Papers by Mario Del Tacca
Experientia, 1988
Figure 3. Comparison of Ca-dependent K-currents in control saline (A) and in the presence of 10 n... more Figure 3. Comparison of Ca-dependent K-currents in control saline (A) and in the presence of 10 nM CARP (B) at different voltages. Numbers on the right to the voltage curves show values by which the neurone was depolarized from the holding potential (t-IP = -50 mV). D-cluster neu-]~oTle. Since both Ca-inward and Ca-activated K-currents decreased simultaneously in the presence of CARP, so that the relationship between them was linear, it is suggested that depression of K(Ca) current is merely the consequence of Ca-inward current inhibition. Recently it has became evident that neuronal membranes possess two types ofvoItage-sensifive calcium channels: a transient, and a slowly inactivating one. In conclusion, the data presented above suggest a specific blocking action of the CARP on slowly inactivating Ca-current component. It is proposed therefore that CARP could be a selective Ca-channel blocker. Our experiments revealed that CARP strongly depresses the Ca-dependent K-current and the slowly inactivating Ca-inward current of snail neurones. In both cases the (Ca)~ may decrease, which is consistent with the idea proposed by Twarog 4, 5 for the relaxation mechanism of catch.
British Journal of Cancer, 1993
The effects of suramin, an inhibitor of growth factor mitogenic activity, were evaluated on basic... more The effects of suramin, an inhibitor of growth factor mitogenic activity, were evaluated on basic fibroblast growth factor (bFGF)-induced proliferation of bovine aortic endothelial cells and on angiogenesis in the chorioallantoic membrane (CAM) of chick embryos. The role of bFGF gene expression in endothelial cell growth was also investigated by using an antisense oligodeoxynucleotide to bFGF. The 4-fold increase in [3H]-thymidine uptake in endothelial cells in vitro upon stimulation with 10 ng ml-' of bFGF was inhibited by suramin 300 jg ml-'. bFGF antisense oligomer (IOjiM) reduced [3H]-thymidine incorporation in exponentially growing cells by 76%; this effect was reversed by bFGF 10 ng ml-'. In the CAM of chick embryos suramin 50 jug was a more potent inhibitor of angiogenesis than the combination of heparin 60 jg/hydrocortisone 50 jig; the mean value of the area with reduced vascularity was significantly larger in suramin-treated CAMs (2.4 cm2) than in heparin/hydrocortisone (0.6 cm2), while the reduction of vascular density was similar (-35 and-29% compared to controls, respectively), In conclusion, the effects of treatments with bFGF and bFGF antisense oligomer demonstrate that bFGF plays a relevant role in endothelial cell proliferation and may be the target of suramin since the drug is able to suppress basal and bFGF-induced endothelial cell growth; in addition to this, suramin is a more potent angiogenesis inhibitor in the CAM than the combination of heparin/hydrocortisone.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2000
The aim of this study was to investigate the clinical pharmacokinetics of 5-fluorouracil (5-FU) a... more The aim of this study was to investigate the clinical pharmacokinetics of 5-fluorouracil (5-FU) and its major metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) in 20 colorectal cancer patients given two dose levels of 5-FU, 250 and 370 mg/m2, administered by i.v. bolus. A reverse-phase high-performance liquid chromatographic method was used for the simultaneous assay of 5-FU and 5-FDHU in plasma samples obtained at baseline and at multiple time points from 5 min to 4 h after 5-FU bolus as well as to assess the activity of dihydropyrimidine dehydrogenase (DPD) in peripheral blood mononuclear cells (PBMCs) before 5-FU dosing. Plasma pharmacokinetic parameters of patients given 250 mg/m2 5-FU were significantly different from those receiving 370 mg/m2; main differences were observed in the trapezoidal areas under the plasma levels-versus-time curve from to to the last measurable concentration (area under the curve, 3.77+/-0.21 versus 13.61+/-2.3 h x microg/ml), peak plasma concentration (...
Neurogastroenterology & Motility, 2006
Prostaglandins regulate various functions throughout the gastrointestinal system. Their biosynt... more Prostaglandins regulate various functions throughout the gastrointestinal system. Their biosynthesis depends on cyclooxygenase isoforms, named COX‐1 and COX‐2. The initial hypothesis that COX‐2 is an inducible enzyme has been challenged and its constitutive expression in the stomach has been established. In this study, an immunohistochemical analysis was performed to evaluate the distribution and cellular localization of COX‐2 in normal human colon. Colonic surgical specimens were processed for COX‐2, protein HuC/HuD, neurofilament, S‐100 protein and CD117/c‐kit immunodetection. COX‐2 protein was found to be constitutively expressed in the colonic wall: detectable amounts were localized in mucosal, submucosal and muscular layers, mainly in the neuromuscular compartment. In particular, COX‐2 was expressed in muscularis mucosae, submucosal ganglia, longitudinal muscle layer and myenteric ganglia, the neurons of which displayed different degrees of immunostaining. Intramuscular inter...
Journal of Pharmacology and Experimental Therapeutics, 2006
This study examines the role played by cyclooxygenase (COX) isoforms (COX-1 and-2) in the regulat... more This study examines the role played by cyclooxygenase (COX) isoforms (COX-1 and-2) in the regulation of colonic neuromuscular function in normal rats and after induction of colitis by 2,4dinitrobenzenesulfonic acid (DNBS). The expression of COX-1 and COX-2 in the colonic neuromuscular layer was assessed by reverse transcription-polymerase chain reaction and immunohistochemistry. The effects of COX inhibitors on in vitro motility were evaluated by studying electrically induced and carbachol-induced contractions of the longitudinal muscle. Both COX isoforms were constitutively expressed in normal colon; COX-2 was up-regulated in the presence of colitis. In normal and inflamed colon, both COX isoforms were mainly localized in neurons of myenteric ganglia. In the normal colon, indomethacin (COX-1/COX-2 inhibitor), SC-560 [5-(4-chloro-phenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] (COX-1 inhibitor), or DFU [5,5-dimethyl-3-(3fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone] (COX-2 inhibitor) enhanced atropine-sensitive electrically evoked contractions. The most prominent effects were observed with indomethacin or SC-560 plus DFU. In the inflamed colon, SC-560 lost its effect, whereas indomethacin and DFU maintained their enhancing actions. These results were more evident after blockade of noncholinergic pathways. In rats with colitis, in vivo treatment with superoxide dismutase or S-methylisothiourea (inhibitor of inducible nitric-oxide synthase) restored the enhancing motor effect of SC-560. COX inhibitors had no effect on carbachol-induced contractions in normal or DNBS-treated rats. In conclusion, in the normal colon, both COX isoforms act at the neuronal level to modulate the contractile activity driven by excitatory cholinergic pathways. In the presence of inflammation, COX-1 activity is hampered by oxidative stress, and COX-2 seems to play a predominant role in maintaining an inhibitory control of colonic neuromuscular function.
British Journal of Clinical Pharmacology, 2002
Aims To investigate the pharmacokinetics and pharmacodynamics of epirubicin and paclitaxel in co... more Aims To investigate the pharmacokinetics and pharmacodynamics of epirubicin and paclitaxel in combination, as well as the effects of paclitaxel and its vehicle Cremophor EL on epirubicin metabolism.Methods Twenty‐seven female patients with metastatic breast cancer received epirubicin 90 mg m−2 i.v. followed 15 min or 30 h later by a 3 h i.v. infusion of paclitaxel 175, 200 and 225 mg m−2. Plasma concentrations of paclitaxel, epirubicin and epirubicinol were measured and the relationship between neutropenia and drug pharmacokinetics was evaluated using a sigmoid maximum effect (Emax) model. Finally, the influence of paclitaxel and Cremophor EL on epirubicin metabolism by whole blood was examined.Results An increase in epirubicinol plasma concentrations occurred after the start of the paclitaxel infusion, resulting in a significant increase in the area under the plasma concentration‐time curve (AUC) of epirubicinol (+0.5 µmol l−1 h [95% CI for the difference: 0.29, 0.71],+0.66 µmol...
Therapeutic Drug Monitoring, 2005
Administration of 5-fluorouracil (5-FU) may be associated with severe toxicities in patients who ... more Administration of 5-fluorouracil (5-FU) may be associated with severe toxicities in patients who are deficient of dihydropyrimidine dehydrogenase (DPD) activity. For this reason, a sensitive HPLC method for the analysis of 5-FU and 5-fluoro-5, 6-dihydrouracil (5-FDHU) was developed in the present study for the determination of DPD activity in nucleated cells of peripheral blood and pharmacokinetic analysis of 5-FU and 5-FDHU in humans. 5-FU and 5-FDHU were extracted from biologic matrices by adding sodium acetate, sodium sulfate, and diethyl ether/propanol. Dried samples were reconstituted in a mobile phase (KH 2 PO 4 35 mmol/L, pH 4.0), isocratically eluted with a Hypersil C 18 stationary phase (25 cm 3 4.6 mm, 10 mm), and detected by a diode array detector (measurement and reference wavelengths, 215 and 360 nm, respectively). 5-Fluorocytosine (internal standard), 5-FDHU, and 5-FU were eluted within 13 minutes of the injection without interferences. Recoveries ranged between 81% to 85% for all compounds, and the method proved to be linear, with a coefficient of linearity of 0.999. The limits of detection and quantification were 3.2 and 16 ng/mL, respectively, and the within-day and between-day CV were less than 10% for both 5-FU and 5-FDHU. The present assay proved to be sufficiently sensitive and specific to evaluate cellular DPD activity and measure 5-FU and 5-FDHU plasma concentrations in cancer patients, thus allowing therapeutic 5-FU monitoring in patients and identification of DPD-deficient subjects at major risk of severe toxicities.
Experimental Eye Research, 1998
The purpose of this study was to evaluate the inhibitory activity of the heparan sulfate suleparo... more The purpose of this study was to evaluate the inhibitory activity of the heparan sulfate suleparoide on vascular cell growth in vitro and angiogenesis in vivo. Human HUV-EC-C endothelial cell proliferation and microvessel sprouting from cultured rat aortic rings were assayed by the bioreduction of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide. The inhibition of the neoforming capillary network in the chorioallantoic membrane of chick embryo (CAM) was evaluated by agarose disks containing suleparoide and applied on the CAM surface. AgNO $ \KNO $ injury was used to induce corneal neovascularization and to evaluate the therapeutic effect of topical suleparoide, while the involvement of bFGF in angiogenesis was evidenced by immunohistochemistry of corneal tissue. Quantitation of angiogenesis in the CAM and the cornea was accomplished by image analysis. Suleparoide dose-dependently inhibited HUV-EC-C cell proliferation (50 % inhibitory concentration [IC &! ], 197n5p15n2 µg ml −") and reduced microvessel sprouting in vitro (IC &! , 351p22 µg ml −"). Likewise, suleparoide 150 µg in agarose disks produced an avascular area of 19n7p2n7 % of the total area of the CAM (P 0n05 as compared to controls). bFGF levels were significantly enhanced in the cornea after AgNO $ \KNO $ injury, and the increase appeared to be time-dependent (25n6p1n8 and 43n2p7n4%, vs. uninjured controls after 24 hr and 48 hr, respectively, P 0n05). Suleparoide 4n8 mg eye −" day −" for six days reduced the length of blood vessels and the area of the cornea infiltrated by them (59n6p7n4% decrease vs. controls, P 0n05). These results demonstrate that suleparoide is an active agent against angiogenesis and suggest that the therapeutic effect of the drug could be of value to treat corneal neovascularization.
Cancer Chemotherapy and Pharmacology, 2006
Recent clinical studies have demonstrated a reduction of irinotecan (CPT-11) gastrointestinal tox... more Recent clinical studies have demonstrated a reduction of irinotecan (CPT-11) gastrointestinal toxicities when the CPT-11 is administered in combination with thalidomide in patients with diagnosis of colorectal cancer. The main purpose of this study was to investigate possible interactions between CPT-11 pharmacokinetics and thalidomide to explain the previously described gastrointestinal toxicity reduction. In our clinical trial, advanced cancer patients were treated with CPT-11 on a dose of 350 mg/m2 at day 1 every 3 weeks. Only at the first cycle, CPT-11 was administered in association with thalidomide on a dose of 400 mg/day given from day 1 to day 14. From the second cycle, the treatment was continued with irinotecan alone at the same dose. Pharmacokinetics analysis of irinotecan and its metabolites, SN-38 and SN-38-glucuronide, were performed at the first and second cycle. A total of 19 patients entered the study. The pharmacokinetic analysis were performed on 16 patients. Pharmacokinetic data suggested a decreased metabolism of irinotecan into SN-38 and SN-38-glucuronide when it was administered with thalidomide. Indeed, area under the time-concentration curve (AUC) of SN-38 was significantly lower at the first cycle than the second cycle (0.99+/-0.45 hxmicrog/ml vs 1.34+/-0.65, respectively, P=0.027) whereas AUC of irinotecan and SN-38-glucuronide were higher at first cycle than second cycle (34.53+/-11.38 hxmicrog/ml vs. 28.42+/-12.23 hxmicrog/ml, P=0.064 and 2.39+/-1.21 h(microg/ml vs. 1.86+/-1.11 hxmicrog/ml, P=0.018, respectively). Our study demonstrates a significant decreased metabolism of CPT-11 into the active metabolite SN-38 when CPT-11 is administered in association with thalidomide. These observations strongly suggest an interaction of thalidomide with CPT-11 metabolism and, at least in part, it might explain the previously described improvement in tolerability.
Cancer Chemotherapy and Pharmacology, 1992
The purpose of this study was to evaluate the optimal timing of ADR-529 administration to protect... more The purpose of this study was to evaluate the optimal timing of ADR-529 administration to protect rats treated with doxorubicin (DXR) against drug-induced cardiotoxicity. Complete electrocardiographic monitoring (QRS complex, So~T segment and T wave) and the histopathological analysis of cardiac tissue were used to assess the degree of heart damage produced in female rats treated with ten i. v. doses of 1 mg/kg DXR over a period of 15 weeks; bodyweight increase and survival were also analyzed to evaluate the toxicity of treatments. Cardiac alterations induced by DXR were compared with those occurring in animals receiving 20 mg/kg i.v. ADR-529 at 30 min prior to DXR administration, starting at the first, third, or sixth DXR dose and given until the end of the study (15th week). Rats treated with DXR were severely cardiomyopathic, showing progressive and irreversible ECG alterations (QRS-complex and So~T-segment widening and T-wave flattening) and marked degeneration of the myocardium (myocyte vacuolation, myofibrillar loss, and endomyocardial fibrosis). The most effective cardiac protection was provided by the administration of ADR-529 beginning with the first or third DXR dose. Delaying treatment with ADR-529 until the sixth DXR dose resulted in a significant reduction in its therapeutic action on heart damage. A significant difference in bodyweight increase and survival was observed between the treatment groups: ADR-529 injected prior to the first DXR dose significantly protected animals :from DXR toxicity, but this schedule was significantly more toxic than the administration of ADR-529 beginning with the third or sixth DXR dose. Taking into account the degree of cardiac protection and the toxicity of combination treatments, the
Journal of Thoracic Oncology, 2007
Clinical Cancer Research, 2010
Our understanding of the molecular pathophysiology of differentiated thyroid cancer (DTC) has dev... more Our understanding of the molecular pathophysiology of differentiated thyroid cancer (DTC) has developed considerably over the last 10 years. Aberrant signaling through B-Raf and Akt has been implicated in the tumorigenesis of DTC. Moreover, these highly vascular tumors have proven to be sensitive to the inhibition of vascular endothelial growth factor receptor (VEGFR-2). It is likely that the multikinase inhibitors, sorafenib, sunitinib, axitinib, and motesanib, whose targets include VEGFR-2, exert their effects primarily through inhibition of endothelial cells. However, as VEGFR-2 is expressed on DTC cells, these compounds may have direct antitumor action. This review will discuss the key signaling pathways involved in thyroid cancer and their implications for targeted therapy. Clin Cancer Res; 16(3); 778–83
Molecular Cancer Therapeutics, 2006
Chemotherapy has produced unsatisfactory results in pancreas cancer and novel approaches, includi... more Chemotherapy has produced unsatisfactory results in pancreas cancer and novel approaches, including treatment tailoring by pharmacogenetic analysis and new molecular-targeted drugs, are required. The scarcity of effective therapies may reflect the lack of knowledge about the influence of tumor-related molecular abnormalities on responsiveness to drugs. Advances in the understanding of pancreas cancer biology have been made over the past decade, including the discovery of critical mutations in oncogenes (i.e., K-Ras) as well as the loss of tumor suppressor genes, such as TP53 and p16INK4. Other studies showed the dysregulation of the expression of proteins involved in the control of cell cycle, proliferation, apoptosis, and invasiveness, such as Bcl-2, Akt, mdm2, and epidermal growth factor receptor. These characteristics might contribute to the aggressive behavior of pancreatic cancer and influence response to treatment. Indeed, the inactivation of p53 may explain the relative resis...
Advanced Drug Delivery Reviews, 2009
The disappointing results in long-term survival of patients who have a resectable non-small cell ... more The disappointing results in long-term survival of patients who have a resectable non-small cell lung cancer (NSCLC) may reflect the lack of knowledge on the way by which molecular abnormalities in neoplastic cells affect responsiveness to adjuvant therapy. This issue deserves intensive investigation to select methodological approaches for a new generation of chemotherapeutic strategies. Remarkable advances in the understanding of NSCLC biology have been made, including the discovery of critical mutations in oncogenes (i.e. K-Ras and c-myc), as well as the loss of tumor-suppressor genes, such as TP53, p16 INK4 or Rb. Other studies demonstrated the role of mutations or deregulation of the expression of several molecular determinants involved in cell cycle control such as epidermal growth factor receptor (EGFR). All these characteristics, as well as alterations in gene products directly related to drug activity, might contribute to the aggressive behaviour of NSCLC. The future challenge of chemotherapy of NSCLC relies on the identification of molecular markers that are predictive of drug sensitivity and are helpful in the selection of chemotherapeutic agents best suited to the individual patient. Other intriguing issues will be the identification of the optimal drug sequence in combination regimens and the pharmacogenetics of severe toxicities. Moreover, due to the developments of novel technologies to decipher genetic alterations involved in tumor progression, new agents are gaining momentum, including inhibitors of intracellular signal transduction, and a large body of research, using prospective clinical trials, should be devoted to this area.
British Journal of Cancer, 2005
The new combination between the nucleoside analogue gemcitabine and the cholesterol-lowering drug... more The new combination between the nucleoside analogue gemcitabine and the cholesterol-lowering drug fluvastatin was investigated in vitro and in vivo on the human pancreatic tumour cell line MIAPaCa-2. The present study demonstrates that fluvastatin inhibits proliferation, induces apoptosis in pancreatic cancer cells harbouring a p21ras mutation at codon 12 and synergistically potentiates the cytotoxic effect of gemcitabine. The pharmacologic activities of fluvastatin are prevented by administration of mevalonic acid, suggesting that the shown inhibition of geranyl-geranylation and farnesylation of cellular proteins, including p21rhoA and p21ras, plays a major role in its anticancer effect. Fluvastatin treatment also indirectly inhibits the phosphorylation of p42ERK2/mitogen-activated protein kinase, the cellular effector of ras and other signal transduction peptides. Moreover, fluvastatin administration significantly increases the expression of the deoxycytidine kinase, the enzyme required for the activation of gemcitabine, and simultaneously reduces the 5 0-nucleotidase, responsible for deactivation of gemcitabine, suggesting a possible additional role of these enzymes in the enhanced cytotoxic activity of gemcitabine. Finally, a significant in vivo antitumour effect on MIAPaCa-2 xenografts was observed with the simultaneous combination of fluvastatin and gemcitabine, resulting in an almost complete suppression and a marked delay in relapse of tumour growth. In conclusion, the combination of fluvastatin and gemcitabine is an effective cytotoxic, proapoptotic treatment in vitro and in vivo against MIAPaCa-2 cells by a mechanism of action mediated, at least in part, by the inhibition of p21ras and rhoA prenylation. The obtained experimental findings might constitute the basis for a novel translational research in humans.
Lung Cancer, 2011
Lung cancer is one of the most lethal tumors and, although standard chemotherapy produces clinica... more Lung cancer is one of the most lethal tumors and, although standard chemotherapy produces clinical response, there has been little improvement in prognosis. Therefore, research effort has focused on target-specific agents, such as sorafenib, which blocks both the RAF/MEK/ERK signalling pathways and receptors involved in neovascularization and tumor progression, including VEGFR-2 and c-Kit. We investigated whether sorafenib would be synergistic with gemcitabine against NSCLC cell lines. Human lung cancer cells A549, CALU-1, CALU-6, H23 and HCC 827 were treated with sorafenib and gemcitabine, alone or in combination, and the cytotoxicity was assessed with CellTiter 96 Non-radioactive cell proliferation kit. Cell cycle and apoptosis were investigated with flow cytometry and fluorescence microscopy, respectively. Moreover, the effects of drugs on Akt (S473), c-Kit (Y823) and ERK (pTpY185/187) phosphorylation were studied with ELISA. Finally, quantitative PCR analysis was performed to assess whether sorafenib and gemcitabine modulated the expression of genes related to drug activity. Gemcitabine and sorafenib synergistically interacted on the inhibition of cell proliferation, and assessment of apoptosis demonstrated that drug associations increased the apoptotic index. Sorafenib reduced c-Kit and ERK activation and gemcitabine inhibited Akt phosphorylation. Moreover quantitative PCR showed that sorafenib modulated the expression of targets related to gemcitabine activity, while gemcitabine induced the expression of RKIP. These data demonstrate that sorafenib and gemcitabine synergistically interact against NSCLC cells, through suppression of Akt, c-Kit and ERK phosphorylation, induction of apoptosis and modulation of dCK, RRM1, RRM2 and RKIP gene expression. The association between traditional cytotoxic agents with new target-specific agents, such as sorafenib, is a challenge for both clinical and preclinical future investigations in lung cancer treatments.
Cancer research, 1994
A growing body of evidence demonstrates the relevant role of the int-2 (FGF-3) oncogene in human ... more A growing body of evidence demonstrates the relevant role of the int-2 (FGF-3) oncogene in human carcinomas. To investigate its angiogenic activity, the human epithelial mammary cell line MCF-10A was infected with a retroviral expression vector carrying the int-2 oncogene. Infected cells were entrapped in an alginate pellet and placed on the chorioallantoic membrane of chick embryos. After 7 days, a dense capillary network was found to grow toward the pellet, whereas parental cells did not show any angiogenic activity. Conditioned medium from int-2-infected cells was injected i.p. twice daily into rats over a period of 10 days. The mesentery of treated rats showed numerous small blood vessels originating from larger vascular arcades and growing through the stromal layer of the mesentery. In control experiments, neither medium for cell culture nor conditioned medium from parental cells was found to induce angiogenesis. In conclusion, the stimulation of blood vessel growth by int-2-in...
This study aimed to define the maximum-tolerated dose (MTD) of fixed dose rate (FDR) of gemcitabi... more This study aimed to define the maximum-tolerated dose (MTD) of fixed dose rate (FDR) of gemcitabine (2 0-2 0-difluorodeoxycitidine) infusion with circulating haemopoietic progenitor support and to evaluate the activity of the treatment. Secondary end points were pharmacokinetic of gemcitabine and difluorodeoxyuridina (dFdU) measured at first course and the activity andexpression profile of cytidine deaminase (CdA) on circulating mononuclear cells. Patients with advanced pancreatic carcinoma received escalating dose of gemcitabine 10 mg m À2 min À1 every 2 weeks with circulating haemopoietic progenitor support. First dose level was 3000 mg m À2 and the doses were increased by 500 mg m À2 until MTD. In all, 23 patients were enrolled. Toxicities were mild or moderate; the only patient treated at 7000 mg m À2 died because of toxicity; therefore; the MTD was established at 6500 mg m À2. The overall response rate was 22.2%. The AUC of gemcitabine showed a dose-dependent increase, while the AUC of dFdU reached a plateau at 4500 mg m À2. A significant relationship was found between the AUC of dFdU and CdA expression and activity (Po0.05). Moreover, progression rate and survival were significantly related to CdA expression and activity levels. The activity of high-dose gemcitabine is not superior to that reported with less intensive FDR schedules. The predictive role of CdA expression and activity on outcome deserves further investigation.
The pharmacogenetic approach to anti-angiogenic therapy should be considered a possible strategy ... more The pharmacogenetic approach to anti-angiogenic therapy should be considered a possible strategy for many pathological conditions with high incidence in Western countries, including solid tumors, age-related macular degeneration or endometriosis. While pharmacogenetic studies are building stronger foundations for the systematic investigations of phenotype-genotype relationships in many research and clinical fields of medicine, pharmacogenetic data regarding anti-angiogenic drugs are still lacking. Here we review preclinical and clinical genetic studies on angiogenic determinants such as vascular endothelial growth factor and vascular endothelial growth factor receptor-2. We suggest that pharmacogenetic profiling of patients who are candidates for the currently available anti-angiogenic agents targeting vascular endothelial growth factor and vascular endothelial growth factor receptor-2 may aid the selection of patients on the basis of their likelihood of responding to the drugs or suffering from toxicity.
To compare thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phospho... more To compare thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) gene polymorphism and expression in colorectal cancer (CRC), and normal mucosa in chemotherapy-naïve patients. TS, DPD and TP mRNA expression was analysed by real-time reverse-transcription polymerase chain reaction in primary CRC and adjacent normal tissues from 53 patients with glyceraldehyde-3-phosphate dehydrogenase as housekeeping gene. TS promoter (TSER and C/G SNP) and DPD IVS14+1G>A genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism assays. Moreover, the correlation between TS, DPD and TP expression and cytotoxicity of 5-fluorouracil was evaluated in Colo 320, HT-29, CaCo-2 and SW620 human CRC cell lines. TP and DPD mRNA expression was significantly different in tumour and normal tissue (7.51+/-13.50 vs. 1.10+/-0.57, P<0.05 and 0.60+/-0.63 vs. 1.17+/-0.55, P<0.0001, respectively), whereas no differences were observed in TS mRNA levels. High-grade, undifferentiated tumours (WHO grade 3) had significantly higher mRNA levels of TS with respect to moderately differentiated (WHO grade 2) carcinomas (0.38+/-0.37 vs. 0.00+/-0.44, respectively; P<0.05). Noteworthy, TS mRNA expression was significantly decreased (P<0.05) in homozygous TSER*3G/3G (-0.35+/-0.35) with respect to pooled homozygous TSER*2/2 and heterozygous TSER*2/3 genotypes (0.14+/-0.41). In-vitro results showed a higher sensitivity to 5-FU of cell lines with the lowest TS expression. The present results demonstrated significant differences in DPD and TP gene expression between normal mucosa and tumour samples, while TSER*3G/3G and high-grade histology were associated with significant variation in TS gene expression in tumour samples.
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Papers by Mario Del Tacca