Drug resistance is the major reason for failure in cancer chemotherapy. Resistance may be either pre-existent (intrinsic resistance), or induced by drugs (acquired resistance), So far, no strategy has been found to overcome resistance, which is based on highly complex and individually variable biological mechanisms. In present clinical practice, drug resistance can only be recognized during treatment, after long lag times. Thus diagnostic tests are re quired, indicating resistance at an earlier stage, in order to avoid unnecessary medication, frequently associated with toxic side-effects. A number of new anti-cancer drugs are now available. In contrast to the unspecifically acting cytostatic chemotherapy, these compounds have targeted actions. However, as recent studies have shown, resistances and severe side-effects can also be found with targeted drugs. With the increasing number of new treatment regimens, the early diagnosis of resistance will optimize therapy, and indeed will be indispensable for individual cancer therapy. The resistance assays available for use in clinical practice should be integrated into cancer therapy. Research into this neglected area needs to be intensified.
Drug resistance is the main cause of the failure of chemotherapy of malignant tumors, resistance being either preexisting (intrinsic resistance) or induced by the drugs (acquired resistance). At present, resistance is usually diagnosed during treatment after a long period of drug administration.In the present paper, methods for a rapid assessment of drug resistance are described. Three main classes of test procedures can be found in the literature, i.e. fresh tumor cell culture tests, cancer biomarker tests and positron emission tomography (PET) tests. The methods are based on the evaluation of molecular processes, i.e. metabolic activities of cancer cells. Drug resistance can be diagnosed before treatment in-vitro with fresh tumor cell culture tests, and after a short time of treatment in-vivo with PET tests. Cancer biomarker tests, for which great potential has been predicted, are largely still in the development stage. Individual resistance surveillance with tests delivering rapid results signifies progress in cancer therapy management, by providing the possibility to avoid drug therapies that are ineffective and only harmful.
Aims A prophylactic use of melatonin as an anti-ageing drug has recently gained public interest due to its radical scavenging property in vitro. The present study was designed to investigate a possible antiatherogenic effect of melatonin and its physiological metabolites by examining their action on the radical-initiated formation of oxidized LDL, which is known to possess a high atherogenic potency. The metabolites investigated were the precursors serotonin and N-acetyl-serotonin and the main breakdown product 6-hydroxymelatonin. Methods The effect of the test substances on the in vitro oxidation of LDL (increase in conjugated diene formation) was investigated at concentrations of 1, 5, and 10 mm. Results Melatonin increased the lag time of formation of oxidized LDL only at a concentration of 10 mm. In contrast, 6-hydroxymelatonin, serotonin and N-acetylserotonin as well as vitamin E showed inhibitory effects starting at 1 mm. Thus the antioxidative action of melatonin was negligible compared with the effect of its main metabolite, its precursors and of vitamin E. Conclusions The present results indicate that the pineal hormone melatonin appears to have little antiatherogenic property as regards the oxidation of LDL. Its main breakdown product 6-hydroxymelatonin, however, inhibits LDL-oxidation comparable to vitamin E. The precursors of melatonin, N-acetyl-serotonin and serotonin may also play a role in the inhibition of LDL oxidation in vivo.
Serum melatonin and its main metabolic product 6-sulfatoxymelatonin were determined in 17 patients with breast cancer (BC) with either a fresh primary tumor (nine) or a secondary tumor (eight) as well as in four patients with untreated benign breast disease (controls). Circadian rhythms were detected in all groups with acrophases around 2 AM for melatonin and around 3 AM for 6-sulfatoxymelatonin. The nocturnal melatonin and 6-sulfatoxymelatonin concentrations were significantly depressed in the group of patients with primary breast cancer compared with controls (P < 0.01, P < 0.025). The circadian amplitudes of melatonin and 6-sulfatoxymelatonin were also depressed by 81% ( P < 0.01) and 63% (P < 0.01). In contrast, patients with secondary BC had nocturnal melatonin and 6-sulfatoxymelatonin concentrations and amplitudes similar to controls. These results demonstrate that the depression of circulating melatonin in patients with primary BC is not due to an enhanced degradation to 6-sulfatoxymelatonin in the liver but must be due to a reduced activity of the pineal gland. Cancer 67: 1681-1684,1991. stage-dependent depression of melatonin in patients A with primary breast cancer was reported by us recently' and we concluded that either a reduced biosynthetic activity of the pineal gland or an enhanced peripheral degradation in the liver may be responsible. To test the latter possibility we determined its main metabolic product, 6-sulfatoxymelatonin. Circulating melatonin is degraded in the liver under the influence of cytochrome P450-dependent monoxygenases to yield 6-hydroxymelatonin. Seventy percent to 80% of this compound is conjugated to 6-sulfatoxymelatoninz~3 which can now be quantified radioimmunologically.4From the *Section of Clinical Pharmacology, Department of Gynecology. University of Tubingen, Tubingen, and the -$Department of Gynecology, University of Bonn, Germany. The authors thank Dr. J. Arendt, Department of Biochemistry, University of Surrey, Guildford, UK, for advice on the radioimmunoassay of 6-sulfatoxymelatonin in her laboratory and for providing material for initial standardization.Address for reprints: Christian Bartsch, PhD, Universitats-Frauenklinik, Schleichstrane 4, W-7400 Tubingen, Germany.Accepted for publication August 27, 1990. Materials and Methods SubjectsThe patients were hospitalized at the
For a long time, oxytocin was regarded as a pregnancy hormone released by the hypophysis to stimulate labour and milk ejection. In the present survey, data have been collected from the literature to show the spectrum of the hitherto known functions of oxytocin outside pregnancy. It is now known that oxytocin receptors can occur almost ubiquitously in the organism, that oxytocin is also formed outside of the brain and that oxytocin has functions in a number of organs. In the first part of the survey, stimuli that contribute to an increase in oxytocin release are compiled. In the second part, details are given on the individual oxytocin targets. Although the majority of findings are based on the results of animal experiments, there are already a number of studies that indicate similar effects of oxytocin in humans. According to the current state of knowledge, oxytocin appears to be involved in functions in the following organs: male and non-pregnant female reproductive tract, pancreas, cardiovascular system, kidney, brain and breast. There are indications that oxytocin may also have actions in other organs. There continues to be a considerable need for research into oxytocin in order to better understand the physiological and pathophysiological actions and to be able to derive possible therapeutic uses. Further light on the spectrum of functions of oxytocin may be cast by the possibility of the use of oxytocin antagonists.
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