[On some methods of study of immunologic thrombopenia].
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Animals↗
Biomedical subjects
G Pratesi
Publications and source records attributed to G Pratesi.
Role of apoptotic response in cellular resistance to cytotoxic agents.
The development of drug resistance is a major obstacle to effectiveness of chemotherapeutic treatment of human tumors with cytotoxic agents. Drug resistance is described as a multifactorial phenomenon, involving the expression of defense factors and/or detoxification mechanisms, alterations in drug-target interactions, and cellular response to specific cytotoxic lesions (in particular, DNA damage). Although the proposed mechanisms may contribute to the development of a variable degree of cellular resistance, it is possible that the cell response (i.e., DNA repair or apoptosis) following DNA damage plays a critical role in determining cellular chemosensitivity. The preclinical observations that tumor response to effective drug treatments is associated with induction of apoptosis support the possibility that a decreased susceptibility to apoptosis (apoptosis resistance) is relevant to clinical resistance. A number of molecular alterations associated with transformation and/or tumor progression may also be implicated in regulation of cell death pathways and in the development of drug resistance. There is evidence that the wild-type p53 is involved in cellular response to DNA damage, including cell cycle regulation, DNA repair, and activation of the pathway leading to apoptosis. Loss of wild-type p53 function could cause resistance to DNA-damaging agents, as a consequence of abrogation of p53-dependent apoptosis. The identification of new agents able to trigger p53-independent apoptosis and the search for biochemical modulators downstream of p53 may be of clinical relevance because many tumors are deficient in p53 function due to mutation or deletion. An overview of the resistance mechanisms is presented, with particular reference to the role of p53 mutations in clinical resistance and of apoptosis-related genes in cellular chemosensitivity.
Animals↗
New developments in antitumor anthracyclines.
Doxorubicin is a major anticancer agent introduced to extended clinical use in the early 1970s. The fulfillment of a wide program of analogue synthesis led to the development of the better tolerated epirubicin and of a highly potent antileukemic drug, idarubicin. In recent years, on the basis of the available information on the molecular requirements for action, a new synthetic program, coupled with target-oriented pharmacological experiments, was carried out. Various interesting derivatives, namely, the 8- and 10-fluoro compounds and the disaccharides, were obtained. The latter compounds exhibited a strong dependence of biological activity on the orientation (axial vs. equatorial) of the second sugar moiety, daunosamine. A member of this group, namely, 7-O-(4'-O-alpha-L-daunosaminyl-2'-deoxy-alpha-L-fucosyl)-4-demetho xy-adriamycinone, is presently undergoing clinical trials as a third generation antitumor anthracycline.
Animals↗
Hyaluronan digestion and synthesis in an experimental model of metastatic tumour.
To approach the question of hyaluronan catabolism in tumours, we have selected the cancer cell line H460M, a highly metastatic cell line in the nude mouse. H460M cells release hyaluronidase in culture media at a high rate of 57 pU/cell/h, without producing hyaluronan. Hyaluronidase was measured in the H460M cell culture medium at the optimum pH 3.8, and was not found above pH 4.5, with the enzyme-linked sorbent assay technique and zymography. Tritiated hyaluronan was digested at pH 3.8 by cells or cell membranes as shown by gel permeation chromatography, but no activity was recorded at pH 7 with this technique. Hyaluronan was digested in culture medium by tumour slices, prepared from tumours developed in nude mice grafted with H460M cells, showing that hyaluronan could be digested in complex tissue at physiological pH. Culture of tumour slices with tritiated acetate resulted in the accumulation within 2 days of radioactive macromolecules in the culture medium. The radioactive macromolecular material was mostly digested by Streptomyces hyaluronidase, showing that hyaluronan was its main component and that hyaluronan synthesis occurred together with its digestion. These results demonstrate that the membrane-associated hyaluronidase of H460M cells can act in vivo, and that hyaluronan, which is synthesised by the tumour stroma, can be made soluble and reduced to a smaller size by tumour cells before being internalised and further digested.
Animals↗
[Electrolyte balance and acid-base equilibrium in high ultrafiltration hemodiafiltration].
Electrolyte and acid-base balance was evaluated in 14 high UF (124 +/- 7 ml/min) hemodiafiltration sessions. The dialysate contained (in mEq/l): Na 138-140, K 2-3, Ca 3.5, Mg 0.5-0.7, Cl 106-110, acetate 38 or acetate 3 and bicarbonate 35-38. The fluid, infused in postdilutional mode, was 23.5 +/- 21 per session (session length 203 +/- 22 minuti), 80% containing Na 138, K 2, Ca 3.5, Mg 1, Cl 109.5, acetate 35 and 20% Na 145, HCO3 100, Cl 45. The balance was: negative for Na (-255 +/- 220 mEq), for K (-74 +/- 22 mEq) and for Mg (-166 +/- 141 mg), positive for Ca (215 +/- 147 mg) and for acetate (590 +/- 15 and 966 +/- 412 mmol); the electrolytes and bicarbonate plasma values were within of close to normal limits during the session. An unphysiological feature was the positive balance of acetate which, though, was metabolized during the interdialytic period as to return to normal predialytic values. Therefore, in high UF HDF, the above combination of dialysate and reinfusate allows a reasonable electrolyte and acid-base balance; however, bicarbonate should be the only buffer in order to avoid unphysiological levels of other buffers in the biological fluids.
Acid-Base Equilibrium↗
[Hemodiafiltration with high-level ultrafiltration versus hemodialysis. Longitudinal study].
A group of well nourished young patients was examined during 2 longterm consecutive high efficiency dialytic schedules to detect possible clinical and biochemical differences. The patients were first studied during hemodialysis with a 1.2 m2 cuprophan membrane and blood flow of 400 ml/min and, then, during hemodiafiltration with an ultrafiltration rate greater than 100 ml/min by using high permeability membranes with a surface greater than or equal to 1.4 m2. As expected by the higher clearances obtained on hemodiafiltration, this technique resulted in a significant reduction of dialysis time and of BUN and serum creatinine, associated with a significant increase of hemoglobin, possibly related to a better deintoxication. Furthermore, the dry body weight decreased significantly during hemodialysis, whereas it increased significantly during hemodiafiltration, despite unchanged dietary habits, indicating possible differences in the nutrients utilization during the 2 dialytic schedules. Therefore, in chronically dialyzed patients, highly permeable synthetic membranes should be preferred to cuprophan because of a supposed better biocompatibility and should be used with the highest ultrafiltration rate in order to obtain a better dialytic efficiency and to avoid the risk of backfiltration.
Adult↗
Malignant transformation of host cells by a human small cell lung cancer xenografted into nude mice.
Malignant transformation of mouse host cells by a human small cell lung cancer (SCLC) was demonstrated by short-term in vitro cultivation of the tumor cells from a xenograft at two different transplant generations. Isoenzyme (LDH) and chromosome analysis showed that out of the 3 cell lines established from this tumor, 1 retained a human karyotype similar to that of the xenograft and 2 were murine transformed cell lines. These murine cell lines produced fibro-sarcoma-like tumors when injected into nude mice. Because of the early in vitro emergence of murine transformed cell populations, it is likely that the transformation process had occurred in vivo. Since in our experience the induction of transformation of host murine cells, also observed directly in vivo, is more frequent with SCLC than other histotypes (lung and colorectal adenocarcinoma), it is suggested that the known production of growth factor by these tumors may contribute to this transformation.
Animals↗
[Non-A, non-B viral hepatitis in patients in chronic hemodialysis].
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Hepatitis C↗
[Mixed connective tissue disease in childhood. Report of a case].
The Authors report a case of MCTD in a 11 years old girl. Initially the disease presented the classical clinical picture of IDM. Successively its evolution was marked by the appearance of the typical clinical features of JRA, SS and of serum antibodies anti-RNP and by absence of antibodies anti-dsDNA and anti-Sm. These data are characteristic of MCTD. The occurrence of this disease in children is extremely rare and the prognosis is related to a possible renal and/or haemopoietic involvement.
Child↗
[Sjogren-Larsson syndrome. Description of a case].
The authors describe a typical case of Sjogren-Larsson Syndrome showing a clear improvement of the spastic paresis after 2 years of physiotherapy and a diet rich in polyunsaturated fatty acids.
Fatty Acids, Unsaturated↗
[A therapeutic plan for optimal control of divalent ions in patients on chronic hemodialysis].
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Aged↗
[Mucha-Habermann disease. Description of a case in childhood].
The authors report a case of Mucha-Habermann disease in childhood. Mucha-Habermann disease is not a very well known, though not infrequent, disease. It is characterized by recurrent erythematous-papular-vesicular skin lesions associated with arthralgia or arthritis or large joints. Prognosis is generally favourable although an evolution towards Pityriasis Lichenoides Chronica and/or Mycosis Fungoides is possible. There are not specific laboratory findings for this form. Diagnosis is essentially based on histology showing an immunopathogenetic vasculitis. At the present time there is not a safe therapy for the disease; there are however indications for the use of Erythromycin and we followed these in our therapy with positive results.
Arthritis↗
Intestinal absorption of tocopherols in homozygous beta-thalassemia. A study of twenty patients.
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Child↗
[A case of systemic sclerosis in childhood complicated by severe digital ulcers].
Systemic sclerosis is a diffuse disorder of connective tissue in which there are inflammatory, fibrotic and degenerative changes in the skin and many internal organs. We describe a case of systemic sclerosis type "acrosclerosis" in a six years old child with Raynaud's phenomenon and gastrointestinal involvement. In the course of illness he presented severe digital ulcerations in the hands and in the feet, responsive to a calcium channel blocking agent nifedipine treatment.
Child↗
Synthesis, antitumor activity, and cardiac toxicity of new 4-demethoxyanthracyclines.
The new anthracycline glycosides 4-demethoxy-4'-deoxydaunorubicin and 4-demethoxy-4'-O-methyldaunorubicin, synthesized by coupling 4-demethoxydaunomycinone with 1-chloro-derivatives of protected 4-O-methyl and 4-deoxydaunosamine derivatives, have been converted into the corresponding doxorubicin analogs. The new compounds have been compared for antitumor effect with the parent drugs and with the previously described 4-demethoxydaunorubicin, 4-demethoxy-4'-epidaunorubicin, and their doxorubicin analogs. All of the new analogs were more cytotoxic against HeLa cells in vitro and were more toxic and more potent in mice than the parent drugs. Comparison at optimal antitumor doses showed that the new analogs were as active as the parent drugs against ascitic P388 leukemia and disseminated Gross leukemia. They were also active when administered orally. The new doxorubicin analogs were slightly more active than doxorubicin against ascitic L1210 leukemia and were markedly more active against disseminated L1210 leukemia. In a parallel activity-cardiotoxicity test in C3H mice repeatedly treated iv, 4-demethoxydoxorubicin, 4-demethoxy-4'-epidoxorubicin, 4-demethoxy-4'-O-methyldoxorubicin, and 4-demethoxy-4'-deoxydoxorubicin showed antitumor activity against mammary carcinoma without inducing the typical myocardial lesions observed after doxorubicin treatment, 4-Demethoxy-4'-O-methyldoxorubicin, because of its high antitumor effectiveness, lack of cardiac toxicity in mice, and activity by the oral route, deserves further study.
Animals↗
Remarkable antitumor activity of 5'-deoxy-5-fluorouridine in human colorectal tumor xenografts.
5'-Deoxy-5-fluorouridine (doxifluridine) is a prodrug of 5-fluorouracil (5FU) selectively activated by tumor cells. Since in clinical studies the side effects of doxifluridine differed after intravenous (i.v.) or oral administration, and oral route was the most promising in preclinical studies with murine models, in this study the drug was tested orally against a panel of human colorectal tumor xenografts with varying degrees of sensitivity to 5FU. Doxifluridine efficacy was comparable to that of 5FU when it was delivered according to a weekly schedule, but it was statistically higher when it was delivered more frequently. Impressive tumor inhibition (between 90 and 97%) was achieved in 4 out of 5 tumor lines after treatments delivered twice a week or daily 5 times a week. No difference in 5FU activity was observed between weekly and biweekly treatments, or between oral and i.v. injections. Moreover, in one tumor line in which different dosages of doxifluridine were investigated, a marked antitumor effect was obtained with a wide range of tolerated doses (4000-8000 mg/kg). Overall, these data indicated that doxifluridine is well tolerated when given orally and frequently. Using an adequate schedule, the prodrug has a better therapeutic efficacy against a variety of human colon cancer models than 5FU.
Animals↗
Gamma-glutamyltranspeptidase activity in human ovarian carcinoma.
Gamma-glutamyltranspeptidase (GGT) is a cell membrane enzyme involved in the hydrolysis and uptake of extracellular glutathione. Histochemically detectable GGT has been shown in several human neoplasms. However, few studies have addressed the quantitative biochemical assessment of GGT activity in human tumors, and the importance of GGT activity in human tumor biology remains to be elucidated. The aim of the present study was to assess biochemically GGT enzyme activity in human ovarian surgical biopsies. GGT activity was assayed in homogenates of surgical samples of ovarian tumors and compared with the clinical data of the patients in order to establish: a) the level of tumor GGT activity, b) its correlation with other clinical parameters of the neoplasms, c) the possibility of the induction in vivo of GGT after anticancer platinum-based therapy, since some of the patients were pretreated. The results indicated that ovarian tumor expresses biochemically relevant GGT activity. The sensitive method used in this study allowed the quantitative evaluation of enzyme activity in all samples examined, showing that GGT activity values in ovarian carcinoma samples were extremely variable among the different subjects, both in untreated neoplasms (6.2 +/- 5.4 mU/mg protein) and in second-look laparotomy biopsies following platinum-based therapy (4.7 +/- 3.8 mU/mg protein). The mean GGT activity in benign ovarian tumors was lower than that in malignant tumors. No significant correlation was found between GGT activity and patient characteristics (tumor stage, age of patients, serum CA125, TAG-72, and GGT levels). However, the biological and pharmacological relevance of GGT expression remain to be elucidated in a large series of tumors.
Adult↗
Effect of serotonin and nicotine on the growth of a human small cell lung cancer xenograft.
Small cell lung cancer (SCLC) cells express cholinergic nicotinic receptors on their membranes, and the stimulatory effect on cell growth of nicotine has been described in cell cultures. We investigated three SCLC cell lines, all showing high levels of fluorescence intensity when labeled with FITC alpha-bungarotoxin in most cells. From one of these cell lines, NCI-N592 a tumor line in athymic nude mice was established. Nude mice were subcutaneously grafted on the same day with tumor fragments and with Alzet osmotic minipumps (200 microliters, 14 days of infusion) infused with serotonin or nicotine to investigate their effects on tumor growth. Two dose levels of each compound were used, namely 20 and 200 micrograms/day. In mice treated with 200 micrograms serotonin, tumors took a shorter time than those of untreated controls to reach 50 mg in volume, meaning that the first steps of tumor growth were faster. In contrast, a delay in tumor appearance was observed in mice treated with low-dose serotonin. No differences were found in tumor growth in the groups of mice treated with nicotine. When the treatment was delivered to already established and vascularized tumors (around 100 mm3), no effect on tumor growth was achieved by serotonin or nicotine. Therefore, in the experimental conditions used in the study, the stimulatory effect of nicotine on an SCLC tumor was not demonstrated.
Animals↗