Biomedical subjects
Publications and source records attributed to M Botta.
Starting from a set of 32 antitubercular compounds, for the first time a three-dimensional pharmacophore model has been derived through a computational approach based on CATALYST software. The model proved to be able to identify compounds belonging to classes of molecules already reported as antitubercular agents.
Malignant pleural mesothelioma is often unresectable at diagnosis, is refractory to cytotoxic agents and is frequently complicated by pleural effusion. The expected survival range for patients with or without involvement of visceral pleura is respectively 1-9 and 9-12 months; mesothelioma-related pleural effusion severely impairs the patients' quality of life and easily relapses after conservative treatments. Intrapleural administration of IL-2 is reported to be effective both in tumor-associated malignant pleurisy and on primary mesothelioma, whereas few data exist about IL-2 systemic administration. In order to assess the palliative and therapeutic activity of IL-2 in unresectable pleural malignant mesothelioma with pleural effusion, we performed a phase II study on 31 consecutive patients (M/F 16/15; median age 61 years, range 40-84; PS ECOG 0 n=7; ECOG 1 n=15; ECOG 2 n=9; stage IA n=13; IB n=9; II n=7; IV=2) who received first-line therapy with intrapleural repeated instillation of 9000000 I.U. IL-2 twice/weekly for 4 weeks, after needle thoracenthesis. In nonprogressing patients, 3000000 I.U. IL-2 were subcutaneously administered thrice weekly for up to 6 months. Toxicity (WHO criteria) with intrapleural IL-2 consisted of grade 3 fever in 6/31 (19%) patients and of cardiac toxicity (failure) grade 3 in one patient (3%); toxicity during subcutaneous treatment was mild to moderate, mainly a flu-like syndrome. In 28/31 (90%) of patients there was no further or minimal (asymptomatic) pleural fluid collection (according to Paladine criteria); pleurisy relapsed only in 1/28 patients after 19 months. Tumor objective response (WHO criteria), evaluated by CT, occurred in seven patients (one CR and six PR; ORR 22%); ten patients achieved SD and 14 patients progressed. Median overall survival was 15 months (range 5-39) in all patients. IL-2 intrapleural administration followed by low-dose IL-2 subcutaneously in pleurisy-complicated malignant mesothelioma is feasible and active both in palliation of pleural effusion and on primary tumor, with manageable toxicity. The overall survival observed in nonprogressing patients warrants further randomized studies with IL-2 aimed to the patient outcome.
Macromolecular Gd(III) complexes may find useful application as contrast agents for magnetic resonance angiography (MRA). Herein two novel systems are reported, namely Gd(DO3ASQ)3-lys16 and Gd(DO3ASQ)30-orn114. Their syntheses are based on the ability of the squaric acid moiety to act as a linker between the DO3A (1,4,7, 10-tetraazacyclododecane-1,4,7-triacetic acid) chelate moiety and the polyamino acidic chain. Moreover, the squaric acid participates in the coordination cage of the Gd(III) ion. The investigation of 1H and 17O NMR relaxation processes of solvent water nuclei allowed a detailed characterization of the systems under study. Gd(DO3ASQ)30-orn114 displays a remarkable ability to enhance the water proton relaxation rate of its solutions, and it may be considered as potential contrast agent for MRA applications.
The sequence dependency of the interaction of taxol with other anticancer drugs is of clinical importance, and may be due to pharmacokinetic changes and/or to inherent differences in the sensitivity of target normal or cancer cells. This study presents results on the in vitro interaction of taxol with doxorubicin, cisplatin, etoposide and vinorelbine in alternate sequences on human hemopoietic progenitors (CFU-GM). Peripheral blood mononuclear non adherent cells were exposed to IC50 of Taxol for 24 hours and then, for 1 hour to IC50 of each of the other drugs. In a second set of experiments the reverse sequence was applied. The cell suspension was subsequently cultured to assay the growth of CFU-GM. A strong sequence dependency characterizes the combination taxol-vinorelbine, while for the other combinations the order of sequence appears to have little impact on in vitro toxicity on CFU-GM. Comparing results on CFU-GM with that obtained in vitro with the same combination sequences on cancer cell lines some remarkable differences show up. Studies on a normal human myeloid line may therefore have a place in preclinical evaluation of sequence of anticancer drug combinations.
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Haemotoxicity is usually the primary and dose-limiting side-effect of docetaxel (TXT) a semysyntetic analogue of paclitaxel which has acquired an important role in anticancer treatment. This research presents the results of an in vitro toxicity study of TXT on myeloid progenitors obtained from healthy volunteers and assayed as CFU-GM. Peripheral blood mononucleated non-adherent cells (MNAC) were incubated for 24 h at standard conditions with increasing concentrations of TXT and then cultured for CFU-GM assay. At every concentration severe CFU-GM growth inhibition was observed. In a second set of experiments MNAC were sequentially exposed to TXT and then to doxorubicin or cisplatin or vinorelbine or etoposide at appropriate concentrations. In a third set the sequence of exposure was reversed. No difference of CFU-GM growth inhibition was observed between the alternate sequences. These findings suggest that the toxicity on CFU-GM in vitro growth of TXT combinations with other anticancer drugs is sequence-independent.
Association of all-trans retinoic acid (ATRA) and amifostine (AMF) might be an alternative in treatment of myelodisplatic syndromes. In this study we undertook a preliminary in vitro research on the effects of a combination of ATRA and AMF on normal hemopoietic progenitors. Mononuclear, non-adherent cells from peripheral blood of normal volunteers, were incubated with AMF, at a the concentration of 500 microM and then cultured for CFU-GM and BFU-E growth adding to culture dishes before gelling ATRA at the concentration 10(-6) and 10(-12)M. Controls were cultures not pre-incubated with AMF, cultures incubated with AMF without addition of ATRA and cultures without addition of any drug. ATRA addition did not have significant effects on hemopoietic progenitors growth. Association of ATRA and AMF do not appear to synergize to stimulate in vitro growth of hemopoietic progenitors.
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Antipancreas autoimmunity is one of several immunity problems in diabetes. Such of its features as are revealed by inhibition of leukocyte migration, lymphocyte transformation in response to insulin antigens, relation between cell autoimmunity and later complications, and the behaviour of peripheral T and B lymphocyte membrane markers are explained. The aetiological role of viral infections is discussed, and the pathogenetic hypothesis deducible from the histological findings. Lastly, the modalities underlying a combination between the HLA (human leukocyte antigen) system and diabetes are considered.
Results obtained wih Nifedipine in 146 coronary patients, 85 of them suffering from coronaro-sclerosis with rest and effort stenocardic attacks, and 61 with post-infarctual stenocardic signs, are reported. In 76% of patients in the first group and in 85% of those in the second, pain symptomatology disappeared rapidly; ECGs also showed attenuation and modification, particularly among angina patients. The drug also led to a reduction in hypertension.
The present report updates a mortality cohort study of workers in the largest Italian asbestos cement plant. The plant had been active in Casale Monferrato in 1907-1986 and produced boards, corrugated sheets, tubes and high-pressure pipes. Raw material included both chrysotile and crocidolite but not amosite. Airborne asbestos concentrations were measured for the first time in 1971 (over 20 ff/cc in most areas). Regular monitoring started in 1978, when the concentration measured in most samples was below 1 ff/cc. The cohort included 3367 blue-collar workers (2605 men and 762 women) employed at the plant at any time between 1950 and 1980. At the end of the follow-up in 1993, 57% were alive, 41% were dead and 2% were either lost or had moved abroad. Mortality in the cohort was compared to mortality rates in Piedmont; local rates have been available only since 1969 and mortality analyses were limited to the period since 1965. Both sexes showed a statistically significant increase in mortality for all causes: lung cancer (males: 162 obs. vs. 65.4 exp.; females 9 vs. 3.2), malignant neoplasm (MN) of the pleura (males 53 vs. 1.7; females 21 vs. 0.4), MN of the peritoneum (males 23 vs. 1.2; females 8 vs. 0.5) and asbestosis (males 118 vs. 0.2; females 14 vs. 0.1). No excesses were observed for MN of the larynx or of the digestive tract. Women show a statistically significant increase in MN of the ovary (7 vs. 2.7) and of the uterus (14 vs. 4.3). Mortality from MN of the lung increased with latency but, in men, showed a curvilinear trend with the highest SMR for those with between 10 and 19 years of employment. The curve could be related to workers with the highest seniority employed in better jobs. The study includes a review of epidemiological studies on mortality among asbestos cement workers.
Vinorelbine (VNB) and Ifosfamide (IFO) have recently been proposed for treatment of non small cell lung cancer (NSCLC). The two drugs separately induce response rates in excess of 20% and, when combined, of 32.56%. Cisplatin (DDP) is considered a standard in chemotherapy of NSCLC affected patients. We report data on the feasibility and the toxicity of an IFO, VNB and DDP combination in comparison with IFO, VNB association. Results obtained show that the IFO, VNB, DDP combination has a more severe toxicity profile than the IFO, VNB combination although not to a degree precluding its feasibility. Responses, however, appear somewhat more favorable than in the group treated with the combination IFO, VNB. It is therefore necessary to ascertain if clinical advantages in survival and symptom palliation offered by IFO, VNB, DDP combination outweigh impairment in quality of life due to its significant toxicity.
A case-control study on pleural malignant mesothelioma (MM) was conducted in Casale Monferrato, where the largest Italian asbestos cement (AC) factory had been operating from 1907 to 1985. In a previous study we observed a five to seven-fold increase in the incidence of MM among people living in that city and never employed in the factory mentioned. The present study includes cases of MM with histological diagnosis over the period 1.1.1987-30.6.1993 among residents in the Local Health Unit (LHU) of Casale Monferrato. Population controls were randomly extracted from the list of the residents in the LHU, matched to cases on sex, date of birth, vital status and date of death. Cases and controls (or their closest relative) were interviewed with a standardised questionnaire focusing on asbestos exposure in the (life-long) residential and occupational histories and in leisure time activities as well as on occupational asbestos exposure of relatives and cohabitants, smoking and chest or occupational diseases. The interview was blind in respect to case or control status. For the analyses the addresses were coded on map grids with a 500 m. mesh size. Statistical analyses were conducted with conditional logistic regression in order to keep the matching between cases and controls. Eighty-eight cases and 244 controls were interviewed (95.6% of cases and 80.1% of controls): 26 and 11 respectively reported an activity in the AC industry. Seven cases and 7 controls were also exposed because of parental occupation. The main analyses are based on the conditional regression model including both occupational and residential exposure. The different modes of exposure are included on an ordinal scale: each subject is classified according to their highest level. Domestic exposure is included as an independent factor. Odds Ratios (OR) are estimated with reference to subjects without either occupational or residential exposure. The OR is 39.3 among subjects reporting occupational exposure, 11.9 among those never engaged in the AC industry but living within 1000 m. of the factory. A statistically significant risk is also observed for persons at some time living in the other areas of Casale Monferrato.
This study presents results on 2'-2'-difluoro-2'deoxycytidine's (dFdC: gemcitabine) in vitro toxicity on peripheral blood CFU-GM and BFU-E obtained from healthy volunteers. Peripheral blood mononucleated non-adherent cells were cultured according to standard methods with continuous exposure (13 days) to dFdC (4,40 and 400 pmol/L) or following 1 hour's, incubation with increasing drug concentrations (1, 10, 100 mumol/L). The results indicate that dFdC has a marked dose-dependent inhibitory effect on the in vitro growth of peripheral blood hemopoietic progenitors., No significant differences were observed for the growth inhibition induced on CFU-GM and BFU-E. Continuous exposure to dFdC gave an IC50 of 4 pmol/L for both CFU-GM and BFU-E. In four chemotherapy naive patients affected by tumors of different type treated with three standard courses of dFdC the variations in the peripheral blood of hemopoietic progenitor level were determined. Patterns of changes were different, but a marked and sustained decrease of both CFU-GM and BFU-E was observed in one case only. The contrast between the apparently rather mild clinical hemotoxicity of dFdC and its in vitro dramatically potent inhibitory activity on hemopoietic progenitors is discussed.