Biomedical subjects

Alberto Abbruzzese

Publications and source records attributed to Alberto Abbruzzese.

24 records · Page 2Linked to original sources

PubMed2004

Oxaliplatin/rituximab combination in the treatment of intermediate-low grade non-Hodgkin's lymphoma of elderly patients.

High and intermediate grade non-Hodgkin's lymphomas (NHL) require treatments with aggressive chemotherapy schedules. However, low grade NHLs display a low chemoresponsiveness and patients aged >65 years often do not tolerate anthracycline and corticosteroid-containing chemotherapy regimens. Therapeutic options in this subset of patients are watchful waiting, oral alkylating agents, purine nucleoside analogues, combination chemotherapy, interferon and monoclonal antibodies. The approval of rituximab, an unconjugated chimeric antibody against the CD20 antigen for the treatment of B-cell NHL marked a milestone in the development of antibody treatment. Moreover, promising results have also been found with oxaliplatin in patients with NHL and reversible, cumulative, peripheral sensory neuropathy is the principle dose-limiting factor of oxaliplatin therapy. On the basis of these considerations we have performed a feasibility study in NHL in patients aged >65 years using as schedule: 130 mg/m2 oxaliplatin every 21 days and 375 mg/m2 rituximab weekly. We have enrolled 8 patients, 2 males and 6 females (mean age 69.2+/-3.1 years; median, 67 years) affected by intermediate or high grade stage III/IV NHL. Six patients have cardiac abnormalities (myocardial function between 45 and 50%) and 1 increase of transaminasemia due to active chronic hepatitis. All the patients included in the study were treated for at least 3 cycles and 31 cycles were completed. We have recorded grade I/II (CTC) neurotoxicity in 30%, grade I anemia in 25% and grade I neutropenia in 20% of the patients. No infusional reactions, liver or renal toxicity neither nausea and/or vomiting were recorded. One complete response, 3 partial response and 3 minimal response were obtained at 11 months of median time follow-up. These results demonstrate the feasibility of this schedule which offers a suitable alternative regimen to treat elderly patients with NHL and shows a good efficacy and an acceptable toxicity profile.

Aged↗

PubMed2003

Ubiquitination of tissue transglutaminase is modulated by interferon alpha in human lung cancer cells.

The addition of 2500 i.u./ml interferon alpha (IFNalpha) for 48 h induced apoptosis, and caused an approx. 4-fold increase in the activity and expression of tissue transglutaminase (tTG), in human lung cancer H1355 cells. However, the increase in mRNA levels for tTG was just 1.6-fold. On the basis of these data, we investigated whether tTG levels may be regulated through regulation of its degradation via ubiquitination. It was found that 2500 i.u./ml IFNalpha induced a time-dependent decrease in tTG ubiquitination. On the other hand, addition of the proteasome inhibitor lactacystin led to accumulation of the ubiquitinated form of the enzyme and to a consequent increase in its expression. Treatment of the cells with the two agents combined antagonized the accumulation of the ubiquitinated isoforms of tTG induced by lactacystin and caused a potentiation of tTG expression. Moreover, the tTG inducer retinoic acid was also able to cause increased expression and ubiquitination of tTG in H1355 cells. The addition of monodansylcadaverine (a tTG inhibitor) to IFNalpha-treated H1355 cells completely antagonized growth inhibition and apoptosis induced by the cytokine. In conclusion, we demonstrate for the first time that tTG is ubiquitinated and degraded by a proteasome-dependent pathway. Moreover, IFNalpha can, at least in part, induce apoptosis through the modulation of this pathway.

Apoptosis↗

PubMed2003

Critical role of both p27KIP1 and p21CIP1/WAF1 in the antiproliferative effect of ZD1839 ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor, in head and neck squamous carcinoma cells.

High expression of the epidermal growth factor receptor (EGFR) has been implicated in the development of squamous-cell carcinomas of head and neck (SCCHN). ZD1839 ('Iressa') is an orally active, selective EGFR-TKI (EGFR-tyrosine kinase inhibitor) that blocks signal transduction pathways implicated in proliferation and survival of cancer cells, and other host-dependent processes promoting cancer growth. We have demonstrated that ZD1839 induces growth arrest in SCCHN cell lines by inhibiting EGFR-mediated signaling. Cell cycle kinetic analysis demonstrated that ZD1839 induces a delay in cell cycle progression and a G1 arrest together with a partial G2/M block; this was associated with increased expression of both p27(KIP1) and p21(CIP1/WAF1) cyclin-dependent kinase (CDK) inhibitors. The activity of CDK2, the main target of CIP/KIP CDK inhibitors, was reduced in a dose-dependent fashion after 24 h of ZD1839 treatment and this effect correlated to the increased amount of p27(KIP1) and p21(CIP1/WAF1) proteins associated with CDK2-cyclin-E and CDK2-cyclin-A complexes. In addition, ZD1839-induced growth inhibition was significantly reduced in cell transfectants expressing p27(KIP1) or p21(CIP1/WAF1) antisense constructs. Overall, these results as well as the timing of the effect of ZD1839 on G1 arrest and p27(KIP1) and p21(CIP1/WAF1) upregulation, suggest a mechanistic connection between these events.

Antineoplastic Agents↗

PubMed2002

Theophylline-induced apoptosis is paralleled by protein kinase A-dependent tissue transglutaminase activation in cancer cells.

It has been reported that theophylline induces growth inhibition and apoptosis in tumour cells. We report that theophylline induces growth inhibition and apoptosis of several human epithelial tumour cells with an IC:50 of 2.5 mM after 48 h of exposure. Moreover, 2.5 mM theophylline induces the accumulation of cancer cells in S-phase of the cell cycle with a concomitant reduction in the percentage of tumour cells in G(1)/G(0) phase. These effects are paralleled by cytoskeletal remodelling with a consequent redistribution of actin fibers and shape change as demonstrated by fluorescence microscopy. The apoptotic death of tumour cells occurs together with an increase in the expression and activity of the pro-apoptotic enzyme tissue transglutaminase (tTGase). All these effects are promptly antagonized by the specific PKA inhibitor KT5720, suggesting the involvement of cAMP intracellular elevation and, consequently, PKA activation. On the other hand, growth inhibition and tTGase expression and activity are potentiated by retinoic acid, a tTGase inducer. Therefore, a mechanistic model of theophylline action and anti-tumour strategies based on the concomitant use of theophylline and agents that potentiate tTGase activity can be hypothesized.

Actin Cytoskeleton↗

PubMed2002

Comparison of two provocative tests for calcitonin in medullary thyroid carcinoma: omeprazole vs pentagastrin.

BACKGROUND: Provocative tests for calcitonin (CT) are fundamental in the diagnosis and follow-up of C-cell disease and in the detection of hereditary medullary thyroid carcinoma (MTC) carriers with unknown RET mutations. A recent report has proposed omeprazole, which can increase endogenous gastrin (GT), as a new provocative test for MTC. METHODS: We compared the omeprazole test (20 mg twice a day for 4 days) to the pentagastrin test (0.5 microg/kg of body weight) for the diagnosis and management of MTC. Twenty healthy individuals and 20 MTC patients with mildly or moderately increased basal CT serum concentrations underwent the pentagastrin and omeprazole tests. RESULTS: In MTC patients, the pentagastrin test produced a significantly higher increase in serum CT than did omeprazole. After the pentagastrin injection, several patients reported unpleasant side effects, including substantial tightness in 38 of 40 participants. No adverse effects were observed during the omeprazole test. A significant direct correlation was recorded between CT% (ratio of CT peak to basal value x 100) and GT% (ratio of GT peak to basal value x 100) during the omeprazole test in MTC patients (r = 0.73; P <0.001). CONCLUSIONS: In spite of several adverse effects, pentagastrin remains the best provocative test for the diagnosis of MTC. Omeprazole may be useful when pentagastrin is contraindicated or refused because of the unpleasant side effects, but further validation is needed.

Adolescent↗

PubMedDate not supplied

Low-dose recombinant IL-2 induces psychological changes: monitoring by Minnesota Multiphasic Personality Inventory (MMPI).

BACKGROUND: Chronic subcutaneous rIL-2 at low doses produces long-lasting immunomodulatory effects and is considered an effective treatment for renal cell carcinoma with marginal activity in malignant melanoma and colorectal cancer. PATIENTS AND METHODS: In this study we evaluated, by Minnesota Multiphasic Personality Inventory (MMPI), the psychological changes induced by rIL-2 in 10 patients with advanced tumors. RESULTS: After 3 months of rIL-2 treatment, 80% of the patients had a significantly increased score on the clinical scale of depression (D) and psychasthenia (Pt) (p<0.01), 70% on the scale of conversion hysteria (Hy) and 60% on the scales of schizophrenia (Sc) and psychopathic deviate (Pd), (p<0.05). These MMPI changes were however not paralleled by disease progression or clinical-overt psychological disease. CONCLUSION: These findings demonstrate that low-dose rIL-2 is a psychoactive treatment, which deserves psychological monitoring The MMPI is feasible for the evaluation of subclinical psychological modifications induced by cytokine immunotherapy.

Adult↗