: T cells with the capacity to reject tumor cells are generated but fail to migrate to tumor sites in IFN-gamma-deficient mice.

IFN-gamma-deficient (IFN-gamma-/-) mice induce potent in vitro immune responses such as anti-allo mixed lymphocyte reaction and CTL responses, whereas they often fail to exhibit in vivo immunity. Here, we investigated whether there exists a defect in tumor rejection responses and if so, which process of responses is impaired. IFN-gamma-/- and wild-type (WT) BALB/c mice were immunized with attenuated syngeneic CSA1M tumor cells. The capacity of T cells to mediate tumor protection was examined in Winn assays to assess the growth of tumor cells admixed with tumor-sensitized T cells. Splenic T cells from both groups of mice exhibited comparable levels of tumor-neutralizing activity. When portions of immunized mice were directly challenged with viable tumor cells, tumor rejection was induced only in WT mice. CD4(+) and CD8(+) T-cell infiltration were observed at the site of tumor challenge in WT mice, whereas such a T-cell infiltration did not occur in IFN-gamma-/- mice. Similarly, splenic T cells from interleukin 12-treated CSA1M-bearing IFN-gamma-/- and WT mice neutralized tumor cells at comparable efficacies in Winn assays. However, the migration of these T cells to tumor masses and the resultant interleukin 12-induced tumor regression took place in WT mice, but neither intratumoral T-cell infiltration nor tumor regression occurred in IFN-gamma-/- mice. These results indicate a critical requirement for IFN-gamma in the process of inducing T-cell migration to tumor sites rather than of generating antitumor protective T cells.

Animals↗
PubMed2001

Tumor response after [(90)Y-DOTA(0),Tyr(3)]octreotide radionuclide therapy in a transplantable rat tumor model is dependent on tumor size.

UNLABELLED: A promising application of radiolabeled somatostatin analogs is peptide receptor-targeted radionuclide therapy of somatostatin receptor-expressing tumors. A suitable radionuclide is (90)Y, which emits high-energy beta-particles with a pathlength of several millimeters in tissue, making it especially promising for treatment of large tumors. METHODS: We investigated the radiotherapeutic effect of different activities (111 and 370 MBq) of [(90)Y-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)(0),Tyr(3)]octreotide in Lewis rats bearing somatostatin receptor-positive rat pancreatic CA20948 tumors of different size (0.08-15 cm(2)) in their flank. RESULTS: Dose-dependent radiotherapeutic effects of (90)Y-labeled octreotide in this rat tumor model were found. Tumor control (100% complete response) was found in animals bearing tumors of 3-9 cm(2) (mean, 7.8 cm(2)) after intravenous injection of the highest activity (370 MBq [(90)Y-DOTA(0),Tyr(3)]octreotide). In rats bearing tumors of < or =1 cm(2) or > or =14 cm(2), the effects were less pronounced (50% and 0% complete response, respectively). In tumors of < or =1 cm(2) the (90)Y radiation energy will not be absorbed completely in the tumor, whereas in tumors of > or =14 cm(2) the increased number of clonogenic and probably hypoxic tumor cells may explain the failure to reach a cure. CONCLUSION: This study shows the ability of [(90)Y-DOTA(0),Tyr(3)]octreotide to control tumor growth, especially in medium-sized tumors. The effect of radionuclide therapy appeared to be dependent on tumor size at the onset of therapy.

Animals↗
PubMed1992

Tumor-bearing mice exhibit a progressive increase in tumor antigen-presenting cell function and a reciprocal decrease in tumor antigen-responsive CD4+ T cell activity.

Splenic CD4+ T cells from BALB/c mice bearing a syngeneic tumor (CSA1M) 2 to 3 wk after the inoculation with CSA1M cells produced IL-2 and macrophage-activating factor upon in vitro cultures. This lymphokine production was achieved without stimulation of these T cells with exogenous stimulating tumor Ag. However, elimination of APC from spleen cells resulted in almost complete abrogation of the capacity of CD4+ T cells to produce IL-2/macrophage-activating factor. The lymphokine production was regained when APC from CSA1M-bearing mice were added back to cultures. APC from normal or another syngeneic tumor (Meth A)-bearing mice failed to regain the lymphokine production. These observations demonstrated that the lymphokines were produced by CD4+ T cells from CSA1M-bearing hosts through their collaboration with APC binding CSA1M tumor Ag in the tumor-bearing state. The lymphokine-producing capacity of whole spleen cells from tumor-bearing mice reached the maximal level around 2 to 3 wk after tumor implantation but gradually decreased with the progress of tumor-bearing stages. Importantly, tumor-bearing stage-related changes were observed in a different fashion in the capacities of anti-CSA1M CD4+ T cells vs CSA1M tumor Ag-binding APC. The capacity of APC increased with the progress of tumor-bearing stages as demonstrated by the stimulation of CSA1M-immunized T cells with APC from different CSA1M-bearing stages. In contrast, the reactivity of anti-CSA1M T cells to APC from a given CSA1M-bearing stage decreased with the tumor-bearing stage. These results demonstrate a stage-related increase tumor Ag-binding APC function, as well as a reciprocal reduction in tumor Ag-responsive CD4+ T cell activity.

Animals↗
PubMed1989

[Anemia in malignant tumor diseases. I. Tumor-induced loss of transferrin and its relation to tumor size and degree of malignancy in the rat model].

Cellular uptake of 67Ga-labelled transferrin by the tumor tissue was studied in rats with tumors of different malignancy and different tumor mass using the slowly growing Morris hepatoma 5123C, the moderately growing Novikoff hepatoma and the very fast and aggressive Yoshida hepatoma AH130. The cellular accumulation of 67Ga-transferrin was found to correlate with the proliferation activity of the tumor. The 67Ga-transferrin concentration in the very fast growing Yoshida hepatoma was 4.8 times higher than the concentration in the slowly growing Morris hepatoma. The uptake of 67Ga-transferrin by the tumors resulted in a faster disappearance of circulating 67Ga-transferrin from the blood. The rate of disappearance correlated with the proliferation activity and the spread of the tumors. Using tumors of identical size the elimination of 67Ga-transferrin from the blood was much faster in the rats with Yoshida hepatoma than in those with the slowly growing Morris hepatoma. On the other hand, using tumors of different tumor size it could be demonstrated that the rate of disappearance of 67Ga-transferrin from the blood correlated directly with tumor mass. It is concluded that cellular incorporation of transferrin within the tumor cells results in a loss of circulating transferrin, which correlates with tumor mass and proliferation of tumor. This mechanism is supposed to be the cause for the hypotransferrinemia seen in patients with malignant tumors.

Anemia↗
PubMed1986

Retardation of tumor growth in mice caused by radiation-induced injury of tumor bed stroma: dependency on tumor type.

Dependency on tumor type of tumor growth retardation caused by the radiation-induced damage of tumor bed stroma, a phenomenon known as the tumor bed effect (TBE), was investigated using two mammary carcinomas designated MCA-4 and MCA-K and two fibrosarcomas designated FSA and NFSA, all syngeneic to C3Hf/Kam mice. Inoculations of tumor cells were given s.c. into the right hind thighs of mice either treated or not treated 1 day earlier with graded doses of gamma-rays; tumor latency and growth rate were determined. Tumor latency was prolonged and tumor growth was retarded, but the magnitude of these two features of TBE greatly depended on radiation dose and tumor type. TBE began to appear at doses of 5-10 Gy and then sharply increased as the dose of radiation was increased up to between 20 and 30 Gy, at which point a plateau was achieved. TBE was also significant after 40 and 60 Gy total dose given in daily fractions of 2 Gy 5 times per week, a schedule commonly used in radiotherapy treatment of cancer patients. Carcinomas exhibited more pronounced TBE than fibrosarcomas, with NFSA showing only minimal TBE. Radiation-inactivated MCA-4 and FSA cells admixed with viable MCA-4 cells reduced tumor latency, but not the tumor growth delay, of resulting MCA-4 tumors in preirradiated legs. In contrast, admixture of irradiated NFSA and viable MCA-4 cells abolished growth delay but did not influence tumor latency of the TBE phenomenon. Thus the type of a tumor growing in the irradiated tissue is a very important factor that determines the expression of TBE.

Animals↗
PubMed2006

Targeted delivery of tumor necrosis factor-alpha to tumor vessels induces a therapeutic T cell-mediated immune response that protects the host against syngeneic tumors of different histologic origin.

PURPOSE: We sought to demonstrate that a single systemic administration of L19mTNFalpha (a fusion protein constituted by the scFv L19 specific for the oncofetal ED-B domain of fibronectin and tumor necrosis factor alpha, TNFalpha) in combination with melphalan induced complete and long-lasting tumor eradication in tumor-bearing mice and triggered the generation of a specific T cell-based immune response that protects the animals from a second tumor challenge, as well as from challenges with syngeneic tumor cells of different histologic origin. EXPERIMENTAL DESIGN AND RESULTS: Treatment with L19mTNFalpha, in combination with melphalan, induced complete tumor regression in 83% of BALB/c mice with WEHI-164 fibrosarcoma and 33% of animals with C51 colon carcinoma. All cured mice rejected challenges with the same tumor cells and, in a very high percentage of animals, also rejected challenges with syngeneic tumor cells of different histologic origin. In adoptive immunity transfer experiments, the splenocytes from tumor-cured mice protected naive mice both from C51 colon carcinoma and from WEHI-164 fibrosarcoma. Similar results were also obtained in adoptive immunity transfer experiments using severely immunodepressed mice. Experiments using depleted splenocytes showed that T cells play a major role in tumor rejection. CONCLUSIONS: The results show that the selective targeting of mTNFalpha to the tumor enhances its immunostimulatory properties to the point of generating a therapeutic immune response against different histologically unrelated syngeneic tumors. These findings predicate treatment approaches for cancer patients based on the targeted delivery of TNFalpha to the tumor vasculature.

Animals↗
PubMed1996

Enhanced tumor outgrowth after peptide vaccination. Functional deletion of tumor-specific CTL induced by peptide vaccination can lead to the inability to reject tumors.

CTL can play an important role in the defense against tumors. Protective CTL-mediated immunity can be established in animal tumor models after vaccination with synthetic peptides representing CTL epitopes. We now report that immunization with synthetic peptides can also lead to CTL tolerance associated with the inability to reject tumors. B6 tumor cells transformed by the human adenovirus early region 1 (Ad5E1) present an Ad5E1A- and an Ad5E1B-encoded CTL epitope to the immune system. CTL clones directed against either of these epitopes are able to eradicate established Ad5E1-induced tumors, showing that these CTL epitopes are targets of CTL that can mediate tumor regression. Here, we show that protective immunity against Ad5E1-expressing tumor cells can be established by immunization with Ad5E1-transformed cells and with an adenovirus vector containing the Ad5E1 region. Protective immunity, in either case, is associated with specific CTL memory. To test whether vaccination with synthetic peptides leads to protection against Ad5E1-expressing tumor cells, we vaccinated mice s.c. with a low dose of the Ad5E1B peptide. This peptide was chosen because the CTL response against the Ad5E1B-encoded CTL epitope contributes most to the antitumor response in B6 mice after vaccination with Ad5E1-transformed cells. Ad5E1B peptide-vaccinated mice were not protected against the outgrowth of Ad5E1-expressing tumor cells, but instead were no longer able to reject a tumor inoculum that was rejected by nonvaccinated mice. Moreover, the protection induced by tumor cell vaccination against Ad5E1B-expressing tumors was gone when the Ad5E1B-encoded CTL epitope was injected a few days before tumor challenge. This is associated with peptide-induced tolerance of Ad5E1B-specific CTL activity. These findings are relevant for the design of therapeutic approaches against both malignancies and T cell-mediated autoimmune diseases.

Adenovirus E1A Proteins↗
PubMed1984

Antitumor activity of murine tumor necrosis factor (TNF) against transplanted murine tumors and heterotransplanted human tumors in nude mice.

The antitumor activity of highly purified tumor necrosis factor (TNF) was tested against eight kinds of murine tumor and five kinds of human tumor heterotransplanted into nude mice. Mice were treated by intravenous or intratumoral injection of TNF, commencing when the tumors were well established. TNF showed an excellent curative effect against all kinds of murine and human tumors tested. Meth A sarcoma, Colon 26, Ehrlich, sarcoma 180, MM 46, MH 134, B16 melanoma, and Lewis lung tumors transplanted into mice underwent tumor necrosis and regression following a single injection of TNF. Sometimes a complete cure was observed in Meth A sarcoma, sarcoma 180, Ehrlich, and MM 46 tumors. Human cancers, SEKI, HMV-I, KATO-III, MKN 45, or KB, heterotransplanted into nude mice, also exhibited tumor necrosis and regression in size following several intratumoral injections of TNF. A great difference in curative effects of TNF was observed in Meth A sarcomas between those transplanted into BALB/c nu/+ and into BALB/c nu/nu mice: following a single intravenous administration the effect was stronger in BALB/c nu/+ than in nu/nu mice. In contrast, tumor necrosis was almost the same in nu/+ and nu/nu mice following intratumoral administration. The present results thus indicate that TNF from mice had an antitumor activity against not only murine tumors but also human tumors. In addition to direct cytotoxicity against tumor cells, TNF induced a host-mediated factor which contributed to the antitumor effects.

Adjuvants, Immunologic↗