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1.
Breast Cancer Res Treat ; 47(1): 57-62, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9493976

ABSTRACT

MDA-468 human breast cancer cells overexpress the EGFR and exhibit a functional TGFalpha-EGFR autocrine pathway. Loss of EGFR expression following stable transfection with an antisense EGFR cDNA containing plasmid down-regulates type I cAMP-dependent protein kinase (PKAI) expression with acquisition of cell growth resistance to the PKAI inhibitor 8-Cl-cAMP. These results suggest that PKAI expression and function are controlled by a TGFalpha-EGFR autocrine pathway in human breast cancer cells overexpressing the EGFR.


Subject(s)
Breast Neoplasms/enzymology , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , DNA, Antisense/pharmacology , ErbB Receptors/physiology , 8-Bromo Cyclic Adenosine Monophosphate/analogs & derivatives , 8-Bromo Cyclic Adenosine Monophosphate/pharmacology , Cyclic AMP-Dependent Protein Kinases/genetics , Down-Regulation , ErbB Receptors/genetics , Female , Humans , Transfection , Transforming Growth Factor alpha/physiology , Tumor Cells, Cultured
2.
Cancer Res ; 57(22): 5107-11, 1997 Nov 15.
Article in English | MEDLINE | ID: mdl-9371510

ABSTRACT

8-Chloro-cAMP (8-Cl-cAMP) is a novel agent that is able to inhibit the growth of a wide variety of cancer cell types in vitro and in vivo and, at doses devoid of toxicity, to achieve plasma concentrations in cancer patients in a range effective for cancer cell growth inhibition. In this study, we have demonstrated that 8-Cl-cAMP, at a dose causing mild or no growth inhibition, synergistically increased the growth-inhibitory effect of paclitaxel or cisplatin in a wide series of cell lines including human breast, lung, ovary, colon, and head carcinomas and melanoma. A similar effect was also observed with another taxane, docetaxel, and with the platinum-derivative carboplatin. 8-Cl-cAMP also markedly enhanced apoptotic cell death induced by each cytotoxic drug. A cooperative antitumor effect was also observed in vivo, because treatment with paclitaxel followed by 8-Cl-cAMP markedly inhibited the growth of GEO human colon cancer xenografts as compared to paclitaxel alone without signs of toxicity. These data demonstrate that 8-Cl-cAMP synergistically increases the antiproliferative activity of taxanes and platinum-derived compounds and provide a rationale to use 8-Cl-cAMP in combination with taxanes and platinum-derived compounds.


Subject(s)
8-Bromo Cyclic Adenosine Monophosphate/analogs & derivatives , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cisplatin/pharmacology , Paclitaxel/pharmacology , Tumor Stem Cell Assay/methods , 8-Bromo Cyclic Adenosine Monophosphate/pharmacology , Animals , Apoptosis/genetics , Cell Division/drug effects , Drug Synergism , Female , G2 Phase , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Mitosis , Neoplasm Transplantation , Transplantation, Heterologous , Tumor Cells, Cultured/drug effects
3.
Clin Cancer Res ; 2(1): 207-14, 1996 Jan.
Article in English | MEDLINE | ID: mdl-9816108

ABSTRACT

The sensitivity of human tumor cells to activated lymphocytes is considered to play an essential role in the antitumor activity of recombinant interleukin-2 (rIL-2)-based immunotherapy. We have investigated the effects of several genes involved in the regulation of cell growth and transformation on the sensitivity of human mammary epithelial MCF-10A cells to non-MHC-restricted, rIL-2-activated lymphocytes. Therefore, the lysability of MCF-10A cells overexpressing activated oncogenes (Ha-ras, erbB-2, and a mutated p53), growth factors [transforming growth factor alpha (TGFalpha)], or cAMP-dependent protein kinase A subunits (RIalpha, RIIbeta, and Calpha) was evaluated comparatively at different effector:target ratios by a 51Cr release assay. Parental MCF-10A, MCF-10A p53-mutated, and MCF-10A RIIbeta cells showed an intermediate sensitivity. Lysability was increased significantly in MCF-10A Ha-ras, MCF-10A TGFalpha, and MCF-10A RIalpha cells, reduced in MCF-10A Calpha cells, and completely abrogated in MCF-10A erbB-2 cells. These differences could not be explained by simple changes in the cell surface expression of MHC class I and intercellular adhesion molecule-1 proteins or by secretion of TGFbeta. Treatment with TAb 250, a mouse anti-p185(erbB-2) monoclonal antibody, or down-regulation of p185(erbB-2) expression resulted in circumvention of MCF-10A erbB-2 cell resistance. We conclude that molecular changes at the single-gene level resulting in alterations of intracellular signaling and/or cell transformation modulate sensitivity of human mammary epithelial cells to non-MHC-restricted, rIL-2-induced cytotoxicity, regardless of MHC class I and/or intercellular adhesion molecule-1 expression or TGFbeta secretion. Furthermore, anti-p185(erbB-2) monoclonal antibodies may be useful as adjuncts to rIL-2 treatment in patients with erbB-2-overexpressing tumors.


Subject(s)
Breast Neoplasms/immunology , Cyclic AMP-Dependent Protein Kinases/physiology , Cytotoxicity, Immunologic , Genes, erbB-2 , Interleukin-2/pharmacology , Lymphocytes/immunology , Animals , Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Female , Histocompatibility Antigens Class I/analysis , Humans , Intercellular Adhesion Molecule-1/analysis , Killer Cells, Lymphokine-Activated/immunology , Mice , Recombinant Proteins/pharmacology , Transforming Growth Factor beta/biosynthesis , Tumor Cells, Cultured
4.
Clin Cancer Res ; 1(2): 161-7, 1995 Feb.
Article in English | MEDLINE | ID: mdl-9815969

ABSTRACT

8-Chloro-cyclic AMP (8-Cl-cAMP), a site-selective cAMP analogue, is a specific inhibitor of type I cAMP-dependent protein kinase (PKAI) and induces growth inhibition in several human and rodent tumor cell lines. The anti-epidermal growth factor receptor (EGFR) mAb 528 is a blocking antibody able to inhibit the in vitro and in vivo growth of several human cancer cell lines that express functional EGFRs. Since enhanced levels of PKAI are generally found in tumor cells and an increase in PKAI expression is induced by transformation through a transforming growth factor alpha/EGFR autocrine pathway, we have evaluated whether treatment with mAb 528 in combination with 8-Cl-cAMP may have an additive or synergistic growth inhibitory effect on human cancer cells. A dose-dependent inhibition of monolayer cell growth was observed in two human colon cancer cell lines (GEO and CBS) and in a human breast cancer cell line (MDA-468) by treatment with either mAb 528 or 8-Cl-cAMP with 50% inhibitory concentration of 2-10 microgram/ml or 20-25 micrometer, respectively. The combined treatment with low noninhibitory doses of mAb 528 (0.25 microgram/ml) and with 8-Cl-cAMP had a more than additive growth inhibitory effect with a 3- to 5-fold reduction in the 8-Cl-cAMP 50% inhibitory concentration in all cell lines tested. This combined treatment was similarly effective in inhibiting the soft agar cloning efficiency of GEO cells. 8-Cl-cAMP treatment of GEO cells induced a dose-dependent increase in cell membrane-associated EGFRs with a maximum 3- to 4-fold increase within 48-72 h of treatment. These results suggest that a double blockade of the PKAI serine-threonine kinase-dependent and of the EGFR tyrosine kinase-dependent pathways is potentially useful in cancer therapy.


Subject(s)
8-Bromo Cyclic Adenosine Monophosphate/analogs & derivatives , Antibodies, Monoclonal/toxicity , Antineoplastic Agents/toxicity , Breast Neoplasms/pathology , Cell Cycle/physiology , DNA Fragmentation/physiology , ErbB Receptors/immunology , 8-Bromo Cyclic Adenosine Monophosphate/toxicity , Cell Cycle/drug effects , Cell Division/drug effects , DNA Fragmentation/drug effects , Epidermal Growth Factor/metabolism , ErbB Receptors/analysis , ErbB Receptors/physiology , Female , Humans , Kinetics , Tumor Cells, Cultured
5.
Clin Cancer Res ; 1(1): 49-56, 1995 Jan.
Article in English | MEDLINE | ID: mdl-9815886

ABSTRACT

Topoisomerase II (Topo II) is an essential enzyme that catalyzes the breakage of double-strand DNA and is the target of several effective anticancer drugs, including the epipodophyllotoxins. The regulatory subunits of the cyclic AMP-dependent protein kinase are differentially expressed in normal and cancer cells. The RIalpha subunit is overexpressed in cells transformed by transforming growth factor-alpha (TGF-alpha) or Ha-ras oncogene. It has been shown that murine cells transformed by Ha-ras become hypersensitive to Topo II-targeting anticancer drugs. In this report we have tested whether any correlation exists between the expression of RIalpha protein and cellular sensitivity of Topo II-targeting drugs. Normal human breast MCF-10A cells and their derivatives overexpressing TGF-alpha, Ha-ras, or the different protein kinase subunits were treated with either Topo II inhibitors, such as etoposide, teniposide, or amsacrine, or with drugs which act independently of Topo II, such as bleomycin. Here we show that MCF-10A TGF-alpha and MCF-10A Ha-ras cells overexpress the RIalpha protein and become hypersensitive to epypodophyllotoxins and amsacrine but not to bleomycin. Direct introduction of the RIalpha gene into MCF-10A induces hypersensitivity to Topo II inhibitor drugs. In contrast, the overexpression of the other protein kinase subunits, RIIbeta or Calpha, does not modify the drug sensitivity of MCF-10A cells. No differences in the mRNA/protein content or in the activity of Topo II were found between hypersensitive cells and parental MCF-10A cells, suggesting that RIalpha may influence drug sensitivity via modulation of events downstream of the Topo II-DNA cleavable complex.


Subject(s)
Amsacrine/toxicity , Bleomycin/toxicity , Cyclic AMP-Dependent Protein Kinases/genetics , Etoposide/toxicity , Genes, ras , Teniposide/toxicity , Topoisomerase II Inhibitors , Transforming Growth Factor alpha/physiology , Breast Neoplasms , Cell Division/drug effects , Cell Survival/drug effects , Cyclic AMP-Dependent Protein Kinase Type II , Cyclic AMP-Dependent Protein Kinases/metabolism , DNA Topoisomerases, Type II/genetics , Female , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , Recombinant Proteins/metabolism , Transfection , Transforming Growth Factor alpha/genetics , Tumor Cells, Cultured
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