Zinc oxide pieces obtained by pressing and slip casting: physical, structural and photocatalytic properties.

Photocatalysis is a promising alternative for the decontamination of effluents. In this paper, immobilized ZnO-based photocatalysts were obtained by pressing and by slip casting. The cylindrical pieces were heat-treated at 800°C. The samples were characterized by the method based on the principle of Archimedes, XRD, FTIR, Raman, diffuse reflectance and SEM. The samples obtained by slip casting presented lower apparent density (3.12 ± 0.04 g/cm3), higher apparent porosity (44.87 ± 0.47%) and smaller grain size (0.48 ± 0.05 µm) when compared to the pressed samples, with mean apparent density of 5.37 ± 0.08 g/cm3, apparent porosity of 1.56 ± 0.10% and grain size of 0.64 ± 0.02 µm. The performances of the samples were attested by the photocatalytic degradation of Rhodamine B (RhB) under UV-C irradiation (maximum intensity at 254 nm). The samples obtained by slip casting showed photocatalytic degradation between 80% and 90%, while the pressed samples showed degradation between 40% and 60%. The reuse of the photocatalysts was evaluated over five cycles of photocatalytic degradation, in which there was no loss of performance of the samples obtained by slip casting; however, the pressed samples showed a loss of photocatalytic efficiency starting from the third-cycle. Photocatalytic assays were carried out with different dye concentrations, in which the slip casting samples showed better photocatalytic efficiency (degradation of 80% for a RhB concentration of 10 mg/L) due to higher porosity and surface area compared to pressed samples, and there was a loss of performance in higher concentrations.

Antimetastatic effects of N-diazoacetyl-glycine derivatives in C57BL mice.

When three diazoacetyl-glycine derivatives, N-diazoacetyl-glycine amide (DGA), N-diazoacetyl-glycine hydrazide (DGI), and N-diazoacetyl-glycine ethyl ester (DGE), were tested against Lewis lung carcinoma in C57BL mice, DGA reduced sharply the number and weight of pulmonary metastases; the effects of DGI and DGE were less pronounced. The growth of the primary tumor was reduced slightly by DGA, but the greater effect was produced by DGI. The absence of correlation between the reduction of the growth of the primary implant and the number of lung secondary tumors for the tested compounds indicated that DGA possesses antimetastatic properties.

Cisplatin-cyclophosphamide-mitomycin combination chemotherapy with supportive care versus supportive care alone for treatment of metastatic non-small-cell lung cancer.

BACKGROUND: Patients with TNM stage IV non-small-cell lung cancer have short survival times. Previous controlled studies comparing chemotherapy and supportive care for the treatment of this type of cancer have not given consistent results, have included patients with different disease stages, and have rarely reported drug dose intensity. PURPOSE: The present trial was designed to assess the safety and the effect on survival of supportive care alone versus chemotherapy with cisplatin, cyclophosphamide, and mitomycin combined with appropriate supportive care in patients with stage IV non-small-cell lung cancer. METHODS: Patients (n = 102) with stage IV non-small-cell lung cancer were randomly assigned to one of two treatment regimens. The combined modality group (52 patients) received supportive care along with cisplatin (75 mg/m2), cyclophosphamide (400 mg/m2), and mitomycin (10 mg/m2) given intravenously at 3-week intervals. The supportive care group (50 patients) received supportive care alone. Randomization was stratified on the basis of histology (squamous versus nonsquamous cell carcinoma), performance status (Karnofsky), and weight loss (during the 6 months preceding randomization). The two groups were well matched for age and sex. Survival analysis was performed after the last patient died. RESULTS: The median number of chemotherapy cycles was 3.5 per patient. Mean weekly delivered doses of drugs were as follows: cisplatin, 22.1 mg/m2; cyclophosphamide, 118 mg/m2; and mitomycin, 2.9 mg/m2. Toxic effects due to chemotherapy were generally mild, but peripheral neuropathy and hematologic and renal toxic effects were observed. In the supportive care group, mean survival was 6.1 months (median, 4.0 months); six patients lived at least 12 months and two lived at least 18 months. In the combined modality group, mean survival was 11.3 months (median, 8.5 months); 20 patients lived at least 12 months, 13 lived at least 18 months, and five lived at least 24 months. Difference in survival was statistically significant (P < .0001). Survival was directly related to initial performance status in both groups (P < .01) and was significantly (P < .01) longer for patients with squamous cell carcinoma than for those with nonsquamous cell carcinoma. CONCLUSIONS: The combination of supportive care and cisplatin-cyclophosphamide-mitomycin therapy offers a survival advantage over supportive care alone in patients with advanced non-small-cell lung cancer. IMPLICATIONS: Metastatic non-small-cell lung cancer, generally considered to be unresponsive or marginally responsive to chemotherapy, can be treated with chemotherapy, with an expectation of prolonging patient survival. Although the results of the present study are encouraging, clinical research should continue to be directed toward developing more effective treatments for this disease.

Antimetastatic action and hematological toxicity of p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt and 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide used as prophylactic adjuvants to surgical tumor removal in mice bearing B16 melanoma.

The treatment of mice bearing i.m. B16 melanoma with equitoxic dosages of the clinically used 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) and of its benzenoid water-soluble analogue p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt (DM-COOK) prior to surgical tumor removal results in a remarkable proportion of cures, even when the treatment is started on already palpable tumors for which surgery alone is ineffective. The survival time of mice which are not cured is also significantly increased with DM-COOK. At the same time, DM-COOK does not affect artificial metastases or spontaneous metastases in mice undergoing surgery and treated with DM-COOK postoperatively. Inhibition of i.m. tumor growth in surgical experiments, and of s.c. tumors in mice not treated with surgery, is significant, although not as pronounced as is necessary to obtain significant prolongation of the life span of the host; the survival time of mice with s.c. tumors treated with both drugs is indeed not significantly increased. DM-COOK thus appears to exert selective antimetastatic effects, unrelated to cytotoxicity for tumor cells, against B16 melanoma in addition to those reported for Lewis lung carcinoma and M5 ovarian reticular cell sarcoma; its therapeutic usefulness is evidenced in adjuvant surgical experiments. DM-COOK, unlike DTIC, is devoid of hematological toxicity for the host. Since, in leukemic mice, it is at least as active as DTIC in increasing the life span of the treated animals, it appears to be an advantageous substitute for DTIC that could undergo preliminary clinical trial.

Selectivity of the antimetastatic and cytotoxic effects of 1-p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt (+/-)-1,2-di(3,5-dioxopiperazin-1-yl)propane, and cyclophosphamide in mice bearing Lewis lung carcinoma.

The effects of two selective antimetastatic agents, 1-p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt (DM-COOK), and (+/-)-1,2-di(3,5-dioxopiperazin-1-yl)propane, have been examined in comparison with those of a cytotoxic agent, cyclophosphamide, in mice bearing Lewis carcinoma. Cyclophosphamide at the two highest dosages causes a strictly related and pronounced inhibition (to less than 10%) of the weight of the s.c. tumor, spontaneous metastases, and lung colonies formed after i.v. injection of tumor cells (artificial metastases); this behavior is consistent with a purely cytotoxic mechanism. At the three dosages used, (+/-)-1,2-di(3,5-dioxopiperazin-1-yl)propane reduces the weight of spontaneous metastases to less than 3%. A dose-dependent reduction of artificial metastasis weight is also observed. At the highest dose, artificial metastasis weight is reduced to about 5%, and s.c. tumor mass is significantly lowered to 40%. These effects are consistent with the combined occurrence of cytotoxic and selective antimetastatic action, although the latter appears to be predominant. At the three dosages used, DM-COOK markedly depresses the weight and number of spontaneous metastases to about 10%, leaving the formation of artificial metastases unaffected and causing no significant effect on primary tumor growth. The effects of these agents on the fractional incorporation of [3H]thymidine in tumor cells further indicate that only DM-COOK is devoid of cytotoxic effects for pulmonary and s.c. tumors. In hosts pretreated with DM-COOK, no reduction in the formation either of spontaneous or of artificial metastases is observed. These data indicate that DM-COOK acts directly on tumor cells and that it presumably inhibits their release from the primary tumor into the bloodstream.

TPMT genotype and the use of thiopurines in paediatric inflammatory bowel disease.

BACKGROUND: Thiopurines are used in the treatment of inflammatory bowel disease. They are metabolised via methylation by thiopurine-S-methyltransferase (TPMT), which displays a genetically determined polymorphic activity. Subjects with reduced TPMT activity have a higher concentration of active thiopurine metabolites and may be at increased risk of bone-marrow suppression. AIMS: To evaluate the relevance of TPMT genotyping in the management of thiopurines therapy in inflammatory bowel disease patients. PATIENTS AND METHODS: Adverse effects and clinical response were determined retrospectively and correlated with TPMT genotype in 70 paediatric inflammatory bowel disease patients. RESULTS: Nineteen patients (27.1%) developed adverse effects; of the 51 who did not, 34 (66.7%) responded to treatment. Five patients (7.1%) were heterozygous for a variant TPMT allele; two of these (40%) were intolerant to thiopurines, compared to 17 of the 65 patients (26.2%) with a wild type gene (O.R. 1.88, 95% CI 0.29-12.2, p=0.61); among the 34 responders, the median dosage of the drug required to obtain remission was lower for mutated than for wild type patients (1.6mgkg(-1)day(-1) versus 2.0mgkg(-1)day(-1), p=0.043). CONCLUSIONS: There was no significant association between adverse effects of thiopurines and TPMT heterozygous genotype, but TPMT genotyping could be useful in establishing the most appropriate dose of thiopurines to start treatment.

Morphological analysis of metastatic potential and antimetastatic drug effects in mice bearing two lines of Lewis lung carcinoma.

Two lines of Lewis lung carcinoma with a different potential to metastasize spontaneously to the lungs have been examined for their cytological and histological characteristics. Metastatic potential appears to be related with parenchymal organization of the primary tumours, since large haemorrhagic areas containing detached tumour cells and the absence of endothelialized capillaries are observed only in the line with high metastatic potential. At the same time, the cytological characteristics of the cells of the two tumour lines are similar, and do not seem to be related with metastatic potential. After treatment with the selective antimetastatic drugs ICRF-159 and DM-COOK, and with DTIC, the histological appearance of the line with high metastatic potential becomes similar to that of the line with low metastatic potential. These data seem to indicate that the early phases of tumour spread occurring in the primary tumour are of relevance for metastatic potential and control by antimetastatic drugs, and suggest that for DTIC such antimetastatic action may participate to its clinical antitumour effects.

Effects of DTIC, DM-COOK and ICRF-159 on the number of circulating Lewis lung carcinoma cells detected by flow cytometry.

Circulating tumor cells can be detected by means of flow cytometry in the blood of mice bearing i.m. Lewis lung carcinoma. This technique can be applied in the case of aneuploid tumors and does not require either concentration of nucleated cells or other processing of the blood samples. It offers the advantages of simplicity and speed and allows quantitative measurement of the number of circulating tumor cells. It can be applied to the study of the effects of drug treatment on the number of circulating tumor cells, for those drugs which do not cause alterations in the nuclear DNA content of normal diploid blood cells. The number of circulating tumor cells determined by flow cytometry is markedly reduced by treatment with ICRF-159, by dimethyltriazene DM-COOK, and also by its clinically used analog, DTIC.

Effects of rotational stress on the effectiveness of cyclophosphamide and razoxane in mice bearing Lewis lung carcinoma.

The effects of conventional vs protected housing, and those caused by the periodic application of a psychological stressor (rotational stress, spatial disorientation) on mice kept in a protected housing, with spontaneous tumor metastasis have been determined in mice implanted with Lewis lung carcinoma as a function of tumor inoculum size and response to treatment with cyclophosphamide and razoxane. With a reduced inoculum size, tumor takes do not occur in mice kept in the protected housing, but do occur with spatial disorientation. With a larger inoculum size, tumor takes occur in all untreated mice, and the weight of spontaneous lung metastasis is significantly increased by spatial disorientation. For mice in protected housing, cyclophosphamide results in the absence of macroscopically detectable tumors in all of the treated mice, whereas the use of spatial disorientation abolishes this therapeutic action. The antimetastatic effects of razoxane are also reduced by rotational stress. These results indicate that housing conditions and a psychological stressor can control tumor takes and metastasis formation. They also indicate that host's antitumor resistance effectors, which are susceptible to neuroendocrine modulation by environmental and psychological stressors, participate to determine the effectiveness of the treatment with a cytotoxic (cyclophosphamide) and antimetastatic (razoxane) antitumor drug.

Effects of prolonged treatment with decarbazine on tumor metastatic potential in mice bearing Lewis lung carcinoma.

The effects of decarbazine on tumour growth and metastatic dissemination upon treatment protracted for 10 tumour transplant generations were examined in mice bearing Lewis lung carcinoma. Primary tumour growth is unaffected by the drug, independently from the duration of the treatment. In contrast, dacarbazine significantly inhibits the formation of lung metastasis. The proportion of mice with metastasis decreases for an increasing number of transplant generations of treatment, and after 10 transplant generations of treatment metastatic capacity is completely lost in immunocompetent mice. The reduction in metastatic potential is relatively stable, being retained for three successive transplant generations without treatment. The metastatic potential of treated tumours in immunosuppressed mice is substantially similar to that in immunocompetent hosts, indicating that chemical xenogenization of tumour cells does not occur as reported for transplantable mouse leukaemias. The results obtained using clonally selected tumour lines with different metastatic potential rule out the selection by dacarbazine of tumour cell sublines with reduced metastatic potential as the mechanism of the drug's action. Upon prolonged treatment, dacarbazine appears to cause a rather stable and dramatic loss in metastatic potential, not accompanied by resistance, which might be attributed to genotypic alteration(s) of tumour cells, and which might participate into the clinical effects of the drug.

Antimetastatic action of the prostacyclin analog iloprost in the mouse.

The antimetastatic activity of the prostacyclin analog Iloprost has been examined in mice bearing Lewis lung carcinoma. An inhibition of lung colony formation is observed when 100 or 200 micrograms/kg Iloprost are administered i.v. 1 h before i.v. injection of tumor cells, which is dependent on the size of tumor inoculum. The effects of 200 micrograms/kg Iloprost persist for 24 h, and are of the same magnitude as those obtained with 10 mg/kg prostacyclin, which last only for 30 min. When treatment with Iloprost is followed by surgical removal of primary tumor, spontaneous metastasis formation is reduced, and the survival time of the treated animals is significantly increased over controls treated with surgery only. The antimetastatic effects of Iloprost appear dissociated from drug's effects on the hemostatic system of the host as indicated by the clot retraction assay, performed after in vivo treatment, using ADP or tumor cells as platelet aggregating agents. Iloprost thus appears to reduce spontaneous metastasis formation and intraoperative tumor cell dissemination, with pharmacological properties more favourable to therapeutic use than those of prostacyclin.

Effects of antimetastatic, antiinvasive and cytotoxic agents on the growth and spread of transplantable leukemias in mice.

The effects of cytotoxic (cyclophosphamide, CCNU, GANU), antiinvasive (vincristine, vinblastine) and antimetastatic (ICRF-159, DM-COOK) agents have been compared in mice-bearing P388 and L1210 leukemias, and TLX5 lymphoma. The drugs tested increase the survival time of the treated mice in a manner consistent with a cytotoxic action in the case of cyclophosphamide, CCNU, GANU, vincristine and vinblastine. Leukemic infiltration of the brain after i.p. tumor implantation has been determined by bioassay of this organ, and is reduced by treatment with all of the drugs tested, with the exception of ICRF-159. DM-COOK appears to increase the life-span of the treated animals by the inhibition of leukemic spread rather than by a cytotoxic action. The marked cytotoxicity of vincristine and vinblastine is sufficient to account for failure to detect any antimetastatic effects of these agents. The lack of antidisseminative effect observed for ICRF-159 under the experimental conditions employed might be connected with the observation that the antimetastatic action of this drug on solid tumors is due to its effects on tumor blood vessels.

Platelet alpha 2-adrenoceptor modifications induced by long-term treatment with indapamide in essential hypertension.

The effect of long-term treatment with indapamide in platelet alpha 2-adrenoceptors has been evaluated in 10 patients with essential hypertension, in a double-blind, cross-over study with placebo. After three months of therapy, indapamide significantly reduced mean blood pressure (from 137 +/- 12 to 116 +/- 6 mm Hg, p less than 0.001), whereas heart rate did not change (from 72 +/- 8 to 73 +/- 7 beats/minute). At the same time, platelet alpha 2-adrenoceptor number increased (from 168.2 +/- 48.4 to 256.8 +/- 14.5 fmol/mg protein, p less than 0.02), whereas the dissociation constant did not change (from 3.79 +/- 2.9 to 4.97 +/- 4.48). The plasma norepinephrine level was significantly reduced after long-term treatment with indapamide (from 275 +/- 118 to 210 +/- 56 pg/ml, p less than 0.02). These results bring about an inhibition of norepinephrine release from sympathetic nerve endings with a likely secondary increase of the number of platelet alpha 2-adrenoceptors.

Preparation and antitumor activity of 1-aryl-3,3-dimethyltriazene derivatives.

Several 1-aryl-3,3-dimethyltriazene derivatives have been synthesized and tested for their antitumor activity against the TLX5 lymphoma in mice. These compounds are characterized by the presence of a carbonyl group bound to the benzene nucleus in the para position to the triazene funciton. Three p-sulfamoyl derivatives have also been included and proved to be inactive. Among the carbonyl derivatives compounds 1 and 20, which can be used as reference, cause ILS of about 50%, respectively, at four and three dose levels. Compound 16, the o-nitro-phenylhydrazone of the hydrazide 1, is active at all six dose levels studied. The adduct 19, obtained from the same hydrazide and p-nitrobenzaldehyde, is active at four dose levels, and the ILS values at two optimum doses are significantly greater than those caused by compound 1.

Characterization of multidrug transporters in a normal renal tubular cell line resistant to doxorubicin. Multidrug transporters in the LLC-PK(1) cell line and its resistant counterpart.

LLC-PK(1) is a proximal tubular cell line derived from normal pig kidney which has a structure and function similar to those of renal proximal tubular cells and which expresses baseline levels of P-glycoprotein. We isolated by drug selection a doxorubicin-resistant cell line (LLC-PK(1)/ADR) that exhibited a multidrug-resistant phenotype; this cell line was characterized by reduced intracellular drug concentrations, an increased drug extrusion, and increased expression of a 170-kDa P-glycoprotein detected by Western blot analysis with monoclonal antibody C219. In addition, an increased expression of MDR1 mRNA was seen by reverse transcriptase-polymerase chain reaction. These results suggest that it is possible to induce the overexpression of P-glycoprotein by chronic treatment with doxorubicin in a normal cell line that physiologically expresses low levels of this protein. This multi-resistant cell line could provide an interesting model for studying the role of P-glycoprotein and the consequence of its induction in a normal tissue.

Mechanism of the antileukemic effects of 1-p-carboxamidophenyl-3,3-dimethyltriazene and its in vitro metabolites.

DM-CONH2, a dimethyltriazene active in prolonging the survival time of mice bearing TLX5 lymphoma, requires metabolic activation by liver homogenate supernatant and cofactors in order to exert in vitro cytotoxic effects on the same tumor cells, as determined by in vivo bioassay of their viability. From the examination of the metabolites produced during these in vitro experiments, it is found that in vitro cytotoxicity is attributable to the generation of MM-CONH2 by oxidative N-demethylation of DM-CONH2. Also the generation of DM-COO is observed, although this compound is not cytotoxic in vitro. The in vivo effects of DM-CONH2 and CM-COOK on TLX5 lymphoma are not caused exclusively by cytotoxic effects of the drugs, since they are evident also when no reduction in the number or viability of peritoneal tumor cells is evident, whereas these parameters are significantly reduced by MM-CONH2. The increase in survival time of mice bearing TLX5 lymphoma caused by the dimethyltriazenes used appears to be caused by the drugs without being subjected to metabolic activation, with a mechanism different from cytotoxicity for tumor cells.

Stress and chemotherapy. Combined effects on tumor progression and immunity in animal models.

In mice bearing Lewis lung carcinoma, rotational and restraint stress specifically increases the formation of lung metastasis, and restraint stress markedly attenuates the antitumor effects of cyclophosphamide. The aim of this investigation was therefore to examine the effects of restraint stress on tumor metastasis in mice bearing MCa mammary carcinoma, and on the effectiveness of CCNU and DTIC. Restraint stress increases MCa mammary carcinoma metastasis, causes a marked reduction in cyclophosphamide activity, and a minor attenuation of the effects of CCNU and DTIC. The possible occurrence of seasonal factors, observed for the increase by rotational stress of Lewis lung carcinoma metastasis, was also determined for cyclophosphamide effectiveness. The survival time of control mice is longer in February than in June, and is not appreciably modified by rotational stress. The effects of cyclophosphamide are similar in both seasonal periods, and are similarly attenuated by rotational stress. The seasonal effects of rotational stress, and the reduction of the effects of cyclophosphamide caused by rotational stress, are accompanied by corresponding variations in the number of CD3+ and CD4+ splenic T-lymphocyte subsets and in the CD4+/CD8+ ratio, respectively. The reported effects of stress on tumor progression and on the effectiveness of cyclophosphamide thus appear to occur via modulation of immune responses of the host directed against the tumor. These data appear of interest for their experimental implications, and suggest the opportunity to consider the role that the stress during treatment may play in determining the effectiveness of clinical antitumor chemotherapy.

Antitumor effects of GANU and other nitrosourea derivatives against transplantable leukemias and solid tumors in mice.

The antitumor effects of GANU have been examined in a panel of mouse tumors for which data appear to be lacking in the literature. GANU has significant activity against P388 leukemia and TLX5 lymphoma, and also against the solid tumors B16 melanoma and Lewis lung carcinoma; pulmonary metastases of this tumor are particularly sensitive to the effects of GANU. The effects of GANU on TLX5 lymphoma and Lewis lung carcinoma are less pronounced than those of BCNU and CCNU, as already reported for L1210 leukemia. In contrast with other results obtained with this tumor, chlorozotocin has a less pronounced effect than GANU, and virtually none in lung metastases of Lewis lung carcinoma.

Effects of an inducer and an inhibitor of hepatic metabolism on the antitumor action of dimethyltriazenes.

To investigate the role of monomethyltriazenes as the active metabolites of antitumor dimethyltriazenes, the in vivo simultaneous treatment with an inducer (phenobarbital, PB) or an inhibitor (carbon tetrachloride, CCl4) of hepatic drug metabolism was examined in mice bearing Lewis lung carcinoma. Treatment with PB or CCl4 with the dosage and schedules employed proved to be effective in markedly modifying the N-demethylation of the three dimethyltriazenes tested, as had been determined in vitro. No unambiguous increase by PB, or decrease by CCl4, which might theoretically be expected if metabolic conversion to monomethyltriazenes was involved, was observed for the antitumor and antimetastatic activity of dimethyltriazenes. At the same time, a difference was noted between the effects on primary tumors and those on metastases. These data support the view that generalizations on the relevance of monomethyltriazenes as the active metabolites responsible for the antitumor and antimetastatic activity of dimethyltriazenes may not be valid.

Melatonin decreases bone marrow and lymphatic toxicity of adriamycin in mice bearing TLX5 lymphoma.

When CBA male mice bearing TLX5 lymphoma were treated in the evening with a single i.v. dose of adriamycin (20-40 mg/Kg), the administration of a single pharmacological dose of melatonin (10 mg/kg s.c.) 1 hr earlier reduced the acute mortality from 10/24 to 2/24. The increase in survival time caused by adriamycin over drug untreated controls was not reduced by melatonin. The administration of melatonin alone did not cause any antitumor or evident toxic effect. Melatonin also attenuated the reduction caused by adriamycin in the number of bone marrow GM-CFU, and of CD3+, CD4+ and CD8+ splenic T-lymphocyte subsets. Reduced and total glutathione levels were decreased in the bone marrow and in the liver cells of the animals treated with adriamycin, and were significantly restored by melatonin. Moreover, lipid peroxidation by adriamycin was reduced by melatonin, as indicated by malondialdehyde measurement in the liver of the treated animals. These data indicate that the protective effects of melatonin against the host toxicity of the prooxidant antitumor drug, adriamycin, might be attributed at least partially to its antioxidant properties. These findings appear of interest in relation to the physiological rhythmic levels of endogenous melatonin and to the chronotoxicology of anthracyclines.