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PubMed1986

[Analysis of serum CA125, CEA, AFP, LDH levels and LDH isoenzymes in patients with ovarian tumors--correlation between tumor markers and histological types of ovarian tumors].

Serum CA125, CEA, AFP, LDH levels and LDH isoenzymes were analyzed in ovarian tumor patients, who were treated at Kyoto University Hospital. CA125 was positive in 10/16 (62.5%) cases of common epithelial carcinoma, especially 100% positive in serous carcinoma, but was negative in mucinous tumors. CA125 was also negative in patients with germ cell and sex cord stromal tumors. CEA was positive in 13/32 (40.6%) cases of epithelial carcinoma, most frequently elevated in patients with mucinous carcinoma, pseudomyxoma peritonei, and Krukenberg tumor. AFP was positive only in those with endodermal sinus tumors. LDH was elevated in 16/39 (41%) cases of epithelial carcinoma, but was not specific for histological types. In contrast, all 8 cases of dysgerminoma, 1 of immature teratoma and 2 of endodermal sinus tumor showed extremely elevated LDH levels. Moreover, the normal pattern or deviation to H subunit of LDH isoenzymes was seen in such cases of germ cell tumor, while deviation to M subunit was noted in epithelial and metastatic tumor patients. These data indicate that each parameter is useful as a tumor marker for the specific histological type of ovarian tumor; CA125 for non-mucinous epithelial carcinoma, CEA for mucinous tumor and Krukenberg tumor, AFP for yolk sac tumor, LDH and LDH isoenzymes for dysgerminoma and other solid germ cell tumors. In addition, preoperative diagnosis of histological types of ovarian tumors may be possible by combining these tumor markers.

Adenocarcinoma↗
PubMed1988

[Analysis of tumor specific immunological response in the patients with malignant brain tumors by the mixed lymphocyte-tumor cell reaction].

In considering immunological approaches to treatment of the patients with malignant brain tumors, it seems very important to enhance the tumor specific immunity. Then, to ascertain whether tumor specific immune response occurs in these patients with malignant brain tumors, lymphocyte blastogenetic responses to tumor cells were examined in 18 patients with malignant brain tumors. Furthermore, to compare the systemic immunological responses with the local responses in the brain tumor tissues, both peripheral blood lymphocyte (PBL) and tumor infiltrating lymphocyte (TIL) were used as blastogenetic stimulators to the tumor cells. The PBL from the patients with malignant gliomas showed any positive blastogenetic response to their own glioma cells in 7 or 12 cases (about 58%). But, TIL from these patients showed a positive response in the only 3 cases (25%). In 6 cases of metastatic brain tumors, otherwise, their PBL showed any positive blastogenetic response to their own tumor cells in 4 of 6 cases (about 67%), and their TIL showed any positive blastogenetic responses in these same 4 cases. So, the tumor specific immunological responses may be stronger in the patient with metastatic brain tumors than in the patient with malignant gliomas. These immunological responses were, furthermore, more weak in the brain tumor tissues than in the systemic immunity. Then, this lymphocyte blastogenetic response to tumor cells were compared with other lymphocyte stimulating examination such as rectine or allogenetic lymphocyte stimulation. Our studies revealed that this lymphocyte blastogenetic response to tumor cells were at lower level compared with rectine such as PHA, PWM, and Con A, or allogenetic lymphocyte stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Expression of class II-MHC antigens by tumor-associated and peritoneal macrophages: systemic induction during tumor growth and tumor rejection.

It was shown previously that combination therapy of tumor-bearing mice resulted in amplification of antitumor responses at the site of tumor rejection and involved some of the classical components of the immunological network. As a continuation of this work, we now show that amplification of immune responses involves an increase in class II-MHC antigen (Ia) expression both at the tumor site and peripherally in the peritoneal cavity. Of further interest, however, was the observation that there was also an increase in Ia expression by tumor-associated macrophages (TAM) and peritoneal macrophages (PMs) in mice bearing progressing tumors. In these experiments, Ia expression by TAM and PMs was assessed in C57BL/6J mice bearing the progressing syngeneic MCA/76-9 sarcoma as well as in mice that had received combination therapy consisting of an intraperitoneal injection of cyclophosphamide (CY) and an intravenous injection of tumor-sensitized T lymphocytes (immune cells). When progressing tumors were analyzed, it was seen that by the fourth day after tumor cell implantation, 45-60% TAM expressed Ia, a level that was sustained throughout the course of tumor growth. The treatment of tumor-bearers with CY had no effect on Ia expression by TAM. However, the number of Ia-expressing TAM increased significantly after combination therapy and, as the tumors regressed, reached a peak of up to 100% in the second week after therapy. TAM were shown by Northern blot hybridization to contain mRNA encoding for the Ia beta chain. When Ia expression by PMs was assessed, it was seen that during tumor progression there was an increased expression of Ia over background (from less than 10 to about 40%), beginning 9-12 days after tumor cell implantation and continuing for the duration of the experiments. This was not influenced by CY injection. Combination therapy significantly increased the number of PMs expressing Ia (up to 80%). Ia expression by PMs could be induced rapidly in vivo by injecting normal B6 mice intraperitoneally (ip) with T cells isolated from tumors induced to regress by combination therapy. PMs isolated up to 15 days after injection were shown to express Ia. Moreover, the ip injection of a mixture of specific MCA/76-9 tumor cells and these tumor-associated lymphocytes resulted in a more rapid rate and a higher level of Ia expression by PMs compared with the level induced by either treatment alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Subcapsular renal transplantation of neurogenic tumors and tumor spheroids. A comparative study of RN6 and RG2 tumor clones after syngeneic and allogeneic transplantation.

The subcapsular renal transplantation tumor model was explored to standardize the growth of rat RN6 neurinoma and RG2 glioma nitrosourea-induced clonal cell lines in syngeneic and allogeneic systems. Growth of RN6 and RG2 tumor spheroids was compared with that of solid subcutaneous tumor pieces transplanted under the renal capsule. Two morphometrical methods were applied to evaluate growth rates. Tumor specimens were examined histologically with regard to their morphology, extent of immune reactions, and development of tumor necroses. The take rate was 98%. In the syngeneic system linear progressive tumor growth was found, while in preirradiated allogeneic rats this was only the case up to 21 to 25 days post transplantation (p.t.). Strong rejection reactions in the allogeneic RN6 tumors were noted from 4 to 7 days p.t. resulting in total tumor rejection after 10 to 14 days. Both kinds of tumors, especially in the first days of growth, were characterized by strong desmoplastic reaction with rich reticulin fiber formation. However, after 10 days, in the center of RG2 subcapsular renal tumors (SRT) this kind of reaction was found only in the vicinity of tumor vessels, while RN6 SRT demonstrated reticulin fibers around tumor cells in all cases studied. The transplantation experiments revealed that the malignant RN6 and RG2 spheroids represent a suitable tool to study three-dimensional early tumor growth in both in vivo and in vitro cultures. The model of spheroid transplantation under the renal capsule is simple to handle and well reproducible. Compared with subcutaneous tumors the SRT model has advantages in early stages of tumor growth because the tumors are clearly visible grossly and can be easily submitted to adequate morphometry, indicating that this model may be suitable for experimental chemotherapy and radiotherapy studies.

Animals↗
PubMed1991

Effector phenotypes and mechanisms of antitumor immune reactivity of tumor-immunized and tumor-bearing mice in two syngeneic tumors.

By using two different syngeneic tumors, Meth A sarcoma and RL male 1 lymphoma of BALB/c origin, the present study was designed to investigate the subset(s) of T cells mediating in vivo antitumor immune responses and some of the effector mechanisms of in vivo protective immunity in BALB/c mice immunized against tumor or bearing tumor. Spleen cells from the mice immunized against Meth A tumor or bearing Meth A tumor inhibited the growth of Meth A tumor in the Winn assay. In the Meth A-immunized mice, L3T4+ (CD4+) cells played a major role in mediating the inhibitory activity against Meth A tumor growth, whereas in the Meth A-bearing mice, the antitumor protective immunity was mediated by both L3T4+ and Lyt-2+ (CD8+) cells. Spleen cells from the Meth A-immunized or Meth A-bearing mice were not able to generate cytotoxic T lymphocytes (CTL) directed against Meth A tumor after the in vitro restimulation of spleen cells with mitomycin C (MMC)-treated Meth A cells, while fresh spleen cells from the Meth A-immunized or Meth A-bearing mice were able to induce the strong delayed-type hypersensitivity (DTH) responses to Meth A tumor. The DTH response to Meth A tumor was mediated by L3T4+ cells in the Meth A-immunized mice and by both L3T4+ and Lyt-2+ cells in the Meth A-bearing mice. In the similar experiments performed in the RL male 1 lymphoma, the antitumor activity in spleen cells from the RL male 1-immunized or RL male 1-bearing mice depended on Lyt-2+ but not L3T4+ cells in the Winn assay. When spleen cells from the RL male 1-immunized or RL male 1-bearing mice were cultured with MMC-treated RL male 1 cells for 5 days, an appreciable CTL response to RL male 1 tumor was induced. These results suggest that the nature of tumor and/or tumor antigens determines which T cell subset is required to exhibit the protective immunity against tumor and thus the different effector mechanisms could be induced in the different tumor models. Furthermore, these data support the conclusion that antitumor T cell responses are affected by the immune state of host to tumor.

Animals↗
PubMed2002

Insulin increases the sensitivity of tumors to irradiation: involvement of an increase in tumor oxygenation mediated by a nitric oxide-dependent decrease of the tumor cells oxygen consumption.

The effects of insulin on tumor oxygenation, perfusion, oxygen consumption,and radiation sensitivity were studied on two different mouse tumor models (TLT, a liver tumor, and FSAII, a fibrosarcoma). Anesthetized mice were infused with insulin i.v. at a rate of 16 milliUnits/kg/min for 25 min. Local tumor oxygenation measurements were carried out using two independent techniques: electron paramagnetic resonance oximetry and a fiber-optic device (OxyLite). Two complementary techniques were also used to assess the blood flow inside the tumor: a laser Doppler system (OxyFlo) and contrast-enhanced magnetic resonance imaging. The oxygen consumption rate of tumor cells after in vivo insulin infusion was measured using high frequency electron paramagnetic resonance oximetry. To know if insulin was able to enhance radiation-induced tumor regrowth delay, tumor-bearing mice were treated with 16 Gy of 250 kV radiation dose after insulin infusion. We provide evidence that insulin increases the local pressure of oxygen of tumors (from 0-3 mm Hg to 8-11 mm Hg) as well as the tumor response to irradiation (increasing regrowth delay by a factor of 2.11). We found that the insulin-induced increase of tumor pressure of oxygen: (a) is not caused by an increase in the tumor blood flow, which is even decreased after insulin infusion; (b) is because of a decrease in the tumor cell oxygen consumption (in vivo insulin consumed oxygen three times slower than control cells); and (c) is inhibited by a nitric oxide (NO) synthase inhibitor, Nomega-nitro-L-arginine methyl ester, when injected i.p. at 15 micromol/kg(-1), 1 h before insulin infusion. We demonstrate by immunoblotting that the NO pathway involves a phosphorylation of endothelial NO synthase and showed a concomitant increase in the cyclic GMP tumor level. These findings provide unique insights into biological processes in tumors, new possible management for treating cancer patients, and raise major questions about the role of insulin secretion (fasting status and diabetes) in the clinical response of tumors to radiation therapy.

Animals↗
PubMed1985

A gelatin sponge model for studying tumor growth: flow cytometric analysis and quantitation of leukocytes and tumor cells in the EMT6 mouse tumor.

This study examined the recruitment of host cells into a progressing EMT6 tumor following the inoculation of tumorigenic cells into a preimplanted gelatin sponge. Tumor cell proliferation occurred to a greater extent in sponge tumors than in tumors obtained by direct subcutaneous injection of tumor cells. Blank sponges, lacking tumorigenic cells and used as controls, elicited an inflammatory response characterized by a modest infiltration of granulocytes and macrophages whose numbers, after Day 7 postimplantation, remained unchanged for 21 days of sponge residence in the animal. In contrast, when the sponge contained tumor cells, there was a continuous increase in host cell infiltration that paralleled the increase in tumor cells. Whether in a sponge or not, tumor cells represented more than half of the recovered cells by Day 21 after tumor cell inoculation. Macrophages comprised the greatest fraction of host cells infiltrating the tumors. Flow cytometric analysis and morphological examination of disaggregated tumors indicated that macrophages (19-51%) made up the largest proportion of host cells followed in order by granulocytes (6-18%) and lymphocytes (2-9%). Sorting of marker-labeled cells revealed that 94% of the surface immunoglobulin-bearing cells were macrophages. Twenty-two % of the cells bearing the Thy 1.2 marker were lymphocytes, and 68% were macrophages. The data confirm the occurrence of a cellular host response in the tumor-bearing animal which is distinct from the foreign body reaction elicited by a blank sponge. Additionally, the sponge system described here represents a recoverable environment that would facilitate the study of in vivo host-tumor cell interactions that occur during early tumor development or later during therapy-induced tumor rejection when a palpable tumor is not present.

Animals↗
PubMed2001

Tumor progression despite efficient tumor antigen cross-presentation and effective "arming" of tumor antigen-specific CTL.

To determine whether APC function or "arming" of CTL for lytic function are the points at which Ags from a nonimmunogenic tumor fail to induce an effective immune response, we established a murine tumor model that expressed intracellular OVA and selected a clone (cOVA-9) that remained susceptible to lysis by specific CD8(+) T cells throughout tumor growth. Viable cOVA-9 tumor cells grew in normal mice at a rate similar to the parental tumor, and vaccination with irradiated cOVA-9 cells did not induce protection against itself or the parental line, confirming its nonimmunogenic status. In vivo evaluation during tumor growth demonstrated persisting tumor Ag cross-presentation accompanied by the generation of potent, specific CTL which were detectable when tumors were barely palpable. Despite the presence of highly active CTL in the tumor-draining lymph nodes, there was no apparent lysis of tumor-associated APC. These data show that tumor-draining APC are not dysfunctional with regard to two crucial processes, in vivo tumor Ag cross-presentation and specific CTL arming, and that failure to prevent tumor growth is not in the induction phase, but in the effector phase and occurs within the tumor itself before the tumor matrix is established.

Animals↗
PubMed2003

Anti-Her-2/neu-IL-2 or heregulin-IL-2 fusions proteins redirect non-tumor specific CTL to the tumor site for tumor eradication.

IL-2 is a T-cell growth factor that has pleiotropic functions on T cells, assisting in activating and expanding immune responses. Interestingly, we have previously found that in the presence of IL-2, CD4(+) or CD8(+) T cells kill tumor cells in an antigen-independent and non-MHC-restricted manner. In this study we took advantage of IL-2 capabilities to induce in this way the killing of tumor cells for immunotherpeutic purposes. We describe a novel mechanism where it is possible to bypass the usage of tumor-specific T cells for adoptive transfer by using non-tumor-specific T cells in combination with an anti-Her-2/neu-IL-2 (neu-Ab-IL-2) or heregulin-IL-2 fusion protein for tumor eradication. T cells in the presence of fusion proteins are capable of inducing the lysis of tumor cells in a non-MHC-restricted manner. This lysis is only observed in T cells that have been stimulated through the TCR, and it is mediated through the Fas-FasL pathway. Moreover, transfer of non-tumor-specific T cells in combination with the fusion proteins, induced the eradication of established Her-2, Her-3, and Her-4 expressing tumor cells in SCID mice. In contrast, the combination of non-tumor-specific T cells plus rIL-2 or irrelevant Ab-IL-2 (anti-hemagglutinin-IL-2) does not induce the elimination of tumors, indicating that the antitumor activity is dictated by the specificity of the fusion protein. These data demonstrate that neu-Ab-IL-2 or heregulin-IL-2 fusion proteins can direct the non-tumor-specific T cells to the tumor site and induce the elimination of tumors. Therefore, combination of non-tumor-specific T cells and antibody/ligand-IL-2 fusion proteins provides an alternative therapeutic strategy to control tumor growth in vivo.

Animals↗
PubMed2006

Early destruction of tumor vasculature in tumor necrosis factor-alpha-based isolated limb perfusion is responsible for tumor response.

Addition of high-dose tumor necrosis factor-alpha to melphalan-based isolated limb perfusion enhances anti-tumor effects impressively. Unfortunately, the mechanism of action of tumor necrosis factor-alpha is still not fully understood. Here, we investigated the effects of tumor necrosis factor-alpha on the tumor microenvironment and on secondary immunological events during and shortly after isolated limb perfusion in soft-tissue sarcoma-bearing rats. Already during isolated limb perfusion, softening of the tumor was observed. Co-administration of tumor necrosis factor-alpha in the isolated limb perfusion with melphalan induced a six-fold enhanced drug accumulation of melphalan in the tumor compared with isolated limb perfusion with melphalan alone. In addition, directly after perfusion with tumor necrosis factor-alpha plus melphalan, over a time-frame of 30 min, vascular destruction, erythrocyte extravasation and hemorrhage was detected. Interstitial fluid pressure and pH in the tumor, however, were not altered by tumor necrosis factor-alpha and no clear immune effects, cellular infiltration or cytokine expression were observed. Taken together, these results indicate that tumor necrosis factor-alpha induces rapid damage to the tumor vascular endothelial lining resulting in augmented drug accumulation. As other important parameters were not changed (e.g. interstitial fluid pressure and pH), we speculate that the tumor vascular changes, and concurrent hemorrhage and drug accumulation are the key explanations for the observed synergistic anti-tumor response.

Animals↗
PubMed1991

Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer.

The tumor necrosis factor alpha (TNF-alpha) gene was introduced by retroviral gene transfer into the TNF-alpha-insensitive tumor cell line J558L. Production of 40 pg/ml TNF-alpha by clone J2T12 consistently did not change the growth rate in vitro, but drastically suppressed tumor growth when injected into syngeneic BALB/c mice. Within 2 wk, 90% of the mice inoculated with J558L cells developed a tumor, but none of the mice injected with J2T12 did so. Within the observation period (greater than 3 mo), 60% of the mice inoculated with J2T12 did not develop a tumor. In the other 40% of the mice, tumor manifestation was significantly delayed. Mice injected simultaneously with J2T12 cells and an anti-TNF-alpha monoclonal antibody developed tumors similar to parental J558L cells. Similarly, the tumor-suppressive effects of TNF-alpha were abolished, e.g., by injection of an anti-type 3 complement receptor (CR3) monoclonal antibody that is known to prevent migration of inflammatory cells. These results and the observation of tumor-infiltrating macrophages suggest that lack of tumorigenicity of J2T12 cells is due to the TNF-alpha secretion by the tumor cells and that TNF-alpha acts indirectly by a mechanism that involves chemotactic recruitment and activation of cells, predominantly of macrophages. In contrast, the tumor growth was not affected when, instead of TNF-alpha, interleukin 6 was expressed by J558L cells. Together, our results support the concept of tumor cell-targeted cytokine gene transfer as a tool for cancer treatment, and particularly demonstrate that extremely low doses of TNF-alpha produced by tumor cells are sufficient to inhibit tumor growth without detectable side effects.

Alkaline Phosphatase↗
PubMed1986

The augmentation of tumor-specific immunity by virus help. III. Enhanced generation of tumor-specific Lyt-1+2- T cells is responsible for augmented tumor immunity in vivo.

The role of vaccinia virus-reactive helper T cells (Th) in augmenting in vivo generation of antitumor protective immunity and the Ly phenotype mediating the enhanced in vivo tumor immunity were investigated. C3H/HeN mice were inoculated i.p. with viable vaccinia virus to generate vaccinia virus-reactive Th activity. The mice were subsequently immunized i.p. with virus-infected syngeneic X5563 and MH134 tumor cells, and spleen cells from these mice were tested for in vivo tumor neutralizing activity. Immunization of virus-primed mice with virus-uninfected tumor cells and of virus-unprimed mice with virus-infected tumor cells failed to result in in vivo protective immunity. In contrast, spleen cells from mice immunized with virus-infected tumor cells subsequent to virus-priming exhibited potent tumor-specific neutralizing activities. Such an augmented generation of in vivo protective immunity was accompanied by enhanced induction of tumor-specific cytotoxic T lymphocyte (CTL) and antibody activities in X5563 and MH134 tumor systems, respectively. However, analysis of the effector cell type responsible for in vivo tumor neutralization revealed that enhanced in vivo immunity was mediated by Lyt-1+2- T cells in both tumor systems. Moreover, the Lyt-1+2- T cells exerted their function in vivo under conditions in which anti-X5563 tumor-specific CTL or anti-MH134 tumor-specific antibody activity was not detected in recipient mice. These results indicate that augmenting the generation of a tumor-specific Lyt-1+2- T cell population is essential for enhanced tumor-specific immunity in vivo.

Animals↗
PubMed1987

The tumor bed effect: dependence of tumor take, growth rate, and metastasis on the time interval between irradiation and tumor cell transplantation.

Experiments were designed to investigate the influence of time interval between leg irradiation and tumor cell transplantation on 3 different aspects of the tumor bed effect (TBE): tumor take, growth rate, and metastasis formation. MCA-4 tumor cells were injected subcutaneously into the legs of syngeneic C3Hf/Kam mice that had been locally irradiated with 30 Gy gamma rays 1, 50, 100, or 200 days previously. Interim TD50 values were higher in the day 1, 50, and 100 preirradiated mice than in controls for about 100 days after tumor cell transplantation. However, the final TD50 values determined 220 days after cell transplantation were marginally lower than controls in the day 1, and 50 preirradiated groups. TD50 values in the day 200 preirradiated group were similar to those of controls at all times after tumor cell injection. Retardation of tumor growth rate was observed in all preirradiated groups, but with a progressive decrease in effect as the time between irradiation and tumor cell injection was increased. In the day 200 preirradiated group it was noted that the degree of tumor growth rate retardation decreased as the number of injected tumor cells was increased. The incidence of lung metastases when the "primary" tumor reached a size of 20 mm was higher than in controls in mice irradiated 1, 50, and 100 days before tumor cell injection, but not in the 200-day preirradiated group. Thus, in this tumor system TBE influences tumor take, growth rate, and lung metastasis formation differently; but for all parameters, the effect decayed with increasing time between irradiation and tumor cell transplantation.

Animals↗
PubMed2005

Detection of circulating tumor cells and of tumor DNA in plasma during tumor progression in rats.

The role and clinical significance of circulating tumor cells and of tumor DNA in the plasma have not yet been clarified. In the present study, we compared rates of detection of tumor-derived DNA in the buffy coat to those in plasma from tumor-bearing rats, and we attempted to correlate these rates with the progression of tumors. We injected DHD/K12-PROb cancer cells subcutaneously into BD-IX rats and divided the animals into six groups according to the time between the injection of tumor cells and euthanasia. After euthanasia, macroscopic metastases were assessed and samples of blood and lung were collected. We used mutant allele-specific amplification by PCR to detect tumor-derived DNA. We detected tumor DNA in lung samples from the first week after inoculation, in plasma from the third week and in the buffy coat from the fifth week. All animals analyzed on the 11th week had macro- or micrometastases in their lungs. Regardless of group, the rate of PCR-positive plasma samples was significantly higher than that of circulating tumor cells (P=0.005). In animals with metastases, this difference was also statistically significant (P=0.008). However, neither the detection of tumor DNA in the plasma nor the presence of circulating tumor cells was strongly correlated with the presence of metastases. Thus, cell-free tumor DNA was detected sooner and more frequently than circulating tumor cells and the dissemination of tumor DNA in the plasma seems to be much more common than detectable hematogenic tumor cells during the spread of colorectal cancer.

Animals↗
PubMed2001

Respiratory-driven lung tumor motion is independent of tumor size, tumor location, and pulmonary function.

PURPOSE: To determine whether superior-inferior lung tumor motion is predictable by tumor size or location, or pulmonary function test results. METHODS AND MATERIALS: Superior-inferior tumor motion was measured on orthogonal radiographs taken during simulation of 22 patients with inoperable lung cancer diagnosed by orthogonal radiographs. RESULTS: The tumor size averaged 5.5 +/- 3.1 cm (range 1.5-12 cm). Seven of 11 central tumors demonstrated some motion compared with 5 of 11 peripheral tumors. Four of 5 upper lobe tumors moved compared with 8 of 17 tumors that were either middle or lower lobe lesions. The mean fourth rib motion was 7.3 +/- 3.2 mm (range 2-15). The mean FeV(1) was 1.8 +/- 1.2 (range 0.55-5.33. The mean diffusing capacity of the lung for carbon monoxide was 14.0 +/- 6.5 (range 7.8-21.9). The mean total lung capacity was 6.5 +/- 1.2 (range 3.3-8.4). None of these parameters correlated with tumor motion. Although lateral tumor motion could not be consistently determined, 1 tumor moved 10 mm anterior-posteriorly. CONCLUSIONS: Lung tumors often move significantly during respiration. Tumor motion is not predictable by tumor size or location, or pulmonary function test results. Therefore, tumor motion must be measured in all patients. Measurement in three dimensions will likely be necessary to maximize the irradiated lung volumes or choose beam arrangements parallel to the major axis of motion.

Adult↗
PubMed2000

Tumor-induced immunosuppression: a barrier to immunotherapy of large tumors by cytokine-secreting tumor vaccine.

An active immunotherapy strategy with cytokine-assisted tumor vaccine, although often effective for small tumor burdens, is much less so for large tumor burdens. This study examines how large tumors might suppress the T cell functions and escape from the immune responses elicited by a granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccine. According to our results, the T cells isolated from the tumor-bearing mice treated late with the vaccine failed to confer protective activity on naive mice against a wild-type tumor challenge, unlike those isolated from the early-treated group. Nevertheless, the antitumor activity of the inactive T cells could be restored on in vitro stimulation. Expression of transforming growth factor beta (TGF-beta) and interleukin 10 (IL-10), the potent immunosuppressive factors, was detected in the parental tumor cell line RLmale 1 (a murine T leukemia cell line), as well as in the tumor region, the levels of which correlated with tumor progression. An in vitro assay of T cell functions revealed that the TGF-beta in the conditioned medium of RLmale 1 cells mainly affected the activation, whereas the IL-1male affected the activation to a lesser extent, but significantly affected the cytolytic activity, of tumor-specific T cells. The immunosuppressive activity of IL-10 was also signified by the findings that administration of the conditioned medium of RLmale 1 cultured in a serum-free medium, in which the TGF-beta activity was then lost while the IL-10 activity still remained, or of recombinant IL-10 to the early-treated group of mice abrogated the known efficacy of tumor vaccine on the small tumors. These data suggested that the efficacy of cytokine-secreting tumor vaccine was blocked by the immunosuppressive factors secreted from the large tumors. The results have important implications for the clinical design of immunotherapeutic strategies for advanced cancer patients.

Animals↗
PubMed2006

Surgery and hematogenous dissemination: comparison between the detection of circulating tumor cells and of tumor DNA in plasma before and after tumor resection in rats.

BACKGROUND: To examine the effects of the surgical manipulation of tumors on the hematogenous dissemination of tumors, we compared rates of detection of tumor-derived DNA in the buffy coat and in plasma from tumor-bearing rats before and after tumor resection. METHODS: We injected DHD/K12-PROb cells subcutaneously into BD-IX rats. Three weeks later, we removed the tumors surgically. Group PERI was sacrificed 3 hours after surgery, group POST-2 was sacrificed 2 weeks later, group POST-4 was sacrificed another 2 weeks later, and group POST-LONG was sacrificed when rats were close to death. In group PERI, four perioperative blood samples were taken. In the other groups, only one blood sample was taken per rat, immediately before euthanasia. We used polymerase chain reaction to detect tumor-derived DNA in buffy-coat, plasma, and lung samples. RESULTS: In group PERI, tumor DNA in plasma was more frequent than circulating tumor cells at all perioperative time points. The difference was statistically significant 3 hours after surgery (P = .035). In group POST-2, there was no detectable metastasis or tumor DNA in blood samples. There were lymphatic and lung metastases in most animals in group POST-4 and in all animals in group POST-LONG. In the last two groups, the frequencies of tumor DNA in the buffy coat and in plasma were similar. CONCLUSIONS: In our animal model, the hematogenous dissemination of tumors due to surgery seemed to be more closely related to tumor-derived cell-free DNA than to circulating tumor cells. In addition, the surgical resection of primary tumors did not inhibit the development of metastases.

Animals↗
PubMed2001

Human accessory cells activate fresh, normal, tumor-distant T lymphocytes but not tumor-infiltrating T lymphocytes to lyse autologous tumor cells in a primary cytotoxic T lymphocyte assay in renal cell carcinoma.

OBJECTIVES: Search for an ideal responder T-lymphocyte source for adoptive T-lymphocyte therapy in renal cell carcinoma (RCC). METHODS: Cytotoxic T-lymphocyte (CTL) activity of (a) normal, tumor-distant, renal T lymphocytes, (b) tumor-infiltrating T lymphocytes and (c) peripheral blood T lymphocytes against autologous tumor epithelial cells (EC) of 10 patients with organ-confined, primary RCC was analyzed in a primary CTL assay. Freshly enriched T lymphocytes were cultured with or without autologous, mitomycin-C-treated normal or tumor EC in the presence or absence of antigen-presenting cells (APC) for 7 days. RESULTS: Both tissue T-lymphocyte populations displayed a similar CD4:CD8 ratio (1:1). Elevated CD62L coexpression of CD4+ T lymphocytes in normal, tumor-distant, renal tissue resulted in a significantly higher transient T-cell activation than that seen in renal tumor tissue (46 vs. 27%; p = 0.002). All trials to induce significant lysis of autologous, renal tumor EC in tumor-infiltrating and peripheral blood T lymphocytes failed. Only when normal, tumor-distant, renal T lymphocytes were stimulated by autologous APC and tumor EC was significant autologous tumor EC lysis obtained (mean 14%; p<0.05). Costimulation by anti-CD3 (mean 21%; p<0.05) or interleukin-2 (mean 31%; p<0.05) further increased tumor EC lysis significantly. CONCLUSIONS: Increased turnover of T lymphocytes in normal, tumor-distant, renal tissue was associated with a higher yield of pre-CTL which can be transformed into a functionally active effector T-cell pool by stimulation via antigen plus APC. Thus, tumor-distant renal tissue has to be included in the tissue-sampling procedure for adoptive immunotherapy.

Antigen-Presenting Cells↗