Clinical activity of patupilone in patients with pretreated advanced/metastatic colon cancer: results of a phase I dose escalation trial.

BACKGROUND: New agents that are active in patients with metastatic colorectal cancer are needed. Patupilone (EPO906; epothilone B) is a novel microtubule-stabilising agent. METHODS: Patients with advanced colon cancer who progressed after prior treatment regimens received intravenous patupilone (6.5-10.0 mg m(-2)) once every 3 weeks by a 20-min infusion (20MI), 24-h continuous infusion (CI-1D) or 5-day intermittent 16-h infusion (16HI-5D). Adverse events (AEs), dose-limiting toxicities (DLTs), pharmacokinetics and anti-tumour activity were assessed. RESULTS: Sixty patients were enrolled. The maximum tolerated dose (MTD) was not reached in the 20MI arm (n=31), as no DLTs were observed. Three patients in the CI-1D arm (n=26) experienced 1 DLT each at 7.5, 8.0 and 9.0 mg m(-2), but MTD was not reached. However, the prolonged 16HI-5D arm was terminated at 6.5 mg m(-2) after two of the three patients developed a DLT. Diarrhoea was the most common AE and DLT, with increased severity at the higher doses (9.0 and 10.0 mg m(-2)). Grade 3 or 4 diarrhoea was observed in 11 (35%) of the patients in the 20MI arm, 4 (15%) of the patients in the CI-1D arm and 2 (67%) of the patients in the 16HI-5D arm. Patupilone activity was observed in the 20MI arm with a disease control rate of 58%, including four confirmed partial responses. The disease control rate in CI-1D arm was 39%. CONCLUSION: Patupilone given once every 3 weeks as a 20-min infusion had promising anti-tumour activity and manageable safety profile at doses that demonstrated therapeutic efficacy.

[Disturbance of synthesis of cholesterol and its precursors in clinically serious conditions]. / Porucha syntézy cholesterolu a jeho prekurzoru u klinicky závazných stavu.

OBJECTIVE: The aim of the study was to elucidate the role and importance of hypocholesterolemia in clinically serious conditions. It was a monocentric, prospective clinical study. MATERIAL AND METHODS: Two groups of patients were recruited to the study--one group were patients with coronary heart disease (CHD), who underwent miniinvasive cardiosurgical operation without extracorporeal circulatio (n = 17) and one group of patients, who sustain polytrauma (n = 19). Thirty six patients were recruited into the study. We performed the determination of sterols (total cholesterol, HDL-cholesterol, LDL-cholesterol, triacylglycerols), and their precursors (beta-sitosterol, campesterol, lathosterol, skvalen), interleukin IL-6 and cortisol in the blood serum. The short version of ACTH stimulation test was performed. The oxidative burst of granulocytes was evaluated. The blood samples were taken on the day of admission, the first, the fourth and the eighth post-operative and post-traumatic day. RESULTS: There was a significant decline of total cholesterol (TC) and LDL-cholesterol level with full recovery during observed period. There was a decline of cholesterol synthesis (lathosterol and lathosterol/cholesterol ratio) together with a decline of total cholesterol. There was a significantly negative correlation between IL-6 level and total cholesterol. Despite no confirmation of disturbance of adrenal function, there was a significantly positive correlation between lathosterol/cholesterol ratio (a de novo cholesterol synthesis marker) and cortisol level after the ACTH stimulation test. There was a significant breakdown of bactericidal function of granulocytes along with a decline of cholesterol level. CONCLUSION: There was decline of endogenous cholesterol synthesis in clinically serious conditions. The cholesterol synthesis rate is negatively influenced by IL-6 level. The rate of endogenous cholesterol synthesis positively correlated with cortisol production by the adrenals and with bactericidal function of granulocytes.

Biochemical and pharmacological effects of mitoxantrone and acetyl-L-carnitine in mice with a solid form of Ehrlich tumour.

BACKGROUND: Dysfunction of the carnitine system in non-tumour tissue following anticancer therapy has been reported. In this setting, supplementation with carnitine derivatives might increase the general metabolic activity of normal cells so that they might better withstand the adverse effects of chemotherapy aimed at tumour cells. Here we investigated the effect of acetyl-L-carnitine (ALC) alone and in combination with the antineoplastic agent mitoxantrone (MX) in an animal cancer model. METHODS: The effects of MX and MX-ALC were assessed based on gain or loss of body weight and on local growth of a solid form of Ehrlich tumour inoculated into mice. We also performed biochemical analyses like serum activities of some enzymes signalling the functioning of the liver, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Total protein, albumin and bilirubin were also determined in serum. Under favourable conditions, the Ehrlich tumour readily forms metastases, and this is the reason why we performed histological studies of samples of both the liver and heart in order to identify changes that may have mediated the observed effect of the treatment. In addition to those studies, the survival time of treated animals against controls was also noted. RESULTS: MX monotherapy was associated with lower body weight gain, fewer metastases, smaller tumour size, and lower dissemination. ALC alone promoted survival, but had no potentiating effect on MX therapy in terms of survival. Serum biochemistry changes associated with MX-ALC treatment consisted of a significant (p < 0.05) increase in AST with MX at 6 or 9 mg·kg(-1) plus ALC 200 mg·kg(-1) and a significant (p < 0.05) reduction in total protein compared to the corresponding MX group; serum albumin and bilirubin remained unchanged. CONCLUSION: ALC in combination with MX, regardless of the dose of MX, led to higher occurrences of metastases with dissemination to the kidneys, lungs, heart, and mediastinum compared to MX treatment alone. These histological findings indicate that ALC is inappropriate to combine with MX in the treatment of a solid cancer. The protective effect of ALC in combination therapy with the cytostatic drug MX was not supported in this study by our findings that the agent did not improve the therapeutic outcomes of MX therapy.

Effect of somatostatin on repair of ionizing radiation-induced DNA damage in pituitary adenoma cells GH3.

Ionizing radiation and somatostatin analogues are used for acromegaly treatment to achieve normalization or reduction of growth hormone hypersecretion and tumor shrinkage. In this study, we investigated a combination of somatostatin (SS14) with ionizing radiation of (60)Co and its effect on reparation of radiation-induced damage and cell death of somatomammotroph pituitary cells GH3. Doses of gamma-radiation 20-50 Gy were shown to inhibit proliferation and induce apoptosis in GH3 cells regardless of somatostatin presence. It has been found that the D(0) value for GH3 cells was 2.5 Gy. Somatostatin treatment increased radiosensitivity of GH3 cells, so that D(0) value decreased to 2.2 Gy. We detected quick phosphorylation of histone H2A.X upon irradiation by the dose 20 Gy and its colocalization with phosphorylated protein Nbs-1 in the site of double strand break of DNA (DSB). Number of DSB decreased significantly 24 h after irradiation, however, clearly distinguished foci persisted, indicating non repaired DSB, after irradiation alone or after combined treatment by irradiation and SS14. We found that SS14 alone triggers phosphorylation of Nbs1 (p-Nbs1), which correlates with antiproliferative effect of SS14. Irradiation also increased the presence of p-Nbs1. Most intensive phosphorylation of Nbs1 was detected after combined treatment of irradiation and SS14. The decrease of the number of the DSB foci 24 h after treatment shows a significant capacity of repair systems of GH3 cells. In spite of this, large number of unrepaired DSB persists for 24 h after the treatment. We conclude that SS14 does not have a radioprotective effect on somatomammotroph GH3 cells.

Fulminant course of metastatic liposarcoma after delivery--case report.

Abdominal liposarcoma is a rare tumor of uncertain prognosis. Radical surgery is possible in about two-thirds of the patients, and the prognosis of patients with inoperable tumors is dismal. Only a few cases of liposarcoma complicating pregnancy have been documented. We report a case of a patient who was diagnosed with metastatic abdominal liposarcoma during the third trimester of the pregnancy. After induced vaginal delivery, palliative surgery was performed and one cycle of systemic combination chemotherapy was administered. Despite the multimodality treatment the patient died of progressive disease within one month after diagnosis. Autopsy revealed high-grade pleomorphic liposarcoma arising from the retroperitoneum with liver and lung metastases.

Evaluation of the antineoplastic activity of mitoxantrone-L-carnitine combination therapy on an experimental solid form of ehrlich tumour in mice.

We have commenced a series of experiments to evaluate the effect of carnitine derivatives on the antineoplastic activity of mitoxantrone (MX) on various animal cancers. This report describes the therapeutic effect of MX in combination with l-carnitine (LCAR) on the growth of a solid form of Ehrlich tumour inoculated into mice. LCAR was administered subcutaneously at doses of either 200 or 100mgkg(-1) on day 6 and 13 after tumour inoculation, 1h prior to the treatment with MX. Mitoxantrone was administered intravenously at doses of 3 or 6mgkg(-1). We found that LCAR had no potentiating effect on the efficacy of MX, in terms of either slowing tumour growth or increasing the survival of mice. Nevertheless, therapeutic effects can be assumed at higher doses of both drugs based on values calculated from an index of relative hazards.

[A cell and genotoxic stress: a reaction to double strand breaks of DNA]. / Bunka a genotoxický stres: reakce na dvojité zlomy DNA.

Double strand breaks (DSB) of DNA represent a major impact on the genome integrity. Cells have developed complex set of reactions for prevention of genotoxic damage and cellular dysfunction. The quickly reacting proteins of human cells include proteinkinases from the family of phophatidylinositol-3-kinase related proteinkinases: ataxia-teleangiectasia mutated (ATM), ataxia-teleangiectasia and Rad3-related (ATR) and catalytic subunit of DNA-dependant proteinkinase (DNA-PKcs). Activated ATM phosphorylates other targets, including proteins p53, Mdm2, Chk1, Chk2, Brca1, Nbs1 and cAb1. This article discusses the molecular response to DSB in detail.

[Possibilities of medical treatment in acromegaly]. / Moznosti medikamentózni lécby akromegalie.

Active acromegaly deteriorates the quality of life and shortens the life expectancy. Surgery is the first-line therapy in the majority of patients, followed by radiotherapy in unsuccessful cases. The surgery cure rate is only one half in the case of macroadenomas and it takes years before radiotherapy normalizes GH and IGF-I levels. In the interim, medical therapy is necessary. Second-generation dopamine agonists (cabergoline) are successful in about one third of patients, especially in those with lower basal IGF-I levels and with adenomas co-secreting prolactin. Somatostatin analogues octreotide and lanreotide are the gold standard of medical treatment - both are available in a form applicable as once-monthly injections. They successfully control disease activity in the majority of patients and induce tumour shrinkage in part of adenomas. Surgical debunking of macroadenomas improves the results of therapy with somatostatin analogues and it is not necessary to discontinue this therapy before radiotherapy. The potential of higher efficiency represent new analogues, binding not only to somatostatin receptor subtype 2, but also to subtype 5 and "dopastatins" that are able to bind both to the somatostatin and the dopamine D2 receptors. The advent of the GH receptor antagonist pegvisomant provides the possibility to normalise IGF-I in virtually every patient. Combined treatment with somatostatin analogues probably enables reduction from daily to weekly injections.

Combined effect of sodium selenite and campthotecin on cervical carcinoma cells.

The effects of selenite, campthotecin and their combination were investigated in cervical carcinoma cell line Hep-2 HeLa during 24h. The measured parameters included morphological changes, proliferation, oxidative stress, mitochondrial status, caspase-3 activation and nuclear fragmentation. Selenite at all but lowest concentrations inhibited cell growth and proliferation and induced cell death characterized by membrane blebbing, oxidative stress and mitochondrial damage, occurring in the absence of caspase-3 activation and nuclear fragmentation. Campthotecin at all concentrations induced gradual apoptosis including all measured morphological and molecular parameters with exception of oxidative stress. A combination of selenite and campthotecin induced both antagonistic and synergistic effects on cervical carcinoma cells. While low selenium concentration slightly reduced cytotoxicity and proapoptotic effects of campthotecin, moderate and higher concentrations of selenium enhanced them, changing simultaneously apoptosis into more necrosis-like death. These results show importance of selenium as a potential modulator and enhancer of campthotecin-based anticancer therapy in nonovarian malignancies.

Inhibition of hormone secretion in GH-secreting pituitary adenomas by receptor-subtype specific somatostatin analogues in vitro.

The aim of the study was to determine the inhibitory effects of somatostatin analogues with relative specificity to somatostatin receptor subtype 2 (SSTR2) (BIM-23197), subtype 5 (SSTR5) (BIM-23268), and their combination on GH and PRL secretion in acromegalic adenomas in vitro. Three types of answer were observed: 1. In one resistant adenoma no inhibition was achieved. 2. The GH secretion in six adenomas was suppressed significantly more (p < 0.01 or p < 0.001 using Mann-Whitney U-test in concentration range of 10(-12) to 10(-8) mol/l) with SSTR2 specific analogue BIM-23197 with no additive effect of compounds combination. 3. In three adenomas the potency of BIM-23197 and BIM-23268 was almost equal and the combination of these SSTR2 and SSTR5 specific compounds had statistically significant additive effect (p < 0.05 or p < 0.01 in concentration range of 10(-12) to 10(-8) mol/l). PRL secretion of five adenomas was more suppressed with SSTR5 specific BIM-23268 (statistically significant in concentrations 10(-10) to 10(-8) mol/l). In conclusion the somatostatin analogue BIM-23268 had an additive effect on suppression of GH secretion in a subset of adenomas, where both SSTR2 and SSTR5 were involved. This effect was not observed in the majority of tumours, where the inhibitory effect seems to be mediated via SSTR2 only.

Light-induced photoactivation of hypericin inhibits cellular growth in pituitary adenoma cell line AtT20/D16v-F2 (hypericin inhibits cellular growth of AtT20/D16v-F2).

Cultivation with 4-8 mumol/l hypericin (specific proteinkinase C inhibitor) activated by light induced high inhibition of the rate of HL-60 cell growth. When hypericin treated cells were not exposed to light growth inhibition was insignificant. Cultivation with light activated hypericin in concentration 16 mumol/l slightly inhibited growth rate of AtT20/D16v-F2 cells. AtT20/D16v-F2 cells did not proliferate in presence of light activated 32 mumol/l hypericin. Evidence of apoptosis was found in HL-60 cells treated with 1-8 mumol/l light activated hypericin, with maximum of apoptotic cells detected after 8 mumol/l light activated hypericin. Light activated hypericin induces both apoptosis and necrosis in dose and time dependent manners in HL-60 cells, but causes only necrosis in AtT20/D16v-F2 cells.

Small bowel permeability in patients with cytostatic therapy.

The purpose of this study was to examine the influence of cytostatic therapy on the barrier function of the small bowel. In 16 patients with tumors in the gastrointestinal tract with metastatic involvement of the liver, small bowel permeability was measured using the lactulose/mannitol test. The patients were treated for 5 d with fluorouracil (750-1000 mg/d) and leucovorin (25-50 mg/d). The examination was performed on the first day, at the beginning of the cytostatic therapy, and also 5, 12, and 28 d after the therapy had begun. In comparing the start and the end of this therapy, the index of permeability was significantly increased (as measured 7 d after the end of therapy). These results show the damage of small bowel barrier after cytostatic therapy.

Cholinesterases in dexrazoxane-treated daunorubicin cardiomyopathy in rabbits.

Changes in cholinesterases activities in daunorubicin cardiomyopathy and in dexrazoxane (DRZX)-treated daunorubicin cardiomyopathy were investigated in rabbits. Acetyl- and butyrylcholinesterase (AChE and BuChE) were determined using Ellman's method. In the serum, a significant decrease of BuChE was observed in the daunorubicin group (9.05 at the beginning and 7.15 microcat/l at the end of the experiment). After DRZX, no significant changes were found and a significant increase in BuChE was observed in the control group (10.26-12.38 microcat/l). AChE activity in the left and right cardiac ventricles was not significantly different between the groups while in the septum there was a significantly lower AChE activity found in the daunorubicin group only. BuChE activity was significantly decreased in the left (15.64 ncat/g) and right (19.27 ncat/g) heart ventricles, in the septum and in the liver in the daunorubicin group. A significant decrease in serum total protein and albumin was demonstrated only in the daunorubicin group. Our results support the hypothesis about the influence of daunorubicin on protein (and enzyme) synthesis in the liver and heart. A protective effect of DRZX on cholinesterases activity was observed. The changes in cholinesterase activities may thus reflect their possible role in cardiomyopathy.

Changes of some biochemical and hematological parameters following administration of daunorubicin in rabbits.

The effects of the repeated i.v. administration of daunorubicin (50 mg/m2, once weekly, max. 9 weeks) were investigated in rabbits in vivo to analyze biochemical and hematological changes. Noninvasive polygraphic records were used to evaluate the function of the heart. The administration of daunorubicin induced changes especially in levels of protein (decrease in total protein and albumin) and of some ions (decrease in calcium, magnesium and phosphorus) as well as in hematological parameters (decrease in erythrocytes, leukocytes and thrombocytes). The results obtained correlate with data on mechanisms of daunorubicin toxicity.

[Diagnosis of echinococcosis in the population of Slovakia]. / Problematika diagnostiky echinokokózy ludí na Slovensku.

Serologically diagnosed cases of echinococcosis in man occurring over the years 1970-1990 are reported. In the given period 292 serum samples were examined obtained from patients clinically suspected of echinococcosis, either with or without indication of localization in different organs. Of the total of 22 serologically positive patients echinococcal cysts were found in the liver in 17 patients (77.27%), in the lungs in three (13.63%) and in two patients the localization was not established. The patients with positive serological finding were within the age range of 33 to 68 years, with the exception of one 11-year-old boy. The value of serological examination of echinococcosis in the subjects involved in our study is highlighted by the findings in those patients who underwent surgery. Both the positive and the negative serological results were confirmed by the surgical findings of the presence or absence of echinococcus. (Tab. 3, Ref. 22.)

[Helminthozoonoses in Slovakia 1981-1987]. / Helmintozoonózy na Slovensku v rokoch 1981-1987.

The incidence of helminthozoonoses in the Slovak Socialist Republic over the years 1981--1987 was assessed on the basis of reports submitted by health and veterinary organizations. The incidence of taeniases exhibited a decreasing trend over the period studied. The occurrence rate of cysticercosis in slaughter cattle was irregularly increasing from 0.65% to 0.90%. Echinococcosis in humans was established only sporadically (4 cases). In animals its extensity was decreasing and dropped to 0.22% in slaughter pigs and to 0.70% in sheep and goats. Trichinosis showed an endemic occurrence (13 cases). Larval toxocariasis increased from 6 to 129 seropositive cases. Hymenolepiasis was diagnosed only in the East Slovakian Region (0.06 to 1.46 cases per 100,000 inhabitants). (Fig. 5, Ref. 3.)

Peptide hormone expression and precursor processing.

Insight in the mechanisms of peptide hormone expression has grown explosively by elucidation of gene, mRNA and preprohormone structures for most hormone systems during the 1980s. The preprohormones vary considerably in size and organization from poly- to mono-protein structures. According to the structural organization and sequence homology the hormones are grouped in families. The prohormones are processed to bioactive peptides by multiple enzymatic modifications during the intracellular transport from the rough endoplasmatic reticulum to the mature secretory granules. The modifications comprise different proteolytic cleavages and amino acid derivatizations. The same prohormone may be expressed in several different cell-types that process the precursor in entirely different ways. Awareness of such cell-specific processing patterns is important for the understanding of ectopic synthesis in neuroendocrine tumours.