Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gut-associated lymphoid cells are modulated by several gut hormones. We postulated that lymphokine-associated-killer (LAK) cell cytotoxicity of lymphocytes isolated from the gut mucosa may be increased by substance P (SP). Intestinal lamina propria mononuclear cells (LPMC) and colonic cancer cells were isolated from operative specimens by successive mechanical and enzymatic dissociation methods. Effector LAK cells were induced by culturing LPMC with recombinant interleukin-2 at a concentration of 250 U/ml. Substance P (10(-5) M) was added to the culture medium. Targets consisted of fresh colon cancer cells, HT-29 (cultured human colon cancer cell line), and control cell lines. After 4 days of incubation, cytotoxicity was measured using a 4-h 51Cr release assay. LAK cells alone showed moderate cytotoxicity against HT-29 and none against fresh colon cancer cells. LAK cells generated in the presence of substance P showed moderate cytotoxicity against HT-29 and strong cytotoxicity against fresh colorectal cancer cells. The percentage of cytotoxicity +/- SEM at various effector to target ratios was [(*) denotes P < 0.05 compared with above]: [table: see text] We conclude that substance P significantly increases LAK cell cytotoxicity against fresh colon cancer cells, but not against cultured cells.
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PMID:Substance P increases in vitro lymphokine-activated-killer (LAK) cell cytotoxicity against fresh colorectal cancer cells. 127 74

Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) widely used for treatment of inflammatory arthritis. Recent experimental and clinical studies suggest that piroxicam, as well as other NSAIDs, may be useful for chemoprevention of colon cancer. While there is less information regarding NSAIDs for chemoprevention of urinary bladder malignancy, there are compelling data which suggest that this should be evaluated. A major effect of NSAIDs is inhibition of cyclooxygenase, the rate-limiting enzyme for conversion of arachidonic acid to important signal molecules, including prostaglandins, which profoundly affect cellular functions in many tissues. The initial enzyme reaction leading to formation of prostaglandin H can be accompanied by cooxidation of xenobiotics resulting in extrahepatic and local tissue production of reactive products which are carcinogenic. The end product prostaglandins, especially prostaglandin E2 (PGE2), are biological modifiers which can significantly affect cell proliferation and tumor growth. High levels of PGE2 stimulate growth of certain tumor cell lines while inhibition of prostaglandin synthesis with indomethacin or piroxicam can cause suppression. The mechanisms for this effect are unclear. Studies in cultured cells exposed to indomethacin show inhibition of G1-to-S phase progression of the cell cycle and a reduction in overall DNA synthesis. It is unclear whether this effect on cell growth results from some direct action of the NSAID or a reduction in prostaglandins or indirectly from modulation of important control signals, such as calcium flux. In addition to cyclooxygenase, NSAIDs can inhibit activity of other enzymes, including phosphodiesterases and cyclic GMP-AMP protein kinases, which may be central to cancer initiation and promotion. NSAIDs can also interfere with transmembrane ion fluxes and with cell-to-cell binding. Prostaglandins can modulate a variety of immunological responses and thereby play an important role in host antitumor immunity. For example, high levels of tissue PGE2 are frequently associated with suppression of immune surveillance and killing of malignant cells. Conversely, immune responses are generally enhanced by drugs that inhibit prostaglandin synthesis. PGE2 can act as a feedback inhibitor for cellular immune processes, such as T-cell proliferation, lymphokine production, and cytotoxicity. This effect is also seen for macrophage activity and natural killer cell toxicity. In general, either increased production of PGE2 or increased sensitivity to normal amounts of PGE2 results in depressed cellular immunity. Cyclooxygenase inhibitors (NSAIDs) such as piroxicam which decrease PGE2 production can stimulate cellular immune function both in vitro and in vivo. A variety of tumor cell lines and human malignancies produce large quantities of prostaglandins.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Piroxicam and other cyclooxygenase inhibitors: potential for cancer chemoprevention. 130 81

Specific and nonspecific stimulation of the host immune system to reject cancer is an attractive concept that is just beginning to mature. Results with crude extracts and nonspecific immune stimulation have been variable. However, the recent observations of improved survival after administration of levamisole plus 5-fluorouracil in the adjuvant setting have made an impact on the treatment of colorectal cancer. Animal studies consistently show that immune therapies are most effective for disease that is not advanced. Thus, the small benefit seen with levamisole, a low toxicity immunomodulator, suggests that much more impressive results can be anticipated with more potent and specific agents. Postsurgical autologous tumor cell vaccine has been effective in some prospective randomized trials; in others, no benefit was found. The identification and purification of allogeneic tumor-associated antigens has lead to enhanced antigen-specific host cell-mediated immunity; this may result in more consistent antitumor effects. The current development of chemically defined immune adjuvants of low toxicity allows tumor-specific immune stimulation to be tested in high-risk apparently healthy patients after resection of colorectal cancer (Stages II and III). The influx of information regarding immune cell populations, cell-surface markers, and cytokines has fostered extensive exploration of lymphocyte stimulation, in vitro cell growth and expansion, and in vivo evaluation in patients with advanced cancer. Modest tumor response rates have been documented with adoptive transfer of lymphokine-activated killer cells and interleukin-2. Improved results are anticipated with the more potent tumor-infiltrating lymphocytes and specific in vitro sensitization of draining lymph node cells to autologous and allogeneic tumor antigens. Murine monoclonal antibodies specific for cell-surface markers, such as carcinoembryonic antigen, have been tested for their value in the diagnosis and therapy of colorectal cancer. A small response rate has been seen with single and multiple injections of C017-1A, a monoclonal antibody specific for colonic and pancreatic cancer. The development of antiidiotypic antibodies in these patients may have been important in those that responded to this type of therapy. However, laboratory evidence suggests that monoclonal antibody conjugated to a cytotoxic agent (i.e., radionuclide, drug, or toxin) should be much more effective. Radioimmunotherapy trials in the nude mouse model bearing human colon cancer xenografts showed good tumor incorporation of the radionuclide (yttrium 90 or iodine 131), inhibition of tumor growth, and long-term survival.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Immunotherapy of colorectal cancer. 151 94

A soluble substance (HT29 factor) produced by HT29 colon cancer cells markedly suppresses mitogen-induced T-cell proliferation and interleukin-2 production. In this study the range of T-cell functions susceptible to the inhibitory effects of the HT29 factor was evaluated. Serum-free conditioned medium was collected from confluent cultures of HT29 cancer cells, concentrated, and subjected to gel filtration chromatography and anion exchange chromatography, resulting in 24.4-fold purification of the HT29 factor with 31% yield. This factor abolished the development of lymphokine-activated killer cells when present during activation of peripheral blood lymphocytes by interleukin-2 but did not affect the lysis of target cells by normal effectors when added in the lysis stage only. The HT29 factor did not affect the generation of concanavalin A-induced suppressor lymphocytes, even though it markedly inhibited synthesis of DNA, RNA, and protein as well as expression of the CD25 (Tac) antigen during mitogen activation of T-cells. The HT29 factor itself did not induce suppressor cells. These results indicate that the immunosuppressive action of the HT29 factor is selective.
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PMID:Selective immunosuppressive action of a factor produced by colon cancer cells. 169 19

Pretreatment of human colon cancer LoVo-H cells and human breast cancer ZR-75 1A cells with low doses of verapamil, a Ca2+ channel blocker, for 48 h has a slight growth stimulatory effect and substantially increases cell sensitivity to lymphokine-activated killer (LAK) mediated cytotoxicity in the standard 51Cr release assay. The role of intracellular Ca2+ levels in determining verapamil effect is demonstrated by cytochemical evidence of intracellular Ca2+ lowering in verapamil-treated cells and by the reversal by the Ca2+ ionophore A-23187 of verapamil-induced sensitivity to LAK-mediated cytotoxicity.
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PMID:Verapamil upregulates sensitivity of human colon and breast cancer cells to LAK-cytotoxicity in vitro. 183 54

The tumoricidal properties of an anti-human colon carcinoma monoclonal antibody (MAb), designated D612 (IgG2a), alone and in combination with IL-2-activated human lymphocytes were investigated in athymic mice bearing LS-174T colon tumor xenografts. Treatment of mice bearing LS-174T tumors (1 day, s.c.) with a single i.v. dose of 400 micrograms of D612 alone resulted in a significant inhibition of tumor growth. Lower doses of D612 had an intermediate effect on tumor growth. Similar inhibition of tumor growth was obtained when D612 was administered in three doses of 400 or 800 micrograms each during the first week after tumor implantation. Mouse macrophages but not splenocytes mediated antibody-dependent cellular cytotoxicity with D612, suggesting that tumor inhibition was due to the participation of host macrophages with D612. Human lymphokine-activated killer (LAK) cells were generated by incubating human peripheral blood mononuclear cells (PBLs) from normal donors with 100 U/ml of IL-2 for 24 h. An administration of human LAK cells did not significantly inhibit the growth of the human xenograft tumor. Adoptive transfer of a single dose of human LAK cells (2 x 10(7), i.v.) into mice treated with a suboptimal dose of D612 (200 micrograms) significantly inhibited tumor growth compared to that obtained with either D612 or LAK cells alone. Similar results were obtained with three doses of D612 plus human LAK cells although there was a tendency for multiple doses of LAK cells alone to show some antitumor effects. LAK cells or PBLs had similar antitumor activities when used in conjunction with D612. When larger established tumors were treated, single or multiple doses of D612 or LAK cells alone were without effect; however, LAK cells plus D612 elicited significant growth inhibition. These results demonstrate that the tumoricidal properties of LAK cells and the D612 MAb can be augmented when used together in the immunotherapy of human colon cancer xenografts.
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PMID:Human lymphokine-activated killer cells augment immunotherapy of human colon carcinoma xenografts with monoclonal antibody D612. 201 97

A poorly immunogenic murine colon cancer was used to investigate mechanisms of antitumor immunity. Injection of tumor cells engineered by gene transfection to secrete IL-2 stimulated an MHC class I-restricted cytolytic T lymphocyte (CTL) response against the parental tumor. The tumor cells secreting IL-2 produced an antitumor response in vivo, even in the absence of CD4+ T cells. Animals immunized with the engineered cells were protected against subsequent challenge with the parental tumor cell line. Similar findings were demonstrated for other tumor types. Thus, provision of a helper lymphokine in a paracrine fashion induced a tumor-specific immune response involving activation of endogenous CTLs and other immune effector cells. These findings demonstrate that the failure of an effective antitumor immune response may be primarily due to a helper arm deficiency of the immune system rather than a paucity of tumor-specific cytotoxic effector cells. Furthermore, they outline a novel strategy for augmenting tumor immunity.
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PMID:Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. 213 72

Incubation of peripheral blood mononuclear cells with interleukin-2 (IL-2) results in the release of a factor which is cytostatic and cytotoxic both to tumor cell lines (A375M, A375P, C480, MCF-7, Hey) and fresh tumor cells (in the human tumor cloning assay), including breast cancer, colon cancer, melanoma, myeloma and ovarian cancer. The factor cannot be detected in a 4-h chromium-release assay, but is best demonstrated after tumor cells have been to it for exposed 3 days. The factor is not cytotoxic to normal peripheral blood leukocytes or normal fibroblasts, and is not toxic to certain targets sensitive to lymphokine-activated killer (LAK) cells, such as K562 and Daudi cells. The factor is diffusible, non-dialyzable, relatively stable to heat and acid and does not contain appreciable amounts of targets resistant to interferon-alpha and beta, tumor necrosis factor beta and interleukin-1. The data suggest that there are several mechanisms of LAK cell activity against tumor cells including one which requires direct interaction of LAK and tumor cells and one which is mediated by LAK cell supernatant. The former is detected by 4-h chromium release while the latter is not.
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PMID:Cytostatic and cytotoxic activity of lymphokine-activated killer cell supernatants. 248 Aug 43

Twenty-five patients with disseminated cancer (nine with renal cell carcinoma, five with melanoma, three with Hodgkin's lymphoma and chronic myelocytic leukemia [CML], two with soft tissue sarcoma, one each with large-cell lymphoma, breast cancer, and colon cancer), 13 males and 12 females, aged 25 to 68, were treated with recombinant human interleukin-2 (rIL2) by continuous infusion and adoptive transfer of autologous lymphocytes activated in vitro with IL2. Patients underwent leukapheresis on days 1, 8, 15, and 22 of the treatment. Cells, bulk activated for 20 hours in serum-free culture medium with 1,000 U IL2/mL in transfusion transfer packs as culture vessels, were transfused the following day. The infusion of IL2 by continuous infusion for six days started immediately after each adoptive transfer for 4 weekly courses. The dose of IL2 was escalated weekly in each patient; starting doses of IL2 were also escalated in subsequent cohorts of patients until maximally tolerated doses were reached. Nine patients had objective tumor regressions (three with renal cell cancer, two with Hodgkin's lymphoma, and one each with melanoma, sarcoma, breast, and colon cancer). Six responses were partial, two were minor, and one was mixed. Responding patients were maintained with IL2 by continuous infusion for six days every 6 to 8 weeks, without adoptive cell transfer. The median duration of responses was 16 weeks (3 to 60 + weeks). Tumor regression was related to the dose of IL2 (greater than or equal to 3.4 x 10(6) U/m2/d for six days) and to the in vivo lymphoproliferative effects of the lymphokine, but not to the total number of cells adoptively transferred. Side effects of treatment were transient and quickly reversible. Renal, hepatic dysfunction, and dyspnea were directly related to the dose of IL2 and to lymphocytosis. Other toxicities were mild hypotension with mild fluid retention, oral mucositis, anemia, thrombocytopenia, fever, and fatigue.
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PMID:Recombinant interleukin-2 by continuous infusion and adoptive transfer of recombinant interleukin-2-activated cells in patients with advanced cancer. 266 33

Murine monoclonal antibodies (MAB) of the IgG3 subclass generated to colorectal tumor-associated glycolipids were assessed for enhancement of antibody-dependent cell-mediated cytotoxicity (ADCC) by interleukin 2 (IL-2). Mononuclear cell preparations containing large granular lymphocyte effectors required only low doses of IL-2 (0.1-10 units/ml) and short exposure (3 h) for maximal enhancement of ADCC. Exposure of mononuclear cells for longer periods (1-6 days) to higher levels of IL-2 (100-1000 units/ml) resulted in the generation of lymphokine-activated killer N cells which were lytically active without antibody. A non-ADCC MAB of the IgG1 subclass showed no ADCC even after stimulation of effector cells with IL-2. Effector cells pretreated with IL-2 showed an enhanced rate of cytolysis of target cells in the presence of antibody. Pretreatment of effector cells with IgG3 MAB resulted in lower ADCC, but pretreatment of target cells or simultaneous addition of MAB and effectors to target cells gave higher levels. These results indicated that ADCC with murine IgG3 is enhanced by levels of IL-2 achievable in current patient trials. The combination of antibody and IL-2-boosted effector cells gives comparable levels of killing to lymphokine-activated killer cells but should not suffer from similar toxicity. The NR-Co-04 antibody in combination with lymphokine may prove effective in treating colon cancer, a disease for which both chemotherapeutic and current biological therapies suggest a need for improved forms of therapies.
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PMID:Murine monoclonal IgG3 to human colorectal tumor-associated antigens: enhancement of antibody-dependent cell-mediated cytotoxicity by interleukin 2. 278 37


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