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2.
Br J Cancer ; 110(4): 875-81, 2014 Feb 18.
Article in English | MEDLINE | ID: mdl-24423921

ABSTRACT

BACKGROUND: We evaluated week-on/week-off axitinib dosing plus chemotherapy in patients with gastrointestinal tumours, including tumour thymidine uptake by fluorine-18 3'-deoxy-3'-fluorothymidine positron emission tomography ((18)FLT-PET). METHODS: During a lead-in period, patients received twice daily (b.i.d.) axitinib 7 mg (n=3) or 10 mg (n=18) for 7 days followed by a 7-day dosing interruption; serial (18)FLT-PET scans were performed before day 1 and on days 7, 10, and 14. Axitinib plus FOLFIRI or FOLFOX was then administered in 2-week cycles; axitinib was interrupted on day 10 of each cycle for 7 days. RESULTS: The maximum tolerated dose of axitinib was 10 mg b.i.d., in a week-on/week-off schedule, combined with FOLFIRI or FOLFOX. Common all-causality grade 3 adverse events were neutropenia (38%), hypertension (33%), and fatigue (29%). Of 21 patients, 2 (10%) had a partial response and 12 (57%) had stable disease. Following 7 days of continuous axitinib dosing, tumour (18)FLT uptake decreased -49% from baseline and recovered to -28% and -17% from baseline, respectively, after 3 and 7 days of axitinib interruption. CONCLUSION: Axitinib administered in a week-on/week-off schedule combined with FOLFIRI or FOLFOX is supported by (18)FLT-PET data and was well tolerated in patients with gastrointestinal tumours.


Subject(s)
Gastrointestinal Neoplasms/diagnostic imaging , Gastrointestinal Neoplasms/drug therapy , Imidazoles/administration & dosage , Indazoles/administration & dosage , Positron-Emission Tomography , Protein Kinase Inhibitors/administration & dosage , Adult , Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Axitinib , Bevacizumab , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Female , Fluorodeoxyglucose F18 , Fluorouracil/therapeutic use , Humans , Imidazoles/adverse effects , Indazoles/adverse effects , Leucovorin/therapeutic use , Male , Maximum Tolerated Dose , Middle Aged , Organoplatinum Compounds/therapeutic use , Protein Kinase Inhibitors/adverse effects , Radiopharmaceuticals , Withholding Treatment
5.
Cancer Gene Ther ; 14(2): 139-50, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17139321

ABSTRACT

We administered an adenoviral vector, Onyx-015, into the hepatic artery of patients with metastatic colorectal cancer involving the liver. Thirty-five patients enrolled in this multi-institutional phase I/II trial received up to eight arterial infusions of up to 2 x 10(12) viral particles. Hepatic toxicity was the primary dose-limiting toxicity observed in preclinical models. However, nearly 200 infusions of this adenoviral vector were administered directly into the hepatic artery without significant toxicity. Therefore, we undertook this analysis to determine the impact of repeated adenoviral exposure on hepatic function. Seventeen patients were treated at our institution, providing a detailed data set on the changes in hepatic function following repeated exposure to adenovirus. No changes in hepatic function occurred with the first treatment of Onyx-015 among these patients. Transient increases in transaminase levels occurred in one patient starting with the second infusion and transient increases in bilirubin was observed in two patients starting with the fifth treatment. These changes occurred too early to be explained by viral-mediated lysis of hepatocytes. In addition, viremia was observed starting 3-5 days after the viral infusion in half of the patient, but was not associated with hepatic toxicity. To further understand the basis for the minimal hepatic toxicity of adenoviral vectors, we evaluated the replication of adenovirus in primary hepatocytes and tumor cells in culture and the expression of the coxsackie-adenoviral receptor (CAR) in normal liver and colon cancer metastatic to the liver. We found that adenovirus replicates poorly in primary hepatocytes but replicates efficiently in tumors including tumors derived from hepatocytes. In addition, we found that CAR is localized at junctions between hepatocytes and is inaccessible to hepatic blood flow. CAR is not expressed on tumor vasculature but is expressed on tumor cells. Spatial restriction of CAR to the intercellular space in normal liver and diminished replication of adenovirus in hepatocytes may explain the minimal toxicity observed following repeated hepatic artery infusions with Onyx-015.


Subject(s)
Adenoviridae/genetics , Colorectal Neoplasms/therapy , Enterovirus/genetics , Liver Neoplasms/secondary , Liver/drug effects , Receptors, Virus/genetics , Adenoviridae/physiology , Cell Line, Tumor , Colorectal Neoplasms/diagnostic imaging , Colorectal Neoplasms/pathology , Genetic Vectors , Humans , Immunohistochemistry , Liver/diagnostic imaging , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/therapy , Tomography, X-Ray Computed , Viral Vaccines , Virus Replication
6.
Oncogene ; 15(22): 2735-42, 1997 Nov 27.
Article in English | MEDLINE | ID: mdl-9401000

ABSTRACT

Mice transgenic for the leukemia oncogene E2A-PBX1 invariably develop lethal, high-grade T-cell lymphomas by 5 months of age. In this study, retroviral insertional mutagenesis was employed to identify oncogenes that cooperate with the E2A-PBX1 transgene in lymphomagenesis. Neonatal retroviral infection substantially reduced length of survival due to accelerated development of lymphomas (81 versus 130 days). The Pim1 gene was targeted by retroviral insertions in 48% of accelerated lymphomas whereas less than 5% contained activated c-Myc and none contained activated Pim2. However, Pim1 DNA rearrangements were frequently sub-stoichiometric and not present at all sites of involvement in an otherwise monoclonal lymphoma indicating that Pim1 activation occurred late in the course of lymphomagenesis. Tumor subpopulations containing activated Pim1 alleles displayed a substantial growth advantage over Pim1 negative cells following serial transfer to secondary, syngeneic recipients. Cooperative interactions were observed in intercrossed Pim1 and E2A-PBX1 transgenic mice in which all double transgenic progeny developed lethal, diffuse T lineage lymphomas by 3 months of age, whereas only 13% of E2A-PBX1 and none of Pim1 single transgenic intercross progeny developed lymphomas by 1 year. Tumors from double transgenic mice were monoclonal providing evidence that additional genetic events were required for transformation. Therefore, Pim1 and E2a-Pbx1 cooperate in T lineage lymphomagenesis but they are not sufficient and the role of Pim1 is more likely to be associated with tumor progression.


Subject(s)
Homeodomain Proteins/metabolism , Lymphoma/genetics , Oncogene Proteins, Fusion/metabolism , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins/metabolism , Thymus Neoplasms/genetics , Animals , Cell Division/genetics , DNA Transposable Elements , Disease Progression , Gene Rearrangement , Homeodomain Proteins/genetics , Leukemia Virus, Murine/genetics , Lymphoma/virology , Mice , Mice, Transgenic , Mutagenesis , Neoplasm Transplantation , Oncogene Proteins, Fusion/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-pim-1 , Retroviridae/genetics , Transgenes
7.
J Interferon Res ; 12(2): 131-7, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1374455

ABSTRACT

Resistance to interferon-alpha (IFN-alpha) in the 38C13 B-lymphoma cell line results in the loss of antiviral, antiproliferative, and immune regulatory functions of IFN-alpha. Mutagenesis with ethylmethylsulfonic acid (EMS), which can induce point mutations in DNA, increases the frequency of resistance to IFN-alpha 20 to 40-fold. In contrast, treatment with 5-azacytidine, which causes hypomethylation of DNA, reduces the frequency of resistance to 5-10% of control. Furthermore, 5-azacytidine treatment reverts IFN-alpha-resistant cells to the IFN-alpha-sensitive state. Resistance to IFN-alpha occurs spontaneously at a rate of approximately 3 x 10(-6) variants/cell.generation, and is stable for more than 30 passages without selection in IFN-alpha. There is no evidence that gene amplification contributes to the high rate of resistance to IFN-alpha in these cells. These results indicate that DNA mutation and methylation are important in the development of IFN-alpha resistance in these cells.


Subject(s)
DNA/metabolism , Interferon-alpha/pharmacology , Lymphoma, B-Cell/metabolism , Animals , Azacitidine/toxicity , DNA/genetics , Drug Resistance/genetics , Ethyl Methanesulfonate/toxicity , Lymphoma, B-Cell/genetics , Methylation , Mice , Mutagenesis/genetics , Tumor Cells, Cultured
8.
J Interferon Res ; 10(6): 627-36, 1990 Dec.
Article in English | MEDLINE | ID: mdl-1964950

ABSTRACT

The human intgerferon (IFN)-inducible 6-16 gene is also induced by tumor necrosis factor (TNF) in human and mouse cells. A reporter gene carrying the IFN regulatory sequences of the human IFN-inducible 6-16 promoter linked to the bacterial chloramphenicol acetyl-transferase gene was transfected into the adipocyte-differentiating fibroblast cell line TA1 and a TNF-resistant derivative (TA1 R-6). Both IFN and TNF induced the 6-16 reporter gene in TA1 cells. However, the induction of 6-16 by TNF was abolished by antibodies to IFNs-alpha/beta. In the TNF-resistant derivative (TA1 R6) TNF failed to induce the 6-16 plasmid construct. IFN, on the other hand, effectively induced the 6-16 promoter in TA1-R6. The block in activation of the 6-16 promoter in TNF-resistant cells can be reversed by the addition of compounds that increased the intracellular concentration of cAMP. These cAMP analogs induced IFN secretion in parental cells but not in the TA1-R6 cells.


Subject(s)
Cyclic AMP/physiology , Promoter Regions, Genetic , Signal Transduction/physiology , Tumor Necrosis Factor-alpha/pharmacology , Animals , Base Sequence , Cell Line , Cycloheximide/pharmacology , DNA/genetics , Drug Resistance , Humans , Interferon Type I/pharmacology , Mice , Molecular Sequence Data , Plasmids , Promoter Regions, Genetic/drug effects , Signal Transduction/genetics
9.
Cancer Res ; 49(15): 4163-9, 1989 Aug 01.
Article in English | MEDLINE | ID: mdl-2787203

ABSTRACT

A stable subline of 38C13 B-cell lymphoma (SIR-1) resistant to the antiproliferative effects of alpha-interferon (IFN) was isolated. In addition to defects in antiproliferative effects of IFN, SIR-1 is defective in IFN-mediated antiviral activity against both encephalomyocarditis virus and vesicularstomatitis virus. It is also defective in the induction of 2'-5'-oligoadenylate synthetase mRNA and enzyme activity, enhancement of H-2 antigen expression, and transient induction and subsequent repression of c-myc by IFN. SIR-1, although completely resistant to IFN in vitro, is more sensitive to IFN than the parental cell line in vivo. IFN treatment at 10(4) units, three times weekly, resulted in a 28% increase in mean survival time and a 1.4% long term survival rate in the IFN-sensitive 38C13 cell line but resulted in a 275% increase in mean survival rate and a 27% long term survival rate in the interferon-resistant SIR-1 mutant. Statistical analysis of 38C13 and SIR-1 with and without IFN treatment demonstrate that: a) the SIR-1 mutant remains sensitive to the cytotoxic effects of IFN in vivo (P less than 0.0001); and b) the mean survival and long term survival of animals with the SIR-1 mutant is significantly greater than for animals with the IFN-sensitive 38C13 cell line (P less than 0.0001). Two additional independently isolated IFN-resistant cell lines (SIR-111 and SIR-E102) also demonstrate significantly enhanced in vivo response to IFN compared to the interferon-sensitive parental (38C13) cells. These results indicate that, for this cell line, the antitumor effects of IFN are mediated by activation of host defenses and that resistance to the in vitro cytotoxic effects of IFN results in a tumor phenotype that is more readily recognized by host defenses and eliminated.


Subject(s)
Interferon Type I/therapeutic use , Lymphoma/therapy , 2',5'-Oligoadenylate Synthetase/analysis , Animals , B-Lymphocytes , Drug Resistance , H-2 Antigens/analysis , Interferon Type I/pharmacology , Lymphoma/enzymology , Lymphoma/pathology , Mice , Mice, Inbred C3H , Proto-Oncogenes , Tumor Cells, Cultured/drug effects , Viruses/drug effects
10.
J Biol Chem ; 264(8): 4583-9, 1989 Mar 15.
Article in English | MEDLINE | ID: mdl-2925656

ABSTRACT

Tumor necrosis factor (TNF) can inhibit the differentiation of preadipocytes to adipocytes and will revert differentiated adipocytes to the preadipocyte state. TNF is not toxic to either adipocytes or preadipocytes when used alone but is highly toxic to these cells when used in conjunction with cycloheximide, yielding virtually 100% killing within 4-6 h of treatment. A cell line (TA1 R-6) was isolated which is resistant to the combined toxic effects of TNF and cycloheximide. This cell line is stable and, unlike the parental cell line, does not morphologically differentiate to adipocytes or express adipocyte-specific mRNAs. It has a more transformed appearance and growth pattern and, while resistant to the toxic effects of TNF and cycloheximide in a 6-h assay, has become sensitive to cytotoxicity induced by TNF used alone in a 3-day assay. The adipocyte differentiation-inducing agents, dexamethasone and indomethacin, block the cytotoxicity induced by TNF alone in the TA1 R-6 line but do not block the rapid cytotoxicity of TNF and cycloheximide in the parental line. These results provide both genetic and pharmacologic evidence that there are at least two distinct or overlapping pathways by which TNF mediates its effects.


Subject(s)
Adipose Tissue/cytology , Tumor Necrosis Factor-alpha/pharmacology , Adipose Tissue/drug effects , Animals , Cell Differentiation , Cell Division/drug effects , Cell Line , Cell Survival/drug effects , Cycloheximide/pharmacology , Dexamethasone/pharmacology , Drug Resistance , Drug Synergism , Indomethacin/pharmacology , Mice , RNA, Messenger/biosynthesis
11.
J Immunol ; 141(8): 2855-60, 1988 Oct 15.
Article in English | MEDLINE | ID: mdl-2971732

ABSTRACT

Combination therapy with syngeneic anti-idiotype antibody and human hybrid rIFN-alpha A/D synergistically increase survival in C3H/HeN mice challenged with a lethal dose of tumor cells. C3H/HeJ mice, which have previously been described to be LPS hyporesponsive and have a defect in Fc gamma R function, did not respond to anti-idiotype therapy as well as C3H/HeN normal mice. This defect was completely corrected in animals treated simultaneously with IFN. Anti-idiotype mAb that was cleaved into F(ab')2 fragments no longer had any antitumor activity alone and could not be enhanced by IFN therapy. These results suggest that antibody is functioning through Fc gamma R-bearing effector cells that are enhanced by IFN therapy. Synergy between IFN and anti-idiotype mAb was maintained in nude mice lacking classical T cells but was reduced in C3H beige mice lacking classical NK/killer cells. IFN did not increase idiotype expression on the tumor cells but did increase H-2 expression. Although we have previously shown that rIFN-alpha A/D can directly kill 38C13 in vitro, an IFN-resistant subclone derived from 38C13, SIR-1, was equally or more responsive to human rIFN-alpha A/D in vivo and had a synergistic antitumor response to combination IFN and anti-idiotype therapy, indicating that IFN acts primarily through host mediated effects rather than direct effects.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Immunoglobulin Idiotypes/immunology , Interferon Type I/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Animals , Antigens, Differentiation/metabolism , B-Lymphocytes , Binding, Competitive , Cell Line , Drug Resistance , Drug Synergism , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Idiotypes/analysis , Mice , Mice, Inbred C3H , Mice, Nude , Receptors, Fc/metabolism , Receptors, IgG , Recombinant Proteins
12.
J Biol Chem ; 259(3): 1727-30, 1984 Feb 10.
Article in English | MEDLINE | ID: mdl-6693433

ABSTRACT

Periodate-oxidized ppp(A2'p)3A was coupled in high yield to an acyl hydrazide derivative of bovine serum albumin and the conjugate was used to immunize rabbits. Several potent and specific antisera were obtained, and one was tested extensively. Fifty per cent of the bound probe ppp(A2'p)3A3'[32P]pCp was displaced by compounds containing the moiety -pA2'pA-at concentrations of 20-60 nM and by compounds containing the moiety -p(A2'p)2A- at 1 nM. The 3',5'-oligoadenylate (A3'p)3A was bound more than 10,000 times less tightly than (A2'p)3A. The antiserum can be used in competition assays in which the amount of an antibody-probe complex is measured after binding to Millipore filters or to polystyrene beads. These assays allow the clear detection of as little as 20 fmol (20 microliters of 1 nM) of 2',5'-oligoadenylates.


Subject(s)
Adenine Nucleotides/analysis , Oligonucleotides/analysis , Oligoribonucleotides/analysis , Adenine Nucleotides/immunology , Cross Reactions , Hemocyanins , Immune Sera , Oligoribonucleotides/immunology , Oxidation-Reduction , Radioimmunoassay , Radioligand Assay , Serum Albumin, Bovine
13.
Anal Biochem ; 136(1): 136-41, 1984 Jan.
Article in English | MEDLINE | ID: mdl-6424500

ABSTRACT

Complex mixtures of 2',5'-oligoadenylates are formed in cells and tissues under several different circumstances, and methods for analyzing such mixtures are reviewed. Separation is achieved by high-performance liquid chromatography and quantitation by competition-binding assays, using three different types of antibodies or a specific binding protein, or by functional assay, using preparations of an endonuclease specifically activated by some of the 2',5'-oligoadenylates. Representative results from three different biological systems are presented. The function of 2',5'-oligoadenylates as activators of intracellular RNA degradation is discussed, along with the possibility that these compounds may serve as signals for other intracellular regulatory processes.


Subject(s)
Adenine Nucleotides/analysis , Oligonucleotides/analysis , Oligoribonucleotides/analysis , Animals , Body Fluids/analysis , Chemical Phenomena , Chemistry , Chromatography, High Pressure Liquid , Female , Haplorhini , Humans , Radioimmunoassay , Rats
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