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Biomedical subjects

A Falcone

Publications and source records attributed to A Falcone.

At least 19 recordsLinked to original sources
PubMed1999

Suramin in combination with weekly epirubicin for patients with advanced hormone-refractory prostate carcinoma.

BACKGROUND: Suramin and epirubicin are both active agents in the treatment of patients with hormone-refractory advanced prostate carcinoma, with demonstrated antitumor synergism in vitro on human prostate carcinoma cells and different dose-limiting toxicities. The authors conducted this Phase II study to determine the feasibility, toxicity, and antitumor activity of suramin in combination with epirubicin. METHODS: Only patients with hormone-independent advanced prostate carcinoma who had progressive disease after the last therapeutic maneuver they had undergone, including antiandrogen withdrawal, entered the study. Suramin was administered initially as a 6-day continuous infusion for 10 consecutive weeks and then for 6 days every 28 days for a maximum of 6 months. Doses were determined by a computer-assisted dosing system that used Bayesian pharmacokinetics to maintain suramin plasma concentrations of 200-250 microg/mL. Cortisone acetate 25 mg, administered at 8 a.m. and 8 p.m. daily, was begun 4 weeks after the initiation of suramin therapy. Epirubicin 25 mg/m2 was given as a weekly intravenous bolus beginning on Day 1 and was continued for a maximum of 6 months. RESULTS: Twenty-six patients entered the study. Toxicities mainly included World Health Organization Grade 1-2 nausea, fatigue, anorexia, neutropenia, peripheral neuropathy, creatinine elevation, proteinuria, and prolonged prothrombin time, whereas Grade 3 toxicities were uncommon. Among 11 patients with measurable disease, 3 (27%) demonstrated an objective response. Among 24 patients evaluated for prostate specific antigen (PSA) response, 8 (33%; 95% confidence interval 16-55%) had a > or =50% decrease in PSA levels, which lasted a median of 32 (range, 8-52) weeks. Median progression free and overall survival were both 8 months. CONCLUSIONS: The combination of suramin and epirubicin used in the current study is feasible, is associated with moderate toxicities, and has antitumor activity in advanced hormone-refractory prostate carcinoma. However, the results obtained with this combination do not represent major improvements in the treatment of patients with this disease, compared with suramin or epirubicin alone or other available treatments.

Aged↗
PubMed1999

Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus-based chemotherapy: a phase II study.

Continuous-infusion (c.i.) 5-fluorouracil (5-FU) can overcome resistance to bolus 5-FU, and leucovorin (LV) enhances the cytotoxic effects of 5-FU, mainly when the duration of exposure to the latter is prolonged. The main objective of this study was therefore to determine the activity of a prolonged infusion schedule of 5-FU + LV in patients with metastatic colorectal cancer resistant to a 5-FU bolus-based chemotherapy. Only patients with metastatic measurable disease in progression during or within 2 months of the end of a 5-FU bolus +/- LV-based chemotherapy were eligible for the study. 5-FU and l-LV were given as a 14-day c.i. every 28 days, the 5-FU dose being 200 mg/m2 per day and the l-LV dose being 5 mg/m2 per day. A total of 59 patients entered the study, of which 48 were resistant to 5-FU + LV and 11, to 5-FU + levamisole. Treatment was well tolerated, and WHO grade 3-4 toxicities were uncommon (11% of patients developed stomatitis and 7%, diarrhea). According to an intent-to-treat analysis, 10 of 59 patients obtained an objective response (1 complete response, 9 partial responses), for an objective response rate of 16% (95% confidence interval 8-25%). The median progression-free survival and overall survival were 4 and 9 months, respectively. The protracted 5-FU + LV c.i. schedule used in the present study is a well-tolerated and moderately active regimen in metastatic colorectal cancer patients resistant to 5-FU bolus +/- LV. Only randomized studies can determine whether this palliative treatment has advantages in comparison with other second-line therapies such as 5-FU c.i. without LV, irinotecan, or oxaliplatin.

Adult↗
PubMed1999

Effects of chronic anti-interleukin-5 monoclonal antibody treatment in a murine model of pulmonary inflammation.

The maturation of eosinophils in bone marrow, their migration to pulmonary tissue, and their subsequent degranulation and release of toxic granule proteins contributes to the pathophysiology observed in asthma. Interleukin-5 (IL-5) is essential for these processes to occur. Therefore, much emphasis has been placed on attempts to inhibit the production or activity of IL-5 in order to attenuate the inflammatory aspect of asthma. In this report, the immunological consequences of long-term exposure to an antibody recognizing IL-5 (TRFK-5) were studied in a murine pulmonary inflammation model. A single dose of TRFK-5 (1 mg/ kg, intraperitoneally) reversibly inhibited antigen-dependent lung eosinophilia in mice for at least 12 wk and inhibited the release of eosinophils from bone marrow for at least 8 wk. Normal responses to aerosol challenge were attained after 24 wk. In mice treated acutely with antibody (2 h before challenge), 50% inhibition of pulmonary eosinophilia occurred when 0. 06 mg/kg TRFK-5 was administered (intraperitoneally; ED50), resulting in 230 ng/ml (IC50) in serum. In mice treated with one dose of TRFK-5 (1 mg/kg) and rested before challenge, the antibody exhibited a half-life of 2.4 wk. After 18 to 19 wk, antigen challenge-induced eosinophilia was inhibited by 50% and serum levels of TRFK-5 were 25 ng/ml. TRFK-5 remaining in mice 8 wk after a single injection of TRFK-5 was sufficient to inhibit at least 50% of the eosinophilia induced in blood 3 h after injection of recombinant murine IL-5 (10 microg/kg, intravenously). To assess the biologic effect of long-term exposure of mice to antibody, several parameters of immune-cell function were measured. Throughout the extended period of activity of TRFK-5 (>/= 12 wk) there were no gross effects on antigen-dependent increases in T-cell recruitment into bronchoalveolar fluid (BALF), in IL-4 and IL-5 steady-state mRNA levels in lung tissue, or in immunoglobulin E (IgE) and IgG levels in serum. There was a small increase in IL-5 steady-state mRNA production in TRFK-5-treated mice after 2 h or 2 wk, but this was not observed at other times examined. In untreated mice, IL-5 steady-state mRNA production in response to antigen challenge decreased > 6-fold with age, although at all time points there was an increase in mRNA levels following challenge. Therefore, at later times, 25 ng/ml rather than 230 ng/ml of TRFK-5 inhibited BALF eosinophilia, probably because of reduced IL-5 levels. Twenty-four weeks after treatment with TRFK-5, when challenge-induced eosinophilia was restored, there was an excess of CD4(+) T cells in BALF from challenged mice. However, these T cells had no measurable effects on other responses to challenge, including cytokine production, B-cell accumulation, and immunoglobulin production in serum. Thus, the biologic duration of TRFK-5 was several months, and its activity was due to the presence of antibody above a therapeutic threshold rather than to any profound effect on the immune system.

Animals↗
PubMed1999

Effects of cyclosporin A and dinactin on T-cell proliferation, interleukin-5 production, and murine pulmonary inflammation.

We compared the effects of cyclosporin A (CSA) and a macrotetrolide antibiotic, dinactin, on human T-cell proliferation and cytokine production induced by stimulation of the T-cell receptor alone (monoclonal antibody [mAb] directed against CD3) or in combination with costimulatory signals (mAbs directed against CD3 and CD28). These agents were also examined in a murine model of interleukin (IL)-5-mediated pulmonary inflammation. Dinactin inhibited T-cell proliferation induced by IL-2, by mAb to CD3, and by mAbs to CD3 plus alpha-CD28 with identical dose-response curves (IC50 = 10-20 ng/ml). Dinactin inhibited cytokine production with IC50 values of 10 ng/ml for IL-4 and IL-5 and 30 or 60 ng/ml for interferon-gamma or IL-2, respectively. Unlike CSA, exogenous IL-2 did not alter the dinactin-mediated effects on T cells, and nuclear run-on and steady-state messenger RNA (mRNA) analysis showed that dinactin inhibited cytokine production through a post-transcriptional mechanism. CSA selectively blocked T-cell receptor-induced T-cell proliferation and cytokine production (IC50 = 10 ng/ml). Under costimulatory conditions, IL-5 synthesis was only minimally inhibited by high concentrations of CSA, and at CSA concentrations of less than 125 ng/ml, IL-5 was significantly increased above control values. Dinactin and CSA reduced pulmonary eosinophilia when administered within 1 d of airway antigen challenge. Of the cytokine mRNAs examined in the lungs of CSA-pretreated, antigen-challenged mice, IL-5 mRNA levels were the least reduced, paralleling the resistance of IL-5 to CSA observed in vitro and suggesting a role for CD28 in the in vivo induction of IL-5.

Animals↗
PubMed1998

Splenectomy and risk of blast transformation in myelofibrosis with myeloid metaplasia. Italian Cooperative Study Group on Myeloid with Myeloid Metaplasia.

An unexpectedly high incidence of blast transformation after splenectomy has been reported in patients with myelofibrosis with myeloid metaplasia. However, whether this was associated with spleen removal after adjustment for risk factors was not determined. We conducted a multicenter historical cohort study of patients with myelofibrosis with myeloid metaplasia diagnosed from January 1970 through January 1994. A total of 549 patients (325 men and 224 women from 22 to 92 years of age; median age, 63 years) were included in the final data set. The Cox's proportional-hazards model was used to identify factors associated with blast transformation and death. To further adjust for factors related to spleen removal assignment, a propensity score for splenectomy was estimated using recursive-partitioning analysis. Blast transformation developed in 78 patients (14.2%). Patients who underwent splenectomy developed more blast transformations than those who were not splenectomized (23 of 87 [26.4%] v 55 of 462 [11.9%]; P < .001). The cumulative incidence of blast transformation 12 years after diagnosis was 27.0% in nonsplenectomized patients and 55.0% in splenectomized ones (P = . 01). The risk factors independently predictive of blast transformation included prior splenectomy (relative risk = 2.61), platelet count less than 100 x 10(9)/L at diagnosis (relative risk = 2.45), and the presence of blasts in peripheral blood at diagnosis (relative risk = 2.31). The relative risk of blast transformation in splenectomized patients increased from 2.2 at 48 months from diagnosis to 14.3 at 12 years. Patients with the same propensity score for splenectomy showed a higher risk for blast transformation on the basis of having undergone splenectomy (P = .02). In conclusion, the risk of blast transformation is significantly increased in subjects who underwent splenectomy and appears to be independent of factors related to spleen removal assignment.

Adult↗
PubMed1998

Eosinophils retain their granule major basic protein in a murine model of allergic pulmonary inflammation.

Accumulation of eosinophils in the lung with concomitant tissue damage are defining histopathologic features of human asthma. Through degranulation and the release of proinflammatory proteins such as major basic protein (MBP), eosinophils may perpetuate this inflammatory response. We investigated the extent of eosinophil degranulation in a murine model of allergic pulmonary inflammation. In this paradigm, the mice develop pulmonary eosinophilia, mucus hypersecretion, tissue damage, and airway edema and hyperreactivity. To evaluate the degree of eosinophil degranulation, we used a polyclonal antibody to murine MBP (mMBP) to perform dot blot analysis of bronchoalveolar lavage (BAL) cells and fluids, and immunohistochemical fluorescent analysis of lung tissue sections. After ovalbumin antigen challenge, we were unable to detect immunoreactive mMBP in the BAL fluids from either nonsensitized or sensitized mice. However, after lysis of the recoverable BAL cells, we were able to detect mMBP by immunoblot analysis, with the levels of immunoreactive mMBP directly related to the number of recoverable eosinophils. We also examined paraffin-embedded, lung tissue sections for patterns of mMBP deposition. Whereas lung sections from allergic mice revealed prominent peribronchial eosinophilia after antigen challenge, tissue sections from nonsensitized animals rarely displayed eosinophils. Despite the presence of numerous eosinophils, no immunohistologic evidence of extracellular mMBP could be found in antigen-challenged allergic mice. Furthermore, rechallenged allergic mice displayed a significant increase in the number of recruited pulmonary eosinophils but all immunoreactive mMBP was still intracellular. We conclude that the recruited pulmonary eosinophils have not substantially degranulated. These results suggest that, in this murine model of allergic inflammation, eosinophil degranulation and release of mMBP does not contribute to the observed pulmonary inflammation and airway hyperreactivity.

Animals↗
PubMed1998

Pharmacokinetic optimisation of the treatment of cancer with high dose zidovudine.

The thymidine analogue zidovudine is currently used for the treatment of HIV-infected patients, as the early development of the drug as an anticancer agent yielded modest results. A comprehensive preclinical analysis, however, showed that inhibitors of de novo thymidylate synthesis, including fluorouracil and methotrexate, enhanced the antiproliferative activity of zidovudine in cancer cells. Significant inhibition of tumour growth was obtained in mice bearing human colon cancer xenografts and given intraperitoneal zidovudine 300 to 600 mg/kg weekly in combination with methotrexate 87.5 mg/kg or intraperitoneal fluorouracil 85 mg/kg, and in pharmacokinetic studies high peak drug plasma concentrations (Cmax) of zidovudine were obtained, ranging from 610.3 to 1698.8 mumol/L. In order to exploit the therapeutic activity of zidovudine, phase I and II clinical studies were designed in combination with fluorouracil and the pharmacokinetic-pharmacodynamic profile of zidovudine was investigated. Clinical responses were obtained in patients treated intravenously with bolus fluorouracil 500 mg/m2, leucovorin and short (90 to 120 minutes) infusions of high dose zidovudine (up to 10 g/m2), generating drug Cmax similar to those obtained in preclinical models. However, in chemotherapy-pretreated patients receiving high dose zidovudine by the oral route (1 to 9 g/m2/day) or 48-hourly continuous intravenous infusion (2 to 20 g/m2/day) in combination with fluorouracil and leucovorin, treatment failures were observed despite high systemic exposure, described as the area under the plasma concentration-time curve and the occurrence of DNA strand breaks in peripheral blood mononucleated cells, the biological expression of zidovudine activity. In conclusion, preclinical and clinical evidence suggest that the schedule of administration of zidovudine is a requisite for the expression of its activity, indicating the importance of concentration-monitored trials to optimise chemotherapy dose administration in patients. The likelihood of tumour response appears to be related to the achievement of high peak plasma concentrations of zidovudine, and constant infusions appear less likely to produce clinical results.

Animals↗
PubMed1998

Anti-inflammatory activity of inhaled mometasone furoate in allergic mice.

Mometasone furoate (CAS 83919-23-7, Sch 32088) is a new inhaled corticosteroid that is being developed to treat allergic inflammatory airway disorders such as rhinitis and asthma. In this study, we investigated the effects of inhaled mometasone furoate in allergic mice that, after antigen challenge, develop an influx of eosinophils and T cells and display an increased mRNA expression of proinflammatory cytokines in the lungs. Mometasone furoate aerosol was generated from metered dose inhalers and delivered into an animal exposure chamber. The mice were exposed to mometasone furoate by nose-only inhalation at respired doses ranging from 0.5-33 micrograms/kg given 24, 18 and 2 h before aeroallergen challenge. The elevated eosinophil numbers in the bronchoalveolar lavage fluid and lung tissues of sensitized, ovalbumin challenged mice were dose-dependently inhibited by inhaled mometasone furoate. Increased numbers of Thy1+ T cells and CD4+ (T-helper) and CD8+ (T-cytotoxic) T cell subsets were seen in the bronchoalveolar lavage fluid of ovalbumin-challenged mice. Pretreatment of these animals with mometasone furoate (33 micrograms/kg) reduced the number of Thy1+ T cells and the T-helper subset. Furthermore, mometasone furoate (33 micrograms/kg) reduced the percentage of CD44+ T-helper cells (activated/memory cells) to the levels observed in non-sensitized, ovalbumin-challenged mice. There were increased levels of steady-state mRNA for interleukin-4, interleukin-5, and to a lesser extent, gamma-interferon in the lungs of sensitized mice after ovalbumin challenge and pretreatment with mometasone furoate reduced the steady-state mRNA levels of these cytokines. Our results demonstrate a potent lung anti-inflammatory effect of inhaled mometasone furoate and identify that inhibition of T cell influx, eosinophil accumulation and modulation of cytokine activity are important components of this response.

Administration, Inhalation↗
PubMed1998

Effect of cyclosporin-A on anemia in idiopathic myelofibrosis.

The recent report of Pietrasanta et al., describe an improvement of anemia in a case of idiopathic myelofibrosis (IMF) treated with cyclosporin-A (CyA) for Psoriatic skin lesions. We have also used CyA in four IMF patients, all with transfusion dependent anemia . We report briefly the clinical aspects, hematological parameters and responses to the treatment for every patient.

Aged↗
PubMed1997

[Infiltrating intramuscular lipoma].

Intramuscular lipomas are rare, benign unencapsulated tumors. They are also called infiltrating lipomas because of their infiltrative growth pattern which, deeply localized, seizes the skeleton muscle. The only obvious symptom is a palpable mass. Microscopically, monovacular fat tissue shows up between the muscle fiber. In extreme cases the preexisting muscle can be totally replaced by fat tissue. A precise pathohistological examination is needed to avoid the mistaken diagnosis of a well-differentiated liposarcoma. Late diagnosis, the extent and the localization of the tumor often do not allow for an R0 resection and influence the postoperative recurrence rates, which lie between 3 and 62%. R0 resections are not desirable when postoperative severe loss of function can be expected. Malfunctions will slowly take place and can greatly be compensated, in contrast to a radical procedure with immediate loss of function.

Aged↗
PubMed1997

Maximum tolerable doses of intravenous zidovudine in combination with 5-fluorouracil and leucovorin in metastatic colorectal cancer patients. Clinical evidence of significant antitumor activity and enhancement of zidovudine-induced DNA single strand breaks in peripheral nuclear blood cells.

BACKGROUND: Experimental studies have demonstrated that 5-fluorouracil (5-FU) enhances zidovudine (AZT)-induced DNA strand breaks and cytotoxicity. Phase I studies have demonstrated that the maximum tolerable dose (MTD) of AZT is 8000 mg/sqm when administered i.v. over two hours after weekly 5-FU + l-leucovorin (LV), and that this combination has promising antitumor activity. The purpose of this study was therefore to evaluate the antitumor activity of weekly bolus 5-FU + LV + AZT, administered at its MTD, and to determine whether 5-FU enhances AZT-induced DNA strand breaks in blood nuclear cells. PATIENTS AND METHODS: Twenty-nine chemotherapy-naïve metastatic colorectal cancer patients with measurable disease entered the study to evaluate the activity of a weekly 5-FU 500 mg/m2 i.v. bolus + LV 250 mg/m2 i.v. two-hour infusion + AZT 8000 mg/m2 i.v. two-hour infusion. In 10 different patients, who during three different weeks received 5-FU + LV, AZT and 5-FU + LV + AZT, DNA strand breaks in blood nuclear cells were determined by a fluorescent analysis of DNA unwinding. RESULTS: Treatment was generally well tolerated and WHO grades III-IV toxicities, consisting mostly of diarrhea (17%), were uncommon. One patient died of severe diarrhea with consequent hypokalemia and cardiac arrhythmia. All patients were considered evaluable for response, and 3 (10%) complete and 10 (35%) partial responses were observed, for an objective response rate of 45% (95% confidence limit interval 26%-64%). Both 5-FU + LV and AZT decreased the percentage of double stranded DNA in nuclear blood cells. The greatest effect was observed with 5-FU + LV + AZT, which reduced the percentage of double stranded DNA to 50% and 36% after 24 and 48 hours, respectively, and this interaction between 5-FU + LV and AZT was found to be cumulative. CONCLUSIONS: These studies demonstrate that the present dose and schedule of AZT in combination with 5-FU + LV has significant activity in metastatic colorectal cancer and that the combination of 5-FU + LV with AZT increases the amount of DNA damage. Therefore, AZT in combination with 5-FU + LV warrants further study in colorectal cancer.

Adult↗
PubMed1997

Clinical results of recombinant erythropoietin in transfusion-dependent patients with refractory multiple myeloma: role of cytokines and monitoring of erythropoiesis.

Recombinant erythropoietin (r-EPO) was administered to 37 patients with advanced, transfusion-dependent and chemo-resistant multiple myeloma (MM), at the fixed dose of 10,000/U s.c., 3 times a week, for 2 months. Thirteen patients (35.1%) achieved a significant response in terms of complete abolition of red cell transfusions. Factors significantly predictive of response were: a) inappropriate production of endogenous EPO, as expressed by a reduced observed/predicted ratio; b) presence of a consistent number of circulating erythroid precursors BFU-E; c) low serum levels of tumor necrosis factor (TNF) and interleukin-1 (IL-1), cytokines with inhibitory activity on erythropoiesis; d) a single line of previously received chemotherapy. Renal failure, bone marrow plasma cell infiltration, serum levels of IL-6 and other main clinical and laboratory parameters did not affect significantly the response to r-EPO. High fluorescence reticulocytes (HFR) and soluble transferrin receptor (sTfR) values were useful to detect an early stimulation of erythropoiesis in responders, while a high percentage of circulating hypochromic erythrocytes (HE), as assessed by an automated counter, identified those patients developing functional iron deficiency during r-EPO treatment. We conclude that about one-third of severely anemic patients with advanced MM, unresponsive to chemotherapy, may benefit by r-EPO therapy. The clinical management of these patients can be accomplished using non-invasive parameters, such as sTfR, HFR and HE.

Adult↗
PubMed1997

Airway eosinophils, T cells, Th2-type cytokine mRNA, and hyperreactivity in response to aerosol challenge of allergic mice with previously established pulmonary inflammation.

Asthma is characterized by acute episodes of nonspecific airway hyperreactivity and chronic pulmonary inflammation exacerbated by stimuli including allergen exposure. In order to reproduce the physiologic and immunologic responses that occur in asthmatic patients, we have characterized a model of antigen-induced inflammation in which allergic mice (B6D2F1) that had been challenged once with aerosolized ovalbumin and had developed a pulmonary cellular infiltrate were rechallenged 1 wk later. Pulmonary inflammation in rechallenged mice was substantially greater than that in single-challenged mice. Eosinophils and activated-memory T cells (CD44+, CD45RBlo) in bronchoalveolar lavage (BAL) fluid accumulated to higher levels and with faster kinetics in response to the second challenge than in response to the first challenge. Eosinophils in lung tissue also accumulated to higher levels but with similar kinetics in response to the second challenge than in response to the first challenge. Similarly, interleukin (IL)-4 and IL-5 steady-state mRNA levels in lung tissue increased after the second challenge and were higher than those measured after a single challenge. Furthermore, treatment of mice with an anti-IL-5 monoclonal antibody 2 h prior to rechallenge inhibited antigen induced eosinophil accumulation in the lungs. In mice challenged twice, peak in vivo bronchoconstrictor responsiveness to acetylcholine was increased following the second challenge compared with that observed following the initial challenge. In contrast, ex vivo tracheal smooth muscle contractile responsiveness to acetylcholine was not altered. Although mucus accumulation and epithelial damage in pulmonary tissue were evident in mice challenged twice, these parameters were slightly reduced compared with those seen at similar times in mice challenged once. Therefore, although these mice exhibit only slight bronchial epithelial damage, the presence of significant inflammation and airway hyperreactivity to acetylcholine as well as slightly increased baseline reactivity demonstrate important similarities with the pathophysiology of asthma.

Administration, Inhalation↗
PubMed1996

Azidothymidine in combination with 5-fluorouracil in human colorectal cell lines: in vitro synergistic cytotoxicity and DNA-induced strand-breaks.

The in vitro cytotoxicity of the combination of azidothymidine (AZT) and 5-fluorouracil (5-FU) against the human colorectal cancer cells SW-480, SW-620 and COLO-320DM was evaluated. The cytotoxic effects of 5-FU and AZT were determined by the assay using 2,3-bis(2-methoxy-4-nitro-5-sulfophenil)-2H-tetrazolium-5-carbo xanilide inner salt (XXT), while drug-induced DNA strand-breaks were measured using a fluorometric analysis of DNA unwinding. After an exposure of 72 h, 5-FU and AZT induced a dose-dependent cytotoxicity against each cell line. The addition of 3, 10 and 30 microM AZT to various concentrations of 5-FU, as well as the addition of 0.5, 1 and 3 microns 5-FU to various concentrations of AZT, resulted in an enhanced cytotoxic effect. Isobologram analysis and the combination index (CI) method demonstrated that the interaction between 5-FU and AZT was clearly synergistic in each cell line, except for the 30% level of effect in SW-620, where borderline synergism was observed. The evaluation of DNA strand-breaks after an exposure of 16 h to 5-FU, AZT or 5-FU + AZT demonstrated that the 5-FU + AZT combination produced the greatest DNA damage, and that this interaction was synergistic in each cell line. In conclusion, our study supports the evidence that the potential antitumour activity of AZT can be modulated by combining it with agents which inhibit thymidylate (dTMP) formation, such as 5-FU, and that the increased cytotoxicity is related to enhanced DNA damage. These findings should encourage further experimental and clinical studies of the potential use of AZT in combination with inhibitors of de novo dTMP synthesis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Treatment of metastatic renal cell carcinoma with constant-rate floxuridine infusion plus recombinant alpha 2b-interferon.

BACKGROUND: Floxuridine (FUDR) and alpha-interferon (IFN) are active agents in advanced renal cell carcinoma, with different dose-limiting toxic effects and antitumor synergism in experimental models. The main purpose of this phase II study was to assess the activity and toxic effects of a combination of FUDR and alpha 2b-IFN in metastatic renal cell carcinoma. PATIENTS AND METHODS: Metastatic renal cell carcinoma patients with measurable disease entered the study. FUDR was administered as a constant-rate continuous infusion for 14 days every 28 days at a starting daily dose of 0.1 mg/kg and with dose escalations of 0.025 mg/kg/day at each subsequent cycle if WHO > or = 2 toxicity had not occurred. IFN-alpha 2b 10 x 10(6) I.U. was administered intramuscularly 3 times per week. RESULTS: Forty-two patients entered the study and a total of 272 cycles of FUDR + alpha 2b-IFN were administered. In 41 evaluable patients WHO grade III-IV toxic effects included nausea and vomiting (22%), diarrhea (32%), stomatitis (12%), fatigue (27%) and anorexia (12%). It was possible to increase the initial FUDR does in 21 (50%) patients; the median FUDR dose intensity was 0.35 mg/kg/week (range 0.18-0.54). Among 39 evaluable patients, 3 (7.5%) complete and 10 (25.5%) partial responses were observed (response rate 33%, 95% confidence interval (CI) 19%-50%) which lasted a median of 13 months (5.5-40+). Responses also occurred in liver (2), in patients pretreated with systemic therapy (5) and in patients who had other unfavourable prognostic characteristics (7). Median progression-free and survival times were 9 and 16 months, respectively. CONCLUSIONS: In this study FUDR + alpha 2b-IFN demonstrated interesting activity in metastatic renal cell carcinoma, showing promise also in patients with unfavourable prognostic characteristics. The antitumor activity of FUDR and alpha 2b-IFN seems to be cumulative, but cumulative toxicity is also observed. These results require confirmation in randomised trials.

Adult↗
PubMed1996

Phase II study of oral doxifluridine in elderly patients with advanced non-small-cell lung cancer.

Elderly patients with advanced non-small-cell lung cancer (NSCLC) are usually excluded from most clinical trials because of the toxicity associated with chemotherapy. About 50% of the new cases of lung cancer occur in patients older than 65 years. Doxifluridine is a fluoropyrimidine derivate which can be administered orally with very low toxicities. This phase II study evaluates the toxicity and activity of a home therapy with oral doxifluridine in elderly advanced NSCLC patients. Thirty-three advanced NSCLC patients, aged 70 years or more, entered the study; median ECOG performance status was 1 (0-2) and 22 patients (66.6%) had metastatic disease. Doxifluridine was given orally in three divided doses, for a total daily dose of 2,250 mg, for 4 consecutive days every week. The treatment was well tolerated; five patients (15%) experienced a grade 3 diarrhea which required doxifluridine dose reduction to 1,500 mg daily. Thirty-one patients are evaluable for response; four partial responses (12.9%) have been observed (95% confidence limit interval 3.6-29.8%); 17 patients (54.8%) had a stabilization of the disease. This study demonstrates that a home therapy with oral doxifluridine in elderly NSCLC patients is feasible and well tolerated and should encourage further studies.

Administration, Oral↗
PubMed1996

T cells are the predominant source of interleukin-5 but not interleukin-4 mRNA expression in the lungs of antigen-challenged allergic mice.

Pulmonary inflammation is characterized by the accumulation of eosinophils and other leukocytes in the lungs of individuals challenged with antigen. Cytokines released by the Th2 lymphocyte subset, especially interleukin-4 (IL-4) and interleukin-5 (IL-5), are also present and thought to play an important role in this process. Previously, we used a model of aerosolized antigen challenge of sensitized mice to show that T cells were necessary for the accumulation of eosinophils and the production of cytokine steady-state messenger ribonucleic acid (mRNA). T cells were isolated from lung tissue at a time (4 h) when high levels of IL-4 and IL-5 mRNAs had accumulated, and from bronchoalveolar lavage fluid (BALF) and lung tissue at a later time (24 h), when inflammation could be detected by lavage. Lung-derived lymphocytes from sensitized challenged mice consisted of approximately 40% Thyl+ T cells (20% CD4+, 13% CD8+, and 6% CD4+/CD8+) and 30% B220+ B cells. Both BALF- and lung-derived T lymphocytes exhibited a similar activated/memory phenotype (CD44+ CD45RBlo), although lung tissue also contained less differentiated cells (CD44+ CD45RBhi). Thyl+ BALF cells isolated by magnetic bead-mediated separation accounted for approximately 88% of the IL-5 mRNA, 21% of the interferon-gamma (IFN-gamma) mRNA, and < 2% of the IL-4 mRNA detected in unseparated samples by reverse transcriptase-polymerase chain reaction (RT-PCR). Thyl+ T cells from lung tissue accounted for approximately 98% and 89% of IL-5 mRNA, 56% and 80% of IFN-gamma mRNA, and 23% and 40% of IL-4 mRNA at 4 h and 24 h after challenge, respectively. These experiments demonstrate that isolated T cells from BALF and lung are responsible for most of the IL-5 mRNA, but not all of the IFN-gamma or IL-4 mRNAs, detected in this model. These results are consistent with human studies indicating T cells as the major source of IL-5 mRNA in the lungs of asthmatic patients.

Animals↗