Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several strategies have been used to stimulate the growth of tumor-specific T cells in place of tumor antigen. One approach is to use pharmacologic agents to activate the second messenger pathways of T-cell activation. In the present study, we examined the ability of the protein kinase C activator bryostatin 1 (B) plus the calcium ionophore ionomycin (I) to stimulate the growth of lymphocytes obtained from the axillary lymph nodes (DLN) draining a progressively growing intradermal plasmacytoma tumor. Draining lymph node cells were initially cultured with autologous tumor cells and 20 U/ml of interleukin-2 (IL-2) for 7 days. The lymphocytes were then incubated with various concentrations of bryostatin 1 plus 1 microM ionomycin and cultured for an additional 14 days in IL-2. DLN cells initially cultured with autologous tumor and then restimulated with 5 nM bryostatin 1 and 1 microM ionomycin exhibited marked in vitro proliferation and 15-fold expansion of cell numbers over 2 weeks. The cells expanded with B/I were predominantly CD8+ T cells and retained specific in vitro cytotoxicity against autologous tumor. When adoptively transferred to mice with established liver metastases, DLN cells restimulated with B/I-mediated specific tumor regression.
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PMID:Bryostatin 1 activates T cells that have antitumor activity. 150 56

Adoptive immunotherapy in humans may be limited by the lack of autologous tumor cells to activate and expand tumor-specific T cells. Pharmacologic manipulation of protein kinase C (PKC) and intracellular calcium may substitute for tumor antigen and stimulate T cells for adoptive immunotherapy. In the present study, we evaluated the ability of the PKC activator Bryostatin 1 (B) plus the calcium ionophore ionomycin (I) to activate lymphocytes obtained from popliteal lymph nodes (DLN) draining an MCA-105 footpad tumor. The adoptive transfer of B/I-stimulated DLN cells eradicated MCA-105 pulmonary metastases. These lymphocytes do not require concomitant IL-2 administration to mediate regression of lung metastases. Three days after intrasplenic injection of tumor cells and splenectomy, mice were given iv injections of B/I-stimulated DLN cells. Adoptive immunotherapy with these cells induced regression of established liver metastases. In an intradermal tumor model, the adoptive transfer of B/I-stimulated MCA-105 DLN cells cured mice of MCA-105 intradermal (id) tumors, but did not induce regression of MCA-206 tumors. Mice cured of MCA-105 id tumors were protected against MCA-105, but not MCA-203, tumor challenge in the footpad 7 weeks after adoptive immunotherapy.
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PMID:Bryostatin 1-activated T cells can traffic and mediate tumor regression. 152 28

A Phase Ib trial of bryostatin 1, a macrocyclic lactone and protein kinase C (PKC) activator, was conducted in patients with refractory nonhematological malignancies with the primary goal of determining whether down-regulation of peripheral blood mononuclear cell (PBMNC) PKC activity could be achieved in vivo in humans. Patients (four patients/cohort) received bryostatin 1 (25 microg/m2) as a 1-h infusion weekly three times every 4 weeks, but to study the schedule dependence of pharmacokinetics and pharmacodynamics, the first dose was administered according to one of three schedules: (a) a 1-h infusion; (b) a 24-h infusion; or (c) a split course (12.5 microg/m2 as a 30-min infusion) on days 1 and 4. Conventional toxicities (grades I-III) included myalgias, fever, anemia, fatigue, phlebitis, and headache; in addition, two patients in cohort 3 experienced transient elevations in liver function tests, although these patients had preexisting liver metastases. No objective clinical responses were encountered. Effects on PBMNC PKC activity were heterogeneous. Several patients in cohorts 1 and 2 experienced significant declines in activity (approximately 50%) that were sustained in some cases for periods of > or = 72 h. Comparison of 72-h with baseline values for all three patient cohorts combined revealed a trend toward PKC down-regulation (P = 0.06; signed rank test). For each schedule, plasma bryostatin 1 levels were below the level of detection of a platelet aggregation-based bioassay (3-4 nm). Bryostatin 1 administration failed to produce consistent alterations in lymphocyte immunophenotypic profiles, interleukin 2-induced proliferation, or cytotoxicity, although two of three samples from patients in cohort 3 did show significant posttreatment increases in proliferation. Moreover, in some patients, bryostatin 1 treatment increased lymphokine-activated killer cell activity. These findings indicate that bryostatin 1 doses of 25 microg/m2 can induce in vivo PBMNC PKC down-regulation in at least a subset of patients and raise the possibility that higher bryostatin 1 doses may be more effective in achieving this effect.
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PMID:Phase Ib trial of bryostatin 1 in patients with refractory malignancies. 953 28

Trefoil factors (TFFs) are protease-resistant peptides that promote epithelial cell migration and mucosal restitution during inflammatory conditions and wound healing in the gastrointestinal tract. To date, the molecular mechanism of TFFs action and their possible role in tumor progression are unclear. In the present study, we observed that premalignant human colonic PC/AA/C1 and canine kidney MDCK epithelial cells are not competent to invade collagen gels in response to exogenously added TFFs (pS2, spasmolytic polypeptide, and intestinal trefoil factor). In contrast, activated src and RhoA exert permissive induction of invasion by the TFFs that produce similar parallel dose-response curves in src-transformed MDCKts.src and PCmsrc cells (EC50=20-40 nM). Cell scattering is also induced by TFFs in MDCKts.src cells. Stable expression of the pS2 cDNA promotes constitutive invasiveness in MDCKts.src-pS2 cells and human colonic HCT8/S11-pS2 cells established from a sporadic tumor. Furthermore, we found that TFF-mediated cellular invasion is dependent of several signaling pathways implicated in cell transformation and survival, including phosphoinositide PI3'-kinase, phospholipase C, protein kinase C, and the rapamycin target TOR. Constitutive and intense expression of pS2 was revealed by Western blot analyses and immunohistochemistry in human colorectal tumors and their adjacent control mucosa during the neoplastic progression, from the adenoma to the liver metastases. Our studies indicated that TFFs can be involved in cell scattering and tumor invasion via autocrine loops and may serve as potential targets in the control of colon cancer progression.
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PMID:Induction of scattering and cellular invasion by trefoil peptides in src- and RhoA-transformed kidney and colonic epithelial cells. 1115 51

The purpose of the study was to determine whether the organ environment can influence the response of colon cancer cells to chemotherapy. The highly metastatic human colon cancer cell line KM12L4, previously selected for production of liver metastases in nude mice, was injected into the cecal wall and into the spleen to produce liver metastases, and into the subcutis of nude mice. Doxorubicin (DOX) at 10 mg/kg or saline (control) was injected intravenously on days 7 and 16 after tumor cell injection. The in vivo response of tumors growing in the cecum, liver, and subcutaneous (s.c.) sites as well as the DOX sensitivity of cell lines established from liver and s.c. tumors were compared. Colon cancers growing s.c. were more sensitive to DOX than tumors growing in the cecal wall or liver of nude mice. The difference in response to DOX between s.c. tumors (sensitive) and liver tumors (resistant) was not due to selection of cell populations with different sensitivity to DOX, or differences in DOX distribution. PKC activity was lower in tumors of the liver and the cecum than in s.c. tumors. The expression of P-glycoprotein as determined by flow cytometric analysis of tumor cells harvested from lesions in different organs correlated inversely with their sensitivity to DOX. Increased levels of P-glycoprotein correlated with mdr-1, mdr-3 mRNA expression as determined by Northern analysis. Collectively, the data show that the organ environment influences the response of human colon carcinoma cells to DOX and recommend that animal models of this disease for experimental therapeutic studies employ orthotopic implantation of tumor cells.
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PMID:Modulation of Doxorubicin sensitivity and level of p-glycoprotein expression in human colon-carcinoma cells by ectopic and orthotopic environments in nude-mice. 2157 80