ABSTRACT
A formal synthetic route to hamigeran B, an antiviral marine natural product with a unique tricyclic molecular architecture, has been developed. The key chemical transformations in the present route include a novel zinc(II)porphyrin-catalyzed photoredox radical cascade cyclization to access a functionalized tetralin, a catalyst-free benzylic radical bromination with NBS by visible-light irradiation, and a samarium(II)-induced cyclization of brominated tetralone possibly via an orthoquinodimethane-like intermediate.
ABSTRACT
Bisphosphonates(BPs)have been widely used for the treatment of hypercalcemia associated with cancer, multiple myeloma bone diseases, and bone metastasis of solid cancers. Many cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ)have been reported in Japan. We report a case of a patient who developed BRONJ after tooth extraction even though the administration of BPs had been discontinued for 23 months. The patient was a 74-year-old woman who had received intravenous BPs from 2003 through 2008. She underwent tooth extraction in 2010. The bone in the extraction socket was exposed for more than 8 weeks. A clinical diagnosis of BRONJ was made. Discontinuation of BPs before surgical dental treatment did not appear to prevent BRONJ in this patient who had received intravenous BPs.
Subject(s)
Bisphosphonate-Associated Osteonecrosis of the Jaw/diagnosis , Bone Neoplasms/drug therapy , Breast Neoplasms/pathology , Diphosphonates/adverse effects , Tooth Extraction/adverse effects , Aged , Bisphosphonate-Associated Osteonecrosis of the Jaw/etiology , Bone Neoplasms/secondary , Breast Neoplasms/drug therapy , Diphosphonates/administration & dosage , Diphosphonates/therapeutic use , Female , Humans , Injections, IntravenousABSTRACT
Chemotherapy for cancer has been reported to have many side effects. Dysgeusia or taste disorder is a common complaint among cancer patients undergoing ambulatory chemotherapy. The present study was undertaken to establish the importance of dysgeusia as a side effect of chemotherapy in these patients. The study included 356 patients who visted Shikoku Cancer Center to undergo outpatient cancer chemotherapy. Of these patients, 156(43.8%)experienced dysgeusia. Of the 156 patients, 34 were male and 122 were female. The incidence of dysgeusia was higher in patients receiving FOLFOX6(oxaliplatin+ 5-FU), docetaxel(DTX), paclitaxel(PTX), docetaxel+cyclophosphamide(TC)or epirubicin+cyclophosphamide(EC) than in those receiving other regimens. When the occurrence of dysgeusia was difficult to define, the changes in taste sensations were subtle for salty and umami taste. This disorder affected appetite: 87.2%of patients experienced loss of appetite. In addition, 66.7% of patients were distressed by this disorder. Dysgeusia may significantly reduce the quality of life of patients undergoing chemotherapy for cancer. Therefore, patient support is important for patients who experience dysgeusia.
Subject(s)
Antineoplastic Agents/adverse effects , Dysgeusia/epidemiology , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Appetite/drug effects , Dysgeusia/chemically induced , Female , Humans , Incidence , Male , Middle Aged , Surveys and QuestionnairesABSTRACT
During the progression of head and neck squamous cell carcinoma (HNSCC), the induction of an epithelial-mesenchymal transition (EMT) program may play a critical role in the dissemination of cells from the primary tumor to distant metastatic foci. The process of EMT involves the activation of several important genes and pathways to help maintain survival and growth and evolve into highly invasive and metastatic variants. In this study, expression microarray analysis identified a set of 145 upregulated genes in EMT-like HNSCC cells. Some of the strongly upregulated transcripts include genes that are reportedly involved in invasion and metastasis, such as DOCK10, LOX, ROBO1 and SRGN. Importantly, the Tbx3 gene, a member of the T-box transcription factor, was strongly upregulated in SCC cells displaying an EMT-like phenotype compared to cells with an epitheloid, non-EMT behavior. Tbx3 was also found to be strongly upregulated at the protein and gene expression level in an experimental model of snail-induced EMT cells. In addition, siRNA-induced Tbx3 depletion modestly suppressed cell invasion while enhancing Tbx3-mediated resistance to anoikis. Our findings provide evidence that Tbx3 overexpression promotes SCC cell survival displaying an EMT phenotype. This set of newly identified genes that are modulated during EMT-like conversion may be important diagnostic biomarkers during the process of HNSCC progression.
Subject(s)
Carcinoma, Squamous Cell/genetics , Epithelial-Mesenchymal Transition/genetics , Gene Expression Profiling , Genes, Neoplasm , Head and Neck Neoplasms/genetics , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cell Survival/genetics , Cell Transformation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Genes, Neoplasm/genetics , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/pathology , Humans , Microarray Analysis , Neoplasm Invasiveness , Squamous Cell Carcinoma of Head and Neck , T-Box Domain Proteins/antagonists & inhibitors , T-Box Domain Proteins/genetics , T-Box Domain Proteins/metabolism , Transcription, Genetic/physiology , Up-Regulation , Validation Studies as TopicABSTRACT
BACKGROUND/AIMS: To clarify clinical parameters predicting sustained viral response (SVR) during 48 weeks pegylated-interferon (peg-IFN)alpha-2b plus ribavirin therapy for Japanese patients with chronic hepatitis C [CH(C)] genotype 1b and high viral titers. METHODOLOGY: One hundred and fifty-one (151) patients receiving peg-IFNalpha-2b plus ribavirin therapy for 48 weeks were enrolled. SVR and clinical parameters were evaluated. The relationship between virological parameters (substitutions in the core and NS5A) and the degree of early viral decrease was also studied. RESULTS: Seventy (46.4%) patients achieved SVR (per protocol analysis). Negative predictive value (NPV) of <2-log10 decrease after 4 weeks of therapy for SVR was 78.0%; similar to that for failing to achieve early viral response (EVR) at 12 weeks (82.2%). CONCLUSIONS: Failure to achieve 2- log10 decrease in the first 4 weeks may be an important predictor of non-SVR during 48 weeks of peg-IFNalpha-2b plus ribavirin therapy; thus, therapeutic plans should be reassessed at that point.
Subject(s)
Antiviral Agents/administration & dosage , Hepacivirus/classification , Hepatitis C, Chronic/drug therapy , Interferon-alpha/administration & dosage , Polyethylene Glycols/administration & dosage , Ribavirin/administration & dosage , Adult , Aged , Aged, 80 and over , Chemokine CXCL10/blood , Female , Genotype , Hepacivirus/genetics , Hepatitis C, Chronic/immunology , Hepatitis C, Chronic/virology , Humans , Interferon alpha-2 , Male , Middle Aged , Recombinant ProteinsABSTRACT
Development of a secondary primary cancer in a skin flap is a rare complication. A 70-year-old man underwent partial laryngopharyngectomy, right neck dissection and reconstruction with a radial forearm free flap in 2004. Five years later, an exophytic tumor was found on the hypopharynx reconstructed with the radial forearm free flap. He underwent total laryngopharyngectomy, left neck dissection and reconstruction with a jejunal free flap in June 2009. Pathological findings suggested this was a primary cancer rather than a metastasis. Localization to the epidermis and dermis indicate that the tumor was derived from the surface of the skin flap.
ABSTRACT
Evidence shows that Bcl-2 family members play a direct role in the development of some human malignancies. However, the mechanism by which Bcl-2 may influence tumor cell invasion and metastasis remains unclear. Ectopic overexpression of Bcl-2 in the human squamous carcinoma cell line HSC-3 enhanced tumorigenicity and experimental pulmonary metastasis. Interestingly, Bcl-2-expressing cells showed morphologic changes that resembled that of cells with an epithelial-mesenchymal transition phenotype. Analysis revealed increased N-cadherin and vimentin expression in parallel with attenuated E-cadherin level, along with enhanced migration and invasive behavior. Zymography studies confirmed elevated levels of matrix metalloproteinase-9 (MMP-9) in media of Bcl-2-expressing cells. siRNA-mediated suppression of N-cadherin expression not only prevented the enhanced invasion but also blocked the increased MMP-9 expression induced by elevated Bcl-2 expression. Accordingly, pharmacologic inhibition of MMP-9 abrogated the increased tumor cell invasion. Furthermore, the Bcl-2-mediated increase in MMP-9 expression and tumor cell invasion was dependent on fibroblast growth factor receptor-1 or extracellular signal-regulated kinase signaling. Collectively, the data establish that Bcl-2 overexpression in squamous carcinoma cells induces a partial epithelial to mesenchymal transition that promotes not only survival but also invasion and metastasis through the N-cadherin/fibroblast growth factor receptor/extracellular signal-regulated kinase pathway.
Subject(s)
Carcinoma, Squamous Cell/metabolism , Cell Dedifferentiation/physiology , Epithelial Cells/metabolism , Mesoderm/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Animals , Cadherins/genetics , Cadherins/metabolism , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/physiopathology , Cell Adhesion/physiology , Cell Lineage/physiology , Cell Shape/physiology , Disease Models, Animal , Epithelial Cells/pathology , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mesoderm/pathology , Mice , Mice, Nude , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/physiopathology , Neoplasm Metastasis/genetics , Neoplasm Metastasis/physiopathology , Neoplasm Transplantation/methods , Phenotype , Proto-Oncogene Proteins c-bcl-2/genetics , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Signal Transduction/physiology , Tumor Cells, CulturedABSTRACT
During cancer progression, tumor cells eventually invade the surrounding collagen-rich extracellular matrix. Here we show that squamous cell carcinoma cells strongly adhere to Type I collagen substrates but display limited motility and invasion on collagen barriers. Further analysis revealed that in addition to the alpha2beta1 integrin, a second collagen receptor was identified as Syndecan-1 (Sdc1), a cell surface heparan sulfate proteoglycan. We demonstrate that siRNA-mediated depletion of Sdc1 reduced adhesion efficiency to collagen I, whereas knockdown of Sdc4 was without effect. Importantly, silencing Sdc1 expression caused reduced focal adhesion plaque formation and enhanced cell spreading and motility on collagen I substrates, but did not alter cell motility on other ECM substrates. Sdc1 depletion ablated adhesion-induced RhoA activation. In contrast, Rac1 was strongly activated following Sdc1 knockdown, suggesting that Sdc1 may mediate the link between integrin-induced actin remodeling and motility. Taken together, these data substantiate the existence of a co-adhesion receptor system in tumor cells, whereby Sdc1 functions as a key regulator of cell motility and cell invasion by modulating RhoA and Rac activity. Downregulation of Sdc1 expression during carcinoma progression may represent a mechanism by which tumor cells become more invasive and metastatic.
Subject(s)
Carcinoma, Squamous Cell , Cell Adhesion/physiology , Cell Movement/physiology , Syndecan-1/metabolism , Animals , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Collagen Type I/genetics , Collagen Type I/metabolism , Focal Adhesions/metabolism , Humans , Integrin alpha2beta1/genetics , Integrin alpha2beta1/metabolism , Neoplasm Invasiveness , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Signal Transduction/physiology , Syndecan-1/genetics , rho GTP-Binding Proteins/genetics , rho GTP-Binding Proteins/metabolismABSTRACT
Hypoxia promotes the invasive and metastatic potential of tumour cells. A recent study has shown that the activation of the chemokine receptor CXCR4 by lack of oxygen in breast cancer is HIF-1-dependent. We have previously demonstrated that CXCR4 signalling is involved in the establishment of lymph node metastasis in oral squamous cell carcinoma (OSCC). In this study, we investigated a correlation between CXCR4 and HIF-1alpha expression in OSCC. Immunohistochemistry showed that CXCR4 was expressed in 20 of 85 OSCC tissues, while HIF-1alpha was expressed in 51 of 85 samples. There was a significant correlation between the expression of CXCR4 and HIF-1alpha. In human OSCC cells, hypoxia markedly enhanced the expression of both HIF-1alpha and CXCR4. Furthermore, synthetic small interfering RNA specific for HIF-1alpha significantly suppressed the expression of this protein, and also attenuated the induction of CXCR4 expression under hypoxic conditions. These results indicated that HIF-1alpha regulated hypoxia-induced CXCR4 expression in OSCC.
Subject(s)
Carcinoma, Squamous Cell/metabolism , Cell Hypoxia/physiology , Gene Expression Regulation, Neoplastic/physiology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Mouth Neoplasms/metabolism , Receptors, CXCR4/biosynthesis , Blotting, Western , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Immunohistochemistry , Middle Aged , RNA, Small Interfering , Receptors, CXCR4/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
PURPOSE: To study the changes in serum ferritin levels in lamivudine (LAM)-treated patients with chronic hepatitis and liver cirrhosis type B and determine whether successful treatment with LAM results in a reduction of serum ferritin levels. METHODS: Thirty patients with chronic hepatitis B virus (HBV) infection were followed prospectively during their treatment with LAM for 12 months. Serum HBV DNA, ferritin levels, and emergence of YMDD mutants were monitored. A case of severe liver cirrhosis with hepatic hemosiderosis that was treated successfully with LAM also is shown as a representative case. RESULTS: Serum alanine aminotransferase and ferritin levels decreased significantly more in the patients treated with LAM without YMDD mutants (n = 23) than those with mutants (n = 7). Hepatic hemosiderosis along with serum iron markers improved greatly in the representative patient. CONCLUSION: Successful treatment with LAM may reduce serum ferritin levels and improve hepatic siderosis in a subset of patients with chronic HBV infection.
ABSTRACT
BACKGROUND/AIMS: The emergence of YMDD mutants in patients who are treated with lamivudine may determine the clinical prognosis. However, currently there are no clinical or virological factors that predict specifically the emergence of the mutants. METHODOLOGY: To define these factors, we analyzed 69 patients with chronic hepatitis B infection who were treated with lamivudine (LAM) and followed prospectively for at least 12 months. RESULTS: Of the 69 patients, 12 (17.4%) developed YMDD mutants up to 12 months after the start of LAM. The incidence of YMDD mutants was slightly higher in those who were younger, had higher HBV DNA titers, lower ALT levels, genotype C, and mutations in the core promoter before treatment. However, we could not find any significant factors that correlated with the appearance of the mutants. CONCLUSIONS: Currently, using conventional virological assays, it is difficult to predict the development of mutants before LAM treatment. Management of flare-ups of hepatitis, due to the appearance of mutants, should always be envisaged when LAM treatment is started.
Subject(s)
Amino Acid Motifs/genetics , Hepatitis B virus/genetics , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/virology , Lamivudine/therapeutic use , Mutation , Reverse Transcriptase Inhibitors/therapeutic use , Adult , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Prospective StudiesABSTRACT
Hypoxia increases the invasive and metastatic potential of tumor cells. Increased expression of c-Met/hepatocyte growth factor (HGF)-receptor protein in response to hypoxia in thyroid papillary carcinomas is hypoxia-inducible factor-1 (HIF-1) dependent. Both HGF and c-Met are expressed in human salivary gland cancers. In the current study, we tested whether c-Met expression was regulated by hypoxia and HIF-1alpha using two human salivary gland cancer cell lines: GFP-ACC2 and GFP-ACCM. Hypoxia enhanced the expression of HIF-1alpha in both cell lines, whereas c-Met was markedly induced only in the GFP-ACCM cells, which have metastatic potential. In the latter, hypoxia also promoted HGF-induced invasiveness. Synthetic small-interfering RNA specific for HIF-1alpha inhibited HIF-1alpha expression in the GFP-ACCM cells, and also suppressed the increase in c-Met expression and HGF-induced invasiveness under hypoxic conditions. These results suggest that hypoxia activates the HGF/c-Met system via HIF-1alpha in human salivary gland cancers and might be involved in their metastasis.
Subject(s)
Neoplasm Proteins/metabolism , Proto-Oncogene Proteins c-met/metabolism , Salivary Gland Neoplasms/metabolism , Cell Hypoxia , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Neoplasm Invasiveness , RNA, Messenger/metabolism , Salivary Gland Neoplasms/pathology , Von Hippel-Lindau Tumor Suppressor Protein/metabolismABSTRACT
The support mechanisms that are involved in lymph-node metastasis of oral squamous cell carcinoma (OSCC) remain largely unknown. Recent studies have demonstrated that tumor cells express chemokine receptors and use chemokines to metastasize to the target organ in many malignancies in humans. In this study, we examined the expression and function of chemokines and their receptors in OSCC. The expression of chemokine receptors was assessed in eight OSCC cell lines. CXCR3 mRNA and protein were expressed in all the OSCC cell lines examined, while CXCR4 mRNA and protein were expressed only in HSC2, HSC3, and Ca9-22 cells. Treatment with the ligand for CXCR4, stromal cell-derived factor-1 (SDF-1), enhanced the motility and invasiveness of OSCC cells expressing CXCR4. However, the CXCR3 ligand, Mig, did not affect the migration or invasiveness of CXCR3-positive cells. We also evaluated the clinical significance of CXCR4 expression immunohistochemically. CXCR4 expression was detected in 27 (30%) of the 90 OSCC tissues tested, and was localized in the membrane and cytoplasm of cancer cells. There was a highly significant correlation between CXCR4 expression and lymph-node metastasis (P=0.0035). Collectively, these findings suggest that CXCR4 might be involved in the lymph-node metastasis of OSCC.
Subject(s)
Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Lymphatic Metastasis/genetics , Mouth Neoplasms/genetics , Mouth Neoplasms/pathology , Receptors, CXCR4/biosynthesis , Gene Expression Profiling , Humans , Immunohistochemistry , Neoplasm Invasiveness , RNA, Messenger/biosynthesis , Receptors, CXCR4/physiology , Receptors, Chemokine/biosynthesis , Receptors, Chemokine/physiology , Tumor Cells, CulturedABSTRACT
5'-deoxy-5-fluorouridine (5'-DFUR, Furtulon) is activated to 5-fluorouracil (5-FU) by thymidine phosphorylase (dThdPase) highly expressed in many types of tumors. In previous studies, we demonstrated that taxanes (paclitaxel or docetaxel) up-regulated the tumor levels of dThdPase and enhanced the efficacy of 5'-DFUR in human colon and mammary xenograft models. In the present study, combination therapy of 5'-DFUR with taxanes in human gastric cancer xenograft models also showed, at the least, additive anti-tumor activity without significant augmentation of toxicity. Furthermore, paclitaxel up-regulated dThdPase expression in the tumor tissues as confirmed with ELISA and immunohistochemistry. These results suggest taxanes would potentiate the efficacy of 5'-DFUR by up-regulating the tumor levels of dThdPase in gastric xenograft models. Clinical trials of 5'-DFUR in combination with taxane against gastric cancer are warranted.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Stomach Neoplasms/drug therapy , Xenograft Model Antitumor Assays/methods , Animals , Bridged-Ring Compounds/administration & dosage , Cell Line, Tumor , Floxuridine/administration & dosage , Humans , Immunohistochemistry , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Stomach Neoplasms/enzymology , Stomach Neoplasms/pathology , Taxoids/administration & dosage , Thymidine Phosphorylase/metabolism , Time Factors , Treatment Outcome , Up-Regulation/drug effectsABSTRACT
Growth-regulated oncogene-1 (GRO-1) is an autocrine growth factor in melanoma and is a member of the CXC family of chemokines which promote chemotaxis of granulocytes and endothelia through binding to CXC receptor 2. A previous article noted that GRO-1 was upregulated in oral cancer using a genome-wide microarray approach. We have examined the expression of GRO-1 in 9 oral squamous cell carcinoma (OSCC) cell lines and 94 OSCC specimens. Using real-time quantitative polymerase chain reaction analyses, GRO-1 expressions were varied in OSCC cell lines. Of the 94 OSCC specimens, 37 (39.4%) showed GRO-1 cytoplasmic immunostaining, and microvessel density revealed a correlation between GRO-1 expression and tumor angiogenesis. GRO-1 expression was also associated with leukocyte infiltration, and lymph node metastasis. These findings suggest a possible relationship between the expression level of GRO-1 and tumor progression.
Subject(s)
Biomarkers, Tumor/analysis , Carcinoma, Squamous Cell/pathology , Chemokines, CXC/analysis , Intercellular Signaling Peptides and Proteins/analysis , Lymph Nodes/pathology , Mouth Neoplasms/pathology , Neovascularization, Pathologic/metabolism , Aged , Carcinoma, Squamous Cell/chemistry , Chemokine CXCL1 , Chemokines, CXC/genetics , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Intercellular Signaling Peptides and Proteins/genetics , Lymph Nodes/metabolism , Lymphatic Metastasis , Middle Aged , Mouth Mucosa/chemistry , Mouth Neoplasms/chemistry , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Vascular endothelial growth factor (VEGF) A is known to play an important role in tumor angiogenesis. The additional members of the VEGF family, VEGF B, C and D have been discovered. VEGF C and D show some selectivity toward lymphatic endothelial cells. However, whether VEGF family members play a role in tumor angiogenesis and lymph node metastasis is largely unknown. The aim of the present study was to explore the role of VEGF family members in oral squamous cell carcinoma (OSCC). We evaluated the expression of VEGF family members by immunohistochemistry, reverse transcription-polymerase chain reaction, and western blotting. All VEGF members were expressed at different levels in OSCC. Immunohistological analysis of VEGF family members expression and microvessel density revealed a correlation between VEGF A and B expression and tumor angiogenesis. Although VEGF A and B expression were detected in both node-positive and node-negative OSCC, VEGF C and D expression was detected frequently in node-positive tumors compared to node-negative tumors. These findings suggest a possible relationship between the expression level of VEGF C and/or D and development of lymphatic tumor spread.
Subject(s)
Carcinoma, Squamous Cell/metabolism , Mouth Neoplasms/metabolism , Neoplasm Proteins/metabolism , Vascular Endothelial Growth Factors/metabolism , Adult , Aged , Blotting, Western , Carcinoma, Squamous Cell/blood supply , Humans , Immunohistochemistry , Lymphatic Metastasis , Microcirculation , Middle Aged , Mouth Neoplasms/blood supply , Neovascularization, Pathologic , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor B/metabolism , Vascular Endothelial Growth Factor C/metabolism , Vascular Endothelial Growth Factor D/metabolismABSTRACT
Capecitabine is an orally available fluoropyrimidine and is finally converted to 5-FU selectively in tumor tissues. In our study, we examined whether the antitumor activity of capecitabine is directly affected by a modulation of dihydropyrimidine dehydrogenase (DPD). The modulations were carried out by the overexpression of DPD in tumor cells and by tumor selective DPD inhibition. The DPD-overexpressing cells were obtained by transfection of human DPD cDNA into HCT116 human colorectal cancer cells. The HCT116 cells bearing DPD cDNA expressed about 13 times higher DPD activities than the parental HCT116 cells, and they became significantly less susceptible to capecitabine than the parental cells when transplanted into nude mice. Administration of RO0094889 that is converted to a DPD inhibitor 5-vinyluracil selectively in tumor tissues restored the antitumor activity of capecitabine against the tumor of the HCT116 cells carrying DPD cDNA and various tumors expressing DPD. As compared to 5-ethynyluracil or 5-vinyluracil, which inhibited DPD not only in tumor tissues but also in other non-cancerous tissues, the effective dose range of RO0094889 in augmenting the efficacy of capecitabine was much broader. These results indicate that the antitumor activity of capecitabine is directly affected by DPD activities in tumor tissues and therefore, the combination of capecitabine and a tumor selective DPD inhibitor, RO0094889, will be beneficial to patients who have tumors with high levels of DPD.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Colorectal Neoplasms/drug therapy , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Enzyme Inhibitors/therapeutic use , Oxidoreductases/antagonists & inhibitors , Animals , Blotting, Western , Capecitabine , Cell Division , Colorectal Neoplasms/enzymology , Colorectal Neoplasms/prevention & control , DNA Primers/chemistry , DNA, Neoplasm/metabolism , Dihydrouracil Dehydrogenase (NADP) , Drug Synergism , Fluorouracil/analogs & derivatives , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Polymerase Chain Reaction , Transfection , Tumor Cells, Cultured/transplantation , Xenograft Model Antitumor AssaysABSTRACT
A combination therapy with CPT-11 and 5-FU/LV has been recently established as a first-line therapy for metastatic colorectal cancer. However, severe adverse effects have also been reported from this combination therapy, and a modality to reduce the adverse effects is desired. 5'-DFUR, a pro-drug of 5-FU, shows less myelotoxicity than 5-FU, and thus it may be a better partner to combine with CPT-11. However, since each drug has the possibility of inducing diarrhea, there is concern about their use in combination therapy. Therefore, in the present study, our aim was to establish an optimal schedule in murine models, which shows no increase in diarrhea but maintains potent antitumor activity. In non-tumor bearing mice, CPT-11 was given i.v. at 100 mg/kg/day q2d x 3, and 5'-DFUR was given p.o. at 172 mg/kg/day daily for 14 days. Each of these doses caused diarrhea in the single treatment. CPT-11 was administered simultaneously or sequentially with 5'-DFUR. With the simultaneously administered schedule, the diarrhea appeared stronger than that found in the CPT-11 single or in the 5'-DFUR single treatment groups. On the other hand, with the sequentially administered schedule the diarrhea was not much stronger than that found in the single agent treatment groups. When CPT-11 and 5'-DFUR administrations were separated by three-day intervals, the diarrhea was not augmented at all. In mice bearing human colorectal cancer COLO 205, the antitumor activity of CPT-11 in the combination with 5'-DFUR was additive in all of the examined schedules. The efficacy in the sequential schedule was the same as in the simultaneous schedule. These results suggest that a sequential administration schedule of CPT-11 and 5'-DFUR would be more tolerable than and equally efficacious to the simultaneous administration schedule. Clinical study of this sequential administration in combination therapy is warranted.
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Agents, Phytogenic/administration & dosage , Camptothecin/analogs & derivatives , Camptothecin/administration & dosage , Colorectal Neoplasms/drug therapy , Floxuridine/administration & dosage , Animals , Antimetabolites, Antineoplastic/adverse effects , Antineoplastic Agents, Phytogenic/adverse effects , Camptothecin/adverse effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Floxuridine/adverse effects , Humans , Irinotecan , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm TransplantationABSTRACT
A series of tumor-activated prodrugs of the inhibitors of dihydropyrimidine dehydrogenase (DPD), an enzyme catabolizing 5-fluorouracil (5-FU: 4g), has been designed and synthesized. RO0094889 (11c) is a prodrug of 5-vinyluracil (4c), a known DPD inhibitor, and was designed to generate 4c selectively in tumor tissues by sequential conversion of 11c by three enzymes: esterase, cytidine deaminase and thymidine phosphorylase, the latter two of which are known to be highly expressed in various tumor tissues. When capecitabine (1), a tumor-activated prodrug of 5-FU, was co-administered orally with 11c, 5-FU in tumor tissues was significantly increased with only a slight increase of 5-FU in plasma as compared with oral capecitabine alone.