Locally advanced non-small cell lung cancer: role of induction chemotherapy in resectable N2 disease.

Patients with resectable stage IIIA-N2 non-small cell lung cancer should receive induction chemotherapy before surgery. The aim is to early control systemic disease, eventually cure the mediastinal tumor spread and improve patients' survival. A recent metanalysis of randomized trials with second-generation platinum-based combinations has reinforced the evidence concerning the benefit of induction chemotherapy followed by surgery versus surgery alone in resectable disease. Moreover a large number of phase II trials have explored the activity and feasibility of platinum-based combinations with third-generation drugs in the same setting. Still opened questions to address with current clinical research are the eventual role of radiotherapy as induction treatment, the impact of definite chemoradiation versus induction treatment followed by surgical resection on local control and survival and finally the non-easy choice between neo-adjuvant and adjuvant chemotherapy.

Correlation between anemia and functional/cognitive capacity in elderly lung cancer patients treated with chemotherapy.

BACKGROUND: Elderly cancer patients are often excluded from clinical trials and no data are available on the impact of chemotherapy-related anemia on their functional status and cognitive functions. This observational study investigates the association between hemoglobin (Hb) level and comprehensive geriatric assessment (CGA) variables (MMSE, ADL/IADL, GDS, CIRS and VAS). PATIENTS AND METHODS: We enrolled 42 consecutive lung cancer elderly patients undergoing chemotherapy that were evaluated at baseline and after each CT cycle at least until cycle 2. Hb association with CGA indexes was expressed using Spearman's non-parametric coefficient r. RESULTS: Higher Hb values were significantly associated with more favourable values of all indexes measuring mental and functional capacity, depression and comorbidities. For all indexes except IADL, improvements from baseline were significantly related with concomitant Hb increases. In 14 patients given erythropoietin during the first two cycles, mean Hb increased from 9.2 to 10.8 g/dl, and the mean values of all CGA indexes were improved. On the contrary, in 18 patients not given erythropoietin, Hb varied from 13.0 to 11.2 g/dl and a parallel worsening in all CGA indexes was observed. CONCLUSIONS: Chemotherapy-related anemia is associated with impairment of functional status and cognitive functions. In elderly cancer patients anemia correction or maintenance could be useful to preserve functional independency and protect from mental decay. However, the study results need to be confirmed on a larger series of patients within a controlled clinical trial.

Therapeutic strategies to improve the efficacy of oxaliplatin in gastrointestinal tumors.

The pharmacological characteristics of oxaliplatin make it one of the better chemotherapeutics to be combined with novel molecular-targeted anticancer treatments for the therapy of gastrointestinal tumors. The purposes of this review article are to report the preliminary data of combined therapy of oxaliplatin with inhibitors of angiogenesis or epidermal growth factor receptor and to suggest novel oxaliplatin-based therapeutic strategies. It is hypothesized that well designed, personalized, molecular-based treatments may improve the efficacy of oxaliplatin for the treatment of colorectal, gastric and pancreatic cancer. It is mandatory to rationalize such an approach by adequate determination of predictive surrogate biomarkers of response related to the targets in each single tumor against which therapy is aimed, using standardized assays and quality control.

Saquinavir up-regulates telomerase activity in lymphocytes activated with monoclonal antibodies against CD3/CD28.

The present study describes the effect of the HIV protease inhibitor saquinavir on telomerase activity and interferon-gamma (IFN-gamma) production of nonadherent mononuclear cells (NA-MNC). Cells obtained from peripheral blood of healthy donors were exposed in vitro to a mixture of monoclonal antibodies against CD3 and CD28 membrane antigens in order to activate prevalently T cell subsets. Treatment with saquinavir was performed at the time of cell stimulation. Thereafter, NA-MNC were tested for telomerase activity (TRAP assay) and interferon-gamma production up to 7 days later. The results show that saquinavir up-regulates telomerase activity and IFN-gamma release in activated NA-MNC. These observations suggest that the anti-HIV effects of saquinavir could be accompanied by other immunopharmacological properties, influencing some aspects of the functional activity of immunocompetent cells. These include possible antagonistic effects against lymphocyte senescence, through telomerase activation, and a potentiating activity on the production of IFN-gamma following T cell activation.

Paclitaxel and docetaxel enhance the metabolism of doxorubicin to toxic species in human myocardium.

Doxorubicin cardiotoxicity is a multifactorial process in which the alcohol metabolite doxorubicinol mediates the transition from reversible to irreversible damage. We investigated whether the tubulin-active taxane paclitaxel increases conversion of doxorubicin to doxorubicinol, thus explaining the high incidence of congestive heart failure when doxorubicin is used with paclitaxel. Specimens of human myocardium from patients undergoing bypass surgery were processed to obtain cytosolic fractions in which doxorubicin was converted to doxorubicinol by NADPH-dependent aldo/keto or carbonyl reductases. In this model, clinically relevant concentrations of paclitaxel (1-2.5 microM) increased doxorubicinol formation by mechanisms consistent with allosteric modulation of the reductases. Stimulation was observed over a broad range of basal enzymatic activity, and was accompanied by a similar pattern of enhanced formation of doxorubicinol aglycone, a metabolite potentially involved in the reversible phase of cardiotoxicity. The closely related analogue docetaxel had effects similar to paclitaxel, but increased doxorubicinol formation over a narrower range of enzymatic activity. The unrelated tubulin-active alkaloid vinorelbine had no effect. These results demonstrate that taxanes have a unique potential for enhancing doxorubicin metabolism to toxic species in human myocardium. The effects on doxorubicinol formation provide clues to explain the clinical pattern of doxorubicin-paclitaxel cardiotoxicity and also caution against the potential toxicity of combining docetaxel with high cumulative doses of doxorubicin.

Anthracycline metabolism and toxicity in human myocardium: comparisons between doxorubicin, epirubicin, and a novel disaccharide analogue with a reduced level of formation and [4Fe-4S] reactivity of its secondary alcohol metabolite.

Secondary alcohol metabolites have been proposed to mediate chronic cardiotoxicity induced by doxorubicin (DOX) and other anticancer anthracyclines. In this study, NADPH-supplemented human cardiac cytosol was found to reduce the carbonyl group in the side chain of the tetracyclic ring of DOX, producing the secondary alcohol metabolite doxorubicinol (DOXol). A decrease in the level of alcohol metabolite formation was observed by replacing DOX with epirubicin (EPI), a less cardiotoxic analogue characterized by an axial-to-equatorial epimerization of the hydroxyl group at C-4 in the amino sugar bound to the tetracyclic ring (daunosamine). A similar decrease was observed by replacing DOX with MEN 10755, a novel anthracycline with preclinical evidence of reduced cardiotoxicity. MEN 10755 is characterized by the lack of a methoxy group at C-4 in the tetracyclic ring and by intercalation of 2, 6-dideoxy-L-fucose between daunosamine and the aglycone. Multiple comparisons with methoxy- or 4-demethoxyaglycones, and a number of mono- or disaccharide 4-demethoxyanthracyclines, showed that both the lack of the methoxy group and the presence of a disaccharide moiety limited alcohol metabolite formation by MEN 10755. Studies with enzymatically generated or purified anthracycline secondary alcohols also showed that the presence of a disaccharide moiety, but not the lack of a methoxy group, made the metabolite of MEN 10755 less reactive with the [4Fe-4S] cluster of cytoplasmic aconitase, as evidenced by its limited reoxidation to the parent carbonyl anthracycline and by a reduced level of delocalization of Fe(II) from the cluster. Collectively, these studies (i) characterize the different influence of methoxy and sugar substituents on the formation and [4Fe-4S] reactivity of anthracycline secondary alcohols, (ii) lend support to the role of alcohol metabolites in anthracycline-induced cardiotoxicity, as they demonstrate that the less cardiotoxic EPI and MEN 10755 share a reduction in the level of formation of such metabolites, and (iii) suggest that the cardiotoxicity of MEN 10755 might be further decreased by the reduced [4Fe-4S] reactivity of its alcohol metabolite.

Doxorubicin metabolism and toxicity in human myocardium: role of cytoplasmic deglycosidation and carbonyl reduction.

The anthracycline doxorubicin (DOX) is an exceptionally good antineoplastic agent, but its use is limited by formation of metabolites which induce acute and chronic cardiac toxicities. Whereas the acute toxicity is mild, the chronic toxicity can produce a life-threatening cardiomyopathy. Studies in laboratory animals are of limited value in predicting the structure and reactivity of toxic metabolites in humans; therefore, we used an ethically acceptable system which is suitable for exploring DOX metabolism in human myocardium. The system involves cytosolic fractions from myocardial samples obtained during aorto-coronary bypass grafting. After reconstitution with NADPH and DOX, these fractions generate the alcohol metabolite doxorubicinol (DOXol) as well as DOX deoxyaglycone and DOXol hydroxyaglycone, reflecting reduction of the side chain carbonyl group, reductase-type deglycosidation of the anthracycline, and hydrolase-type deglycosidation followed by carbonyl reduction, respectively. The efficiency of each metabolic route has been evaluated at low and high DOX:protein ratios, reproducing acute, single-dose and chronic, multiple-dose regimens, respectively. Low DOX:protein ratios increase the efficiency of formation of DOX deoxyaglycone and DOXol hydroxyaglycone but decrease that of DOXol. Conversely, high DOX:protein ratios facilitate the formation of DOXol but impair reductase- or hydrolase-type deglycosidation and uncouple hydrolysis from carbonyl reduction, making DOXol accumulate at levels higher than those of DOX deoxyaglycone and DOXol hydroxyaglycone. Structure-activity considerations have suggested that aglycones and DOXol may inflict cardiac damage by inducing oxidative stress or by perturbing iron homeostasis, respectively. Having characterized the influence of DOX:protein ratios on deglycosidation or carbonyl reduction, we propose that the benign acute toxicity should be attributed to the oxidant activity of aglycones, whereas the life-threatening chronic toxicity should be attributed to alterations of iron homeostasis by DOXol. This picture rationalizes the limited protective efficacy of antioxidants against chronic cardiomyopathy vis-à-vis the better protection offered by iron chelators, and forms the basis for developing analogues which produce less DOXol.