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1.
Cell Cycle ; 8(19): 3172-81, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19755861

ABSTRACT

AZD1152, an Aurora kinase inhibitor with selectivity for Aurora B kinase, can enhance the effect of ionizing radiation (IR). The aim of this study was to evaluate and to mechanistically explore scheduling effects of AZD1152 on tumor responses to IR, in three different settings: neoadjuvant (AZD1152 before IR), adjuvant (IR before AZD1152), or concomitant treatments (AZD1152 plus one single IR dose). A more pronounced tumor growth delay was observed in the neoadjuvant and adjuvant schedules as compared to the concomitant schedule. However, AZD1152 enhanced the efficacy of IR when concomitant IR was fractionated over several days. Histopathological examination revealed that AZD1152 + IR induced polyploidy, multinucleation and micronuclei in vivo. Time-lapse videomicroscopy confirmed that cell death induced by AZD1152 + IR was preceded by multinucleation and the formation of micronuclei, which both are hallmarks of mitotic catastrophe. Caspase inhibition or removal of the pro-apoptotic protein Bax did not ameliorate the long-term cell survival of AZD1152-treated cancer cells. In contrast, a chemical inhibitor of CHK1, Chir124, sensitized cancer cells to the lethal effect of AZD1152. Altogether, these data support the contention that AZD1152 mediates radiosensitization in vivo by enhancing mitotic catastrophe, which can be used as a biomarker of treatment efficacy.


Subject(s)
Mitosis , Organophosphates/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Quinazolines/pharmacology , Radiation, Ionizing , Animals , Apoptosis/drug effects , Aurora Kinase B , Aurora Kinases , Caspases/metabolism , Cell Line, Tumor , HCT116 Cells , Humans , Mice , Mice, Nude , Protein Serine-Threonine Kinases/metabolism , Transplantation, Heterologous
2.
Int J Radiat Oncol Biol Phys ; 74(4): 1242-50, 2009 Jul 15.
Article in English | MEDLINE | ID: mdl-19545790

ABSTRACT

PURPOSE: Oral mucositis is a common side effect induced by radio/chemotherapy in patients with head and neck cancer. Although it dramatically impairs patient quality of life, no efficient and safe therapeutic solution is available today. Therefore, we investigated the protective efficacy of a new heparan mimetic biopolymer, RGTA-OTR4131, used alone or in combination with amifostine, for oral mucositis and simultaneously evaluated its effect on tumor growth in vitro and in vivo. METHODS AND MATERIALS: A single dose of 16.5 Gy was selectively delivered to the snout of mice, and the effects of OTR4131 or amifostine-OTR4131 were analyzed by macroscopic scoring and histology. The effect of OTR4131 administration on tumor growth was then investigated in vitro and in xenograft models using two cell lines (HEP-2 and HT-29). RESULTS: Amifostine and OTR4131 significantly decreased the severity and duration of lip mucosal reactions. However, amifostine has to be administered before irradiation, whereas the most impressive protection was obtained when OTR4131 was injected 24 h after irradiation. In addition, OTR4131 was well tolerated, and the combination of amifostine and OTR4131 further enhanced mucosal protection. At the tumor level, OTR4131 did not modify HEP-2 cell line clonogenic survival in vitro or protect xenografted tumor cells from radiotherapy. Of interest, high doses of OTR4131 significantly decreased clonogenic survival of HT-29 cells. CONCLUSIONS: RGTAs-OTR4131 is a well-tolerated, natural agent that effectively reduces radio-induced mucositis without affecting tumor sensitivity to irradiation. This suggests a possible transfer into the clinic for patients' benefit.


Subject(s)
Amifostine/therapeutic use , Glucans/therapeutic use , Lip/radiation effects , Radiation Injuries, Experimental/prevention & control , Radiation-Protective Agents/therapeutic use , Stomatitis/prevention & control , Amifostine/administration & dosage , Animals , Cell Line, Tumor , Drug Administration Schedule , Drug Therapy, Combination , Female , Glucans/administration & dosage , HT29 Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Nude , Radiation Dosage , Radiation-Protective Agents/administration & dosage , Random Allocation , Xenograft Model Antitumor Assays/methods
3.
Anticancer Res ; 25(6B): 4357-62, 2005.
Article in English | MEDLINE | ID: mdl-16309240

ABSTRACT

Ritonavir, a protease inhibitor, has been successfully applied in the treatment of HIV infection. Reports of dramatic improvement of AIDS-related cancers, such as primary central system lymphoma after radiation therapy as well as Kaposi's sarcoma, led to the recent discovery of the "non viral" antitumor activity of HIV protease inhibitors. This study was designed to detect the antitumor effect of Ritonavir when combined with ionizing radiation both in vitro and in vivo in the HEP-2 head and neck carcinoma model. Inhibition of tumor growth was observed when mice were treated with Ritonavir alone and this effect was enhanced when combined with ionizing radiation. No adverse effect or significant toxicity in the hosts' body weights was seen between the different treatment and control groups throughout the experiments. A marked antiproliferation effect of the combination was observed in vitro. A marked reduction of angiogenesis was detected within the tumor sections from the Ritonavir combined with irradiation group as compared with the Ritonavir or irradiation alone groups. Western blot analysis showed that apoptosis was induced by an increased expression of Bax and decreased expression of Bcl-2 after treatment with Ritonavir and ionizing radiation. Thus, the antitumor effect of the latter combination is associated with the enhancement of radiation-induced apoptosis and inhibition of angiogenesis. These data suggested that Ritonavir could clinically improve the tumor response to radiation therapy, especially in head and neck carcinoma.


Subject(s)
Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/radiotherapy , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/radiotherapy , Ritonavir/pharmacology , Animals , Apoptosis/drug effects , Apoptosis/radiation effects , Carcinoma, Squamous Cell/blood supply , Cell Growth Processes/drug effects , Cell Growth Processes/radiation effects , Cell Line, Tumor , Combined Modality Therapy , Female , Head and Neck Neoplasms/blood supply , Head and Neck Neoplasms/pathology , Humans , Mice , Mice, Nude , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/radiotherapy , Radiation-Sensitizing Agents/pharmacology , Xenograft Model Antitumor Assays
4.
Cancer Res ; 63(10): 2513-7, 2003 May 15.
Article in English | MEDLINE | ID: mdl-12750274

ABSTRACT

Frequent deregulation of cyclin-dependent kinase (CDK) activation associated with loss of cell cycle control was found in most of human cancers. A recent development of a new class of antineoplasic agents targeting the cell cycle emerged as a small molecule CDK inhibitor, roscovitine, which presents potential antiproliferative and antitumoral effects in human tumors. Additional studies reported that roscovitine combined with cytotoxic agents can cooperate with DNA damage to activate p53 protein. However, little is known about the biological effect of roscovitine combined with ionizing radiation (IR) in human carcinoma, and no studies were reported thus far in p53 mutated carcinoma. In the breast cancer cell line MDA-MB 231, which lacks a functional p53 protein, we found a strong radiosensitization effect of roscovitine in vitro by clonogenic survival assay and in vivo in MDA-MB 231 xenograft model. Using Pulse Field Gel Electrophoresis, a strong impairment in DNA-double-strand break rejoining was observed after roscovitine and IR treatment as compared with IR alone. Cell cycle analysis showed a G(2) delay and no increase in radiation-induced apoptosis in the cells treated with IR or roscovitine and IR. On the other hand, we found a significant induction in micronuclei frequency after roscovitine and IR treatment as compared with IR alone. This effect was also observed in BALB murine cells in contrast to SCID murine cells, which are deficient in DNA-PKcs, suggesting a possible DNA-double-strand break repair defect in the nonhomologous end joining pathways. In MDA-MB 231 cells, the radiosensitization effect of roscovitine was associated with an inhibition of the DNA-dependent protein kinase activity caused by a marked decrease in Ku-DNA binding by using the electrophoretic mobility shift assay. In conclusion, we found a novel effect on DNA repair of the CDK inhibitor roscovitine, which acts as a radiosensitizer in vitro and in vivo in breast cancer cells lacking a functional p53.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/radiotherapy , DNA Helicases , Purines/pharmacology , Radiation-Sensitizing Agents/pharmacology , Animals , Antigens, Nuclear/metabolism , Apoptosis/drug effects , Apoptosis/radiation effects , Cell Cycle/drug effects , Cell Cycle/radiation effects , Combined Modality Therapy , DNA Repair/drug effects , DNA, Neoplasm/genetics , DNA, Neoplasm/metabolism , DNA-Activated Protein Kinase , DNA-Binding Proteins/metabolism , Female , Humans , Ku Autoantigen , Mice , Mice, Inbred BALB C , Mice, Nude , Mice, SCID , Nuclear Proteins , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Roscovitine , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
5.
Oncogene ; 22(15): 2260-71, 2003 Apr 17.
Article in English | MEDLINE | ID: mdl-12700662

ABSTRACT

The Epstein-Barr virus (EBV) is involved in the carcinogenesis of several human cancers such as nasopharyngeal carcinoma (NPC) and Burkitt lymphoma (BL). Given the consistent role of EBV in transformation and maintenance of malignant phenotype, antiviral strategies provide an attractive approach to target EBV-expressing cells. In that aim, we have tested the Cidofovir, which is an acyclic nucleoside phosphonate analog known to exert an antiproliferative activity in some human virus-related tumors. Here, we show that Cidofovir induces a downregulation of the EBV oncoprotein LMP1 associated with a decrease of the antiapoptotic Bcl-2 and an increase of the proapoptotic Bax protein in Raji (BL) and C15 (NPC) cells. Using BL cell line BL2 B95-8 (BL2 infected with the B95.8 strain of EBV), we addressed the relation between EBV genome expression and modulation of viral oncoproteins by Cidofovir and/or ionizing radiation (IR). Cidofovir was able to significantly reduce LMP1 and EBNA2 mRNA and protein expression. This effect was associated with inhibition of proliferation, stimulation of apoptosis, and decrease of Bcl-2 expression in BL2 B95.8 cells. In addition, Cidofovir enhanced the radiation-induced apoptosis and the radiosensitivity through the proteolytic cleavage of death effectors caspase-9 and -3, which was specifically induced by combined treatment in EBV-positive cells compared to their negative counterparts. Furthermore, the combined treatment in nude mice led to a complete tumor remission without increasing toxicity in two human EBV-related cancer xenografts (Raji and C15). These results provide the basis for a novel anticancer strategy to enhance the therapeutic ratio of IR in EBV-related cancers.


Subject(s)
Antiviral Agents/pharmacology , Burkitt Lymphoma/radiotherapy , Carcinoma/radiotherapy , Cytosine/analogs & derivatives , Cytosine/pharmacology , Epstein-Barr Virus Infections/radiotherapy , Gene Expression Regulation, Viral/drug effects , Herpesvirus 4, Human/drug effects , Nasopharyngeal Neoplasms/radiotherapy , Oncogene Proteins, Viral/biosynthesis , Organophosphonates , Organophosphorus Compounds/pharmacology , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Proto-Oncogene Proteins/biosynthesis , Radiation Tolerance/drug effects , Tumor Virus Infections/radiotherapy , Animals , Antiviral Agents/therapeutic use , Apoptosis/drug effects , Apoptosis/radiation effects , Burkitt Lymphoma/drug therapy , Burkitt Lymphoma/pathology , Burkitt Lymphoma/virology , Carcinoma/drug therapy , Carcinoma/pathology , Carcinoma/virology , Caspase 3 , Caspase 9 , Caspases/metabolism , Cell Division/drug effects , Cidofovir , Combined Modality Therapy , Cytosine/therapeutic use , Enzyme Activation/drug effects , Enzyme Activation/radiation effects , Epstein-Barr Virus Infections/drug therapy , Epstein-Barr Virus Infections/pathology , Female , Genes, bcl-2 , Herpesvirus 4, Human/metabolism , Humans , Mice , Mice, Nude , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/virology , Oncogene Proteins, Viral/genetics , Organophosphorus Compounds/therapeutic use , Proto-Oncogene Proteins/genetics , Remission Induction , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolism , Tumor Cells, Cultured/radiation effects , Tumor Cells, Cultured/transplantation , Tumor Cells, Cultured/virology , Tumor Stem Cell Assay , Tumor Virus Infections/drug therapy , Tumor Virus Infections/pathology , Tumor Virus Infections/virology , Viral Matrix Proteins/biosynthesis , Viral Matrix Proteins/genetics , Xenograft Model Antitumor Assays , bcl-2-Associated X Protein
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