Biomedical subjects

F Innocenti

Publications and source records attributed to F Innocenti.

At least 19 recordsLinked to original sources

PubMed2006

Epirubicin/paclitaxel/etoposide in extensive-stage small-cell lung cancer: a phase I-II study.

The aim of this study was to evaluate feasibility and toxicity of escalating doses of epirubicin and paclitaxel plus fixed dose of etoposide and to define the activity of the triplet in extensive disease small-cell lung cancer. Thirteen patients entered the phase I study: the maximum tolerated doses were epirubicin (EpiDX) 90 mg m-2 and paclitaxel (P) 175 mg m-2 with febrile neutropenia as dose-limiting toxicity. The recommended schedule for this regimen for the phase II study was EpiDX 75 mg m-2, P 175 mg m-2, etoposide (E) 100 mg m-2 intravenous (fixed dose) days 1-3 with courses repeated every 21 days. The prophylactic use of colony-stimulating factors (CSFs) was not allowed. Twenty patients entered the phase II trial: median age was 61 years (range 50-70), median Eastern Cooperative Oncology Group performance status 0 (0-2); nine patients had visceral disease and 17 had more than two metastatic sites. A total of 100 courses were administered with a median of 5 (range 1-6) per patients. Main toxicity (NCI-CTC) was myelosuppression: neutropenia grades 3 and 4 in 16 and 35% of the courses, respectively. Seven episodes of febrile neutropenia were documented and one patient required hospital admission. Nonhaematological toxicity was moderate. Seven out of 19 evaluable patients achieved a complete response (37%), nine patients (47.3%) a partial response with an overall response rate of 84.2% (95% confidence interval=60.4-96.6). In this poor prognostic population of patients the triplet epirubicin/paclitaxel/etoposide showed high antitumour activity with mild nonhaematological side effects. The use of CSFs should be able to improve the haematological profile.

Aged↗

PubMed2005

High-resolution pulsed-field-ionization zero-kinetic-energy photoelectron spectroscopic study of the two lowest electronic states of the ozone cation O3+.

The pulsed-field-ionization zero-kinetic-energy (PFI-ZEKE) photoelectron spectrum of jet-cooled O3 has been recorded in the range 101,000-104,000 cm(-1). The origins of the X 1A1-->X+ 2A1 and X 1A1-->A+ 2B2 transitions could be determined from the rotational structure of the bands, the photoionization selection rules, the photoionization efficiency curve, and comparison with ab initio calculations. The first adiabatic ionization energy of O3 was measured to be 101,020.5(5) cm(-1) [12.524 95(6) eV] and the energy difference between the X+ 2A1 (0,0,0) and A+ 2B2 (0,0,0) states was determined to be DeltaT0=1089.7(4) cm(-1). Whereas the X-->X+ band consists of an intense and regular progression in the bending (nu2) mode observed up to v2+=4, only the origin of the X-->A+ band was observed. The analysis of the rotational structure in each band led to the derivation of the r0 structure of O3+ in the X+ [C2v,r0=1.25(2) A,alpha0=131.5(9) degrees ] and A+[C2v,r0=1.37(5) A,alpha0=111.3(38) degrees ] states. The appearance of the spectrum, which is regular up to 102,300 cm(-1), changes abruptly at approximately 102,500 cm(-1), a position above which the spectral density increases markedly and the rotational structure of the bands collapses. On the basis of ab initio calculations, this behavior is attributed to the onset of large-amplitude motions spreading through several local minima all the way to large internuclear distances. The ab initio calculations are consistent with earlier results in predicting a seam of conical intersections between the X+ and A+ states approximately 2600 cm(-1) above the cationic ground state and demonstrate the existence of potential minima at large internuclear distances that are connected to the main minima of the X+ and A+ states through low-lying barriers.

Journal Article↗

PubMed2004

Increased dose-intensity of gemcitabine in advanced non small cell lung cancer (NSCLC): a multicenter phase II study in elderly patients from the "polmone toscano group" (POLTO).

Gemcitabine is usually administered at a planned dose-intensity (DI) from 750 to 800 mg/m2/week. Preclinical data have suggested a possible dose-response relationship of gemcitabine. A multicenter phase II study was conducted to evaluate the activity in terms of no progression rate (complete responses+partial responses+stable diseases) of gemcitabine administered at an increased DI (1000 mg/m2/week) in elderly advanced non-small-cell lung cancer (NSCLC) patients. Secondary endpoints were to evaluate tolerability, progression free survival and overall survival. Elderly (age>or=70 years) chemo-naive advanced NSCLC patients, ECOG PS 0-2, were treated with intravenous gemcitabine 1500 mg/m2 intravenous (30 min infusion) on days 1 and 8 every 21 days for four courses. One hundred and twenty-two patients with a median age of 75 years (range 70-84) entered the study. The following grade 3 (NCI-CTC) haematological toxicities were reported (percent of patients): neutropenia 2.4%, thrombocytopenia 1.6%, anaemia 2.4%. No grades 3-4 non-haematological toxicities were observed. Among 111 evaluable patients 52 (46.8%) no progressions, 17 (15.3%) partial responses (WHO criteria), 35 (31.5%) stable diseases and 59 (53.2%) progressions were observed. Median time to progression was 3.2 months and median duration of survival was 5.4 months. The overall 1-year survival rate was 27%. Although increased dose-intensity of gemcitabine in elderly NSCLC patients is feasible without severe toxicities, this does not seem to be associated with an increased activity and efficacy in comparison to standard gemcitabine regimens with lower dose-intensities.

Age Factors↗

PubMed2003

IL-2 receptor blockers in liver transplantation: initial experience with daclizumab in Chile.

UNLABELLED: Monoclonal antibodies against the interleukin 2 receptor have been developed in an effort to decrease rejection rates and spare calcineurin inhibitors when renal dysfunction occurs after transplant. While success has been reported in kidney transplantation, its effectiveness in liver transplantation is less clear. METHODS: This prospective nonrandomized study including adult patients was performed between October 2000 and April 2003. Two groups of immunosuppressive regimens were compared: group A received 2 g of methylprednisolone intraoperatively followed by a rapid reduction with intention to withdraw by month 4, continuing on Neoral monotherapy. Cellcept was also given for 2 months in the absence or for up to 4 months in the presence of rejection. Group B received the same immunosuppressive regimen but, in addition, daclizumab 1 to 1.5 mg/kg on day 1 and day 5 posttransplant. Rejection diagnosis is made on histology basis. Protocol biopsies were performed in all the patients on day 7 and if indicated by biochemistry thereafter. RESULTS: Both groups were similar in terms of preoperative CHILD score, serum creatinine, incidence of status I, donor and recipient age and ischemia times. The mean follow-up time was 20 months for Group B (n = 24) and 7 months for Group A (n = 10). The 1-month and 1-year rejection rates are 29.1% and 41% in Group A versus 20% and 30% in group B. Rejection severity was similar between both groups. One-year patient and graft survival rates were 96% and 92% in group A and 100% for both in Group B. CONCLUSIONS: In this series, daclizumab induction therapy seems to display a trend toward a lower rejection rate without increasing infectious complications nor affecting graft survival rates.

Adult↗

PubMed2003

High-dose consolidation chemotherapy with Idarubicin and alkylating agents following induction with gemcitabine-epirubicin-paclitaxel in metastatic breast cancer: a dose finding study.

Preliminary randomized studies have failed to show a survival benefit of high-dose chemotherapy with alkylators in advanced breast cancer. Idarubicin is an active agent in breast cancer and is suitable for dose escalation. We designed a dose finding study with escalating high-dose idarubicin (HD-Ida) followed by fixed high-dose thiotepa+melphalan (HD-TM) with peripheral blood progenitor cells (PBPC) in MBC patients with stable disease or in partial response after six courses of induction chemotherapy with gemcitabine 1000 mg/m(2) days 1 and 4, epirubicin 90 mg/m(2) day 1, taxol 175 mg/m(2) day 1 (GET). Aims of the study were to identify the maximum tolerated dose (MTD) of idarubicin, to evaluate the cardiac safety and activity of HD-Ida and HD-TM after GET and to study the pharmacokinetic profile of idarubicin and idarubicinol. A total of 14 patients were treated. Idarubicin was administered as a 48 h continuous i.v. infusion at the following dose levels: 40 mg/m(2) (three patients), 50 mg/m(2) (three patients), 60 mg/m(2) (five patients) and 70 mg/m(2) (three patients). Mucositis was the dose-limiting toxicity and the MTD was 60 mg/m(2). C(max) of Idarubicin and idarubicinol were 7.7+/-2.0 and 26.3+/-9.7 ng/ml at 40 mg/m(2) and increased to 14.8+3.0 and 47.4+12.6 ng/ml at 70 mg/m(2). AUCt(0-264) of idarubicin and idarubicinol increased from 423.2+/-111.6 and 2581+/-606 hng/ml at 40 mg/m(2) to 732.8+/-140.2 and 4590+/-1258 hng/ml at 70 mg/m(2). Conversion rates after HD-Ida and HD-TM were 28.6 and 38.5%, respectively. No episodes of cardiac toxicity were observed. We conclude that HD-Ida followed by HD-TM is feasible and devoid of cardiac toxicity. Moreover, the activity of HD-Ida after a epirubicin-containing regimen suggests incomplete cross-resistance between the two drugs.

Adult↗

PubMed2002

Severe 5-fluorouracil toxicity associated with a marked alteration of pharmacokinetics of 5-fluorouracil and its catabolite 5-fluoro-5,6-dihydrouracil: a case report.

OBJECTIVE: To describe the altered pharmacokinetics of 5-fluorouracil (5-FU) and its major catabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) in a 52-year-old woman affected by a severe 5-FU toxicity. METHODS: Toxicities were rated according to World Health Organization. 5-FU and 5-FDHU plasma concentrations and dihydropyrimidine dehydrogenase (DPD) activity of peripheral blood mononuclear cells (PBMC) were measured by HPLC analysis. RESULTS: After a single cycle of 5-FU therapy the patient developed grade 4 diarrhea and stomatitis, grade 3 vomiting, neutropenia, and dermatitis. Compared to a control population, 5-FU AUC, elimination half-life, and C(max) were markedly increased (24.75 vs. 9.25 +/- 0.63 h microg/ml, >5 vs. 0.36 +/- 0.05 h, and 58.54 vs. 37.2 +/- 4.03 microg/ml, respectively) whereas systemic clearance was decreased (12 vs. 51.29 +/- 2.97 l/h/m2); also 5-FDHU AUC (3.3 vs. 12.35 +/- 0.7 h microg/ml) and C(max) (3.4 vs. 4.56 +/- 0.15 microg/ml), which was reached with delay, were reduced. Surprisingly, the PBMC DPD activity (110.8 pmol/min/mg protein) and urinary uracil (68.32 micromol/g urinary creatinine) were within normal range. CONCLUSIONS: Our results show the altered 5-FU and 5-FDHU pharmacokinetics in a severe 5-FU toxicity case due to an impairment of the hepatic DPD activity and suggest the necessity of a pharmacological evaluation of 5-FU treated patients.

Alopecia↗

PubMed2002

Update on pharmacogenetics in cancer chemotherapy.

This review describes how genetic differences among patients may change the therapeutic outcome in cancer chemotherapy. Severe toxicity in genetically predisposed patients is predominantly associated with mutations in drug metabolism enzyme genes, and an update on genetic intolerance to 6-mercaptopurine, 5-fluorouracil, and irinotecan is provided. Moreover, recent findings pointed out that the methylenetetrahydrofolate reductase (MTHFR) C677T mutation might change patient susceptibility to the toxic effects of the cyclophosphamide, methotrexate, 5-fluorouracil (CMF) regimen and raltitrexed. Finally, it is emerging that not only toxicity, but also response to chemotherapy could be influenced by pharmacogenetic determinants, and the clinical relevance of polymorphisms in thymidylate synthase (TS) and glutathione-S-transferase (GST) genes is discussed.

Antineoplastic Agents↗

PubMed2001

Pharmacogenetics in cancer treatment.

Interindividual variability in the efficacy and toxicity of drug therapy is associated with polymorphisms in genes encoding drug-metabolizing enzymes, transporters, or drug targets. Pharmacogenetics aims to identify individuals predisposed to high risk of toxicity from conventional doses of cancer chemotherapeutic agents. We review the role of genetic polymorphisms in UGT1A1 and TPMT, as well as mutations in DPD, in influencing drug disposition and toxicity. Recent studies show that pharmacogenetic determinants may also influence treatment outcomes. We discuss the clinical significance of polymorphisms in TS, MTHFR, and FCGR3A, as well as the polymorphic DNA repair genes XPD and XRCC1, in influencing response to chemotherapy and survival outcomes. Finally, the potential implications of transporter pharmacogenetics in influencing drug bioavailability are addressed.

Antineoplastic Agents↗

PubMed2001

Cardiac and vascular remodeling in older adults with borderline isolated systolic hypertension: the ICARe Dicomano Study.

Although borderline isolated systolic hypertension (ISH), defined as a blood pressure of 140 to 159/<90 mm Hg, is a proven cardiovascular risk factor, the major clinical trials on treatment of ISH have used a cutoff of 160 mm Hg. Moreover, no data exist on the cardiovascular modifications associated with borderline ISH. Therefore, we compared subjects with borderline ISH to subjects with diastolic hypertension (diastolic blood pressure > or =90 mm Hg) or ISH. Community-dwelling residents (age > or =65 years) of a small town in Italy (Dicomano) underwent extensive clinical examination, echocardiography, carotid ultrasonography, and applanation tonometry. Only untreated subjects were included in this analysis: 95 with diastolic hypertension, 87 with borderline ISH, and 43 with ISH. Despite lower systolic and mean pressures in borderline ISH, left ventricular mass was similar to that in diastolic hypertension. In univariate and multivariate analysis, pulse pressure but not systolic pressure was related to left ventricular mass. Borderline ISH subjects had a tendency to greater carotid cross-sectional area and stiffness index than did diastolic hypertensive subjects despite lower mean carotid pressure, whereas the number of atherosclerotic plaques was similar in the 2 groups. Pulse pressure but not systolic pressure was independently related to carotid remodeling. In our community-based, older population, individuals with borderline ISH had a similar prevalence of left ventricular hypertrophy and carotid atherosclerosis as that of subjects with diastolic hypertension, despite lower systolic and mean pressures. Among blood pressure values, pulse pressure was the single or strongest independent predictor of cardiovascular remodeling.

Aged↗

PubMed2001

Thymoglobulin induction decreases rejection in solitary pancreas transplantation.

BACKGROUND: Solitary pancreas transplants, both pancreas transplant alone (PTA) and pancreas after kidney (PAK), have higher rejection rates and lower graft survivals than simultaneous pancreas-kidney transplants (SPK). The aim of this study is to compare three different antibody induction regimens in solitary pancreas transplant recipients and to assess the role of surveillance pancreas biopsies in the management of these patients. METHODS: Solitary pancreas transplant recipients between 01/98 to 02/00 (n=29) received induction with either daclizumab (1 mg/kg on day 0, 7, 14), OKT 3 (5 mg/day x0-7), or thymoglobulin (1.5 mg/kg/day x0-10). Maintenance immunosuppression was similar for the three groups. All rejections were biopsy-proven either by surveillance/protocol or when clinically indicated. RESULTS: The 1-year graft survival was 89.3% overall and 91.7% in the thymoglobulin group. Thymoglobulin significantly decreased rejection in the first 6 months when compared with OKT3 or daclizumab (7.7 vs. 60 vs. 50%). Acute rejections were seen on surveillance biopsies in the absence of biochemical abnormalities in 40% of patients. CONCLUSIONS: Thymoglobulin induction regimen led to a low incidence of acute rejection and a high rate of graft survival in solitary pancreas transplants. In addition, surveillance biopsies were useful in the detection of early acute rejection in the absence of biochemical abnormalities.

Adult↗

PubMed2001

The risk of second malignant tumors and its consequences for the overall survival of Hodgkin's disease patients and for the choice of their treatment at presentation: analysis of a series of 1524 cases consecutively treated at the Florence University Hospital.

PURPOSE: To quantify the incidence of second malignant tumors (SMT) as a whole and that of second "solid" tumors (SST) and leukemia (L) in a large series of 1524 Hodgkin's disease (HD) patients (pts) treated at the Florence University Hospital (UFH); to define the clinical and therapeutic features possibly related with SMT occurrence; to evaluate the consequences of SMT for the overall survival of the series studied and for the choice of the treatment of HD at presentation. METHODS AND MATERIALS: From 1960 to 1991, 1524 pts with HD, Clinical Stage (CS) I--IV have been treated at the UFH. Overall treatment consisted of radiation alone (RT, 36%), chemotherapy alone (CHT, 21%), or both (RT + CHT, 43%). The cumulative probability (CP) of SMT, SST, and L was calculated for the whole series and for the different clinical and therapeutic subgroups, and the results compared with uni- and multivariate analysis ("internal" comparison, IC). Standardized incidence ratios (SIR) for different SMT types (estimated on the basis of gender, age, period specific incidence rates of the general population) have been also calculated ("external" comparison, EC). The impact of the SMT-related mortality on the survival of the entire series has been estimated. RESULTS: A 14.9% 20-year CP of SMT was registered, along with a SIR of 2.04 (95% confidence interval [CI]: 1.2--2.5). Both IC and EC showed a statistically significant relationship between L incidence and treatment with CHT, alone or in combination with RT. A significant excess of breast cancers has been observed in RT-treated patients with longer follow-up (SIR, 2.9); an excess of other common SST (lung, non-Hodgkin's lymphomas) is evident in pts treated with either RT, RT + CHT, or CHT. The actuarial long-term survival of the series would have been better of about 3%, in absence of the SMT mortality possibly due to HD treatment, which is almost equally divided between patients treated with RT alone, CHT alone, and RT + CHT. CONCLUSIONS: SMT represent an important late event in HD long-term survivors. The relationship between L and treatment with CHT seems to be the most clearly defined. The effect of SMT on the survival of the entire series, although not negligible, does not seem to justify by itself substantial alterations in the current standards for the treatment of HD at presentation.

Adult↗

PubMed2001

High-dose thiotepa and melphalan with hemopoietic progenitor support following induction therapy with epirubicin-paclitaxel-containing regimens in metastatic breast cancer (MBC).

BACKGROUND: Preliminary data from phase III randomized studies have failed to show benefit of HDC given as consolidation after anthracycline and alkylating-based chemotherapy in metastatic breast cancer (MBC). Moderate activity of induction regimens and selection of chemoresistant clones are among the possible reasons for these disappointing results. We therefore have designed a phase II study where high-dose alkylating agents are given as consolidation after an induction treatment including the most active agents (epirubicin and paclitaxel) without alkylating agents. PATIENTS AND METHODS: Patients with MBC not previously treated with chemotherapy for metastatic disease were eligible. After six courses of epirubicin-paclitaxel +/- gemcitabine patients received a course of thiotepa 600 mg/m2 + melphalan 160 mg/m2 with hemopoietic support. Pharmacokinetic parameters of thiotepa and melphalan were measured and related to treatment outcomes. The L-VEF of the patients was monitored before and after treatment. RESULTS: Forty-eight patients have been treated. Before HDC 14 patients were in CR, and 34 in PR. A median of 6.92 x 10(6) (range 1.53-16.6) CD34+ cells/kg were reinfused after HDC. Median days (range) to neutrophils > 0.5 x 10(9)/l and platelets > 20,000 x 10(9)/l were 9.5 (9-33) and 10 days (9-32), respectively. Symptomatic CHF was observed in two patients (4.1%). Cmax and AUC of thiotepa showed a linear relationship with time to progression (TTP) and overall survival (OS): r2 = 0.6. After HDC the conversion rate from PR to CR was 44.1%. At five years progression-free and overall survival rates are 37.5% and 65%, respectively. A treatment-related death was observed. CONCLUSIONS: High-dose thiotepa and melphalan after an epirubicin-paclitaxel-containing treatment is feasible, devoid of significant cardiotoxicity and very active. Pharmacokinetic parameters of high-dose thiotepa might be linked to treatment outcome.

Adult↗

PubMed2001

Outcome of the use of pediatric donor livers in adult recipients.

The prolonged waiting time caused by the lack of donor livers leads to an increasing number of terminally ill patients waiting for lifesaving liver transplantation. To rescue these patients, transplant programs are accepting donor organs from the expanded donor pool, using donors of increasingly older age, as well as from the pediatric age group, often despite significant mismatch in liver size. We investigated the outcome of 102 consecutive liver transplantations using pediatric donor livers in adult recipients. One-year graft survival using donors aged 12 years or younger (group 1, n = 14) and donors aged 12 to 18 years (group 2, n = 88) was compared. In addition, risk factors for graft loss and vascular complications were analyzed. The 1-year graft survival rate in adult transplant recipients in group 1 was 64.3% compared with 87.5% in those in group 2 (P =.015). The main cause of graft loss was arterial complications, occurring in 5 of 16 transplant recipients (31.3%). Major risk factors for graft loss and vascular complications were related to the size of the donor: age, height and weight, body surface area of donor and recipient, and warm ischemic time. We conclude that the outcome of small pediatric donor livers in adult recipients is poor, mainly because of the increased incidence of arterial complications. When a pediatric donor is used in an adult recipient, ischemic time should be kept to a minimum and anticoagulative therapy should be administered in the immediate postoperative period to avoid arterial complications. However, because small pediatric donors are the only source of lifesaving organs for the infant recipient, the use of small pediatric donor livers in adults should be avoided.

Adolescent↗

PubMed2001

Pharmacogenetics of anticancer agents: lessons from amonafide and irinotecan.

Amonafide and irinotecan are anticancer drugs representative of the clinical relevance of N-acetyltransferase (NAT) and uridine diphosphate glucuronosyltransferase (UGT) polymorphisms in cancer chemotherapy, respectively. Amonafide, a substrate for the polymorphic NAT2, has an active metabolite, N-acetyl-amonafide. Using caffeine as a probe, slow and rapid acetylators of amonafide were identified. Fast acetylators experienced greater myelosuppression than did slow acetylators, and a reduced dose of amonafide for fast acetylators has been recommended. A pharmacodynamic model based on acetylator phenotype, pretreatment white blood cell count, and gender has been proposed for dose individualization. The strategy adopted for amonafide is a model for future investigations in pharmacogenetics, although amonafide is no longer in clinical development. SN-38, the active metabolite of irinotecan, is glucuronidated to the inactive SN-38 glucuronide by UGT1A1, the isoform catalyzing bilirubin glucuronidation. Genetic defects in UGT1A1 determine Crigler-Najjar and Gilbert's syndromes characterized by unconjugated hyperbilirubinemia. Gilbert's syndrome often remains undiagnosed and occurs in up to 19% of individuals. Gilbert's syndrome is due to a homozygous TA insertion in the TATAA promoter of UGT1A1, leading to the mutated (TA)(7) allele. Irinotecan toxicity depends on the individual glucuronidation rate of SN-38. Decreased SN-38 glucuronidating activity has been found in livers obtained from individuals carrying the (TA)(7) allele. A phenotyping procedure for UGT1A1 has not been identified and genotyping of the UGT1A1 promoter in patients receiving irinotecan may identify patients at increased risk of toxicity. A clinical trial at the University of Chicago is ongoing to demonstrate the predictive significance of UGT1A1 genotyping for irinotecan pharmacodynamics.

Adenine↗

PubMed2001

Epirubicin glucuronidation is catalyzed by human UDP-glucuronosyltransferase 2B7.

Epirubicin is one of the most active agents for breast cancer. The formation of epirubicin glucuronide by liver UDP-glucuronosyltransferase (UGT) is its main inactivating pathway. This study aimed to investigate epirubicin glucuronidation in human liver microsomes, to identify the specific UGT isoform for this reaction, and to correlate epirubicin glucuronidation with other UGT substrates. Microsomes from human livers were used. UGTs specifically expressed in cellular systems, as well as two UGT2B7 variants, were screened for epirubicin glucuronidation. Epirubicin, morphine, and SN-38 glucuronides were measured by high-pressure liquid chromatography. The mean +/- S.D. formation rate of epirubicin glucuronide in human liver microsomes (n = 47) was 138 +/- 37 pmol/min/mg (coefficient of variation, 24%). This phenotype was normally distributed. We screened commercially available UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 for epirubicin glucuronidation. Only UGT2B7 converted epirubicin to its glucuronide. No differences in epirubicin glucuronidation were found in HK293 cells expressing the two UGT2B7 variants at position 268. Catalytic efficiency (V(max)/K(m)) of epirubicin glucuronidation was 1.4 microl/min/mg, a value higher than that observed for morphine, a substrate of UGT2B7. Formation of epirubicin glucuronide was significantly related to that of morphine-3-glucuronide (r = 0.76, p < 0.001) and morphine-6-glucuronide (r = 0.73, p < 0.001). No correlation was found with SN-38, a substrate of UGT1A1 (r = 0.04). UGT2B7 is the major human UGT catalyzing epirubicin glucuronidation, and UGT2B7 is the candidate gene for this phenotype. The reported tyrosine to histidine polymorphism in UGT2B7 does not alter the formation rate of epirubicin glucuronide, and undiscovered genetic polymorphisms in UGT2B7 might change the metabolic fate of this important anticancer agent.

Catalysis↗

PubMed2000

Manumycin inhibits ras signal transduction pathway and induces apoptosis in COLO320-DM human colon tumour cells.

The aim of the present study was to assess the cytotoxicity of manumycin, a specific inhibitor of farnesyl:protein transferase, as well as its effects on protein isoprenylation and kinase-dependent signal transduction in COLO320-DM human colon adenocarcinoma which harbours a wild-type K-ras gene. Immunoblot analysis of isolated cell membranes and total cellular lysates of COLO320-DM cells demonstrated that manumycin dose-dependently reduced p21 ras farnesylation with a 50% inhibitory concentration (IC50) of 2.51 +/- 0.11 microM and 2.68 +/- 0.20 microM, respectively, while the geranylgeranylation of p21 rhoA and p21rap1 was not affected. Manumycin dose-dependently inhibited (IC50 = 2.40 +/- 0.67 microM) the phosphorylation of the mitogen-activated protein kinase/extracellular-regulated kinase 2 (p42MAPK/ERK2), the main cytoplasmic effector of p21ras, as well as COLO320-DM cell growth (IC50 = 3.58 +/- 0.27 microM) without affecting the biosynthesis of cholesterol. Mevalonic acid (MVA, 100 microM), a substrate of the isoprenoid synthesis, was unable to protect COLO320-DM cells from manumycin cytotoxicity. Finally, manumycin 1-25 microM for 24-72 h induced oligonucleosomal fragmentation in a dose- and time-dependent manner and MVA did not protect COLO320-DM cells from undergoing DNA cleavage. The present findings indicate that the inhibition of p21ras processing and signal transduction by manumycin is associated with marked inhibition of cell proliferation and apoptosis in colon cancer cells and the effect on cell growth does not require the presence of a mutated ras gene for maximal expression of chemotherapeutic activity.

Alkyl and Aryl Transferases↗

PubMed2000

Variable correlation between 6-mercaptopurine metabolites in erythrocytes and hematologic toxicity: implications for drug monitoring in children with acute lymphoblastic leukemia.

Nineteen pediatric patients affected by acute lymphoblastic leukemia (ALL) were examined weekly with respect to 6-mercaptopurine nucleotide (6-MPN) and 6-thioguanine nucleotide (6-TGN) levels in erythrocytes during the course of maintenance treatment with 6-MP 50 mg/m2 per d and results were related to various parameters of bone marrow function to assess, in the same individual, the level of reliability of 6-MP metabolites in predicting a later change in peripheral blood cell counts. Median values for 6-MPN and 6-TGN were 57 and 200 pmol/8 x 10(8) erythrocytes, respectively, as measured by reversed-phase high-performance liquid chromatography (HPLC). 6-TGN levels in erythrocytes were inversely related with white blood cell count (r = -0.463, p < 0.0001, n = 361), absolute neutrophil count (r = -0.386, p < 0.0001, n = 347), erythrocyte (r = -0.354, p < 0.0001, n = 287), and platelet counts (r = -0.24, p < 0.0001, n = 319) in the majority of patients (n = 10-12), while no correlation was found for 6-MPN. In the remaining children, no evidence of correlation was demonstrated between 6-TGN levels and myelotoxicity. The results confirm the role of 6-TGN as the reference cytotoxic metabolite for evaluating the exposure to 6-MP and identifying treatment compliance in ALL children but indicate the limits of a follow-up based solely on metabolite levels and suggest that a more correct approach remains the double monitoring of 6-TGN and blood cell count with differential.

Adolescent↗

PubMed2000

Pharmacogenetics: a tool for individualizing antineoplastic therapy.

This article reviews the clinical relevance of pharmacogenetics in cancer chemotherapy, with emphasis on drugs for which genetic differences in enzyme metabolism have been demonstrated to affect patient outcome. About 10% of children with leukaemia are intolerant to mercaptopurine (6-mercaptopurine) because of genetic defects in mercaptopurine inactivation by thiopurine S-methyltransferase. However, mercaptopurine dose intensity, a critical factor for outcome in patients deficient in thiopurine S-methyltransferase, can be maintained by means of thiopurine S-methyltransferase phenotyping or genotyping. Patients with reduced fluorouracil (5-fluorouracil) catabolism are more likely to be exposed to severe toxicity. The measurement of dihydropyrimidine dehydrogenase activity in patients cannot be considered fully predictive, and the role of dihydropyrimidine dehydrogenase gene variants in this syndrome has yet to be clarified. With regard to irinotecan, patients with Gilbert's syndrome phenotype have reduced inactivation of the active topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN-38) caused by a mutation in the UDP-glucuronosyltransferase 1A1 gene promoter. This subset of patients is more likely to be exposed to irinotecan toxicity and could be identified by genotyping for gene promoter variants. Finally, the experience with amonafide represents a model for dose individualization approaches that use simple phenotypic probes.

Adenine↗