Antineoplastic Substances Research Articles

Molecular modeling of 3‑chloro-3-phenylquinoline-2,4‑dione, crystal structure and cytotoxic activity for developments in a potential new drug

3-Chloro-3-phenylquinoline-2,4‑dione (2) is an intermediate product in the synthesis of 1-phenyl-2H,6H-imidazo[1,5-c]quinazoline-3,5‑dione (PhIC). PhIC, its intermediates, and derivatives belong to quinolines or quinazolines - heterocyclic compounds with biological activity. However, only compound 2 contains nitrogen and chlorine atoms in the structure and has the most probability of having anticancer properties. In this work, the crystal structure of compound 2 was investigated by X-Ray crystallography and the molecular modeling was made by DFT methods. The cytotoxic activities of 3‑hydroxy-3-phenylquinoline-2,4‑dione, 3‑chloro-3-phenylquinoline-2,4‑dione and 3-amino-3-phenylquinoline-2,4‑dione, respectively compounds 1, 2, and 3 (with quinoline ring), and 2-(2-hydroxypropyl)-6-H-imidazo[1,5-c]quinazoline-3,5‑dione – compound 4 (with imidazoquinoline ring) against the cell lines: mouse fibroblast L929 and human gastric adenocarcinoma cells (AGS) were tested. The crystal structure of compound 2 was established and the intermolecular interactions were described. Only one pair of enantiomers was found in the unit cell, whereas molecular modeling showed two pairs of enantiomers AA’ and BB’ are stable. The enantiomer pairs can transform into each other to better spatial packing in the crystal. Compounds 2 and 4 show high cytotoxic activity against the L929 line at the concentration range 0.05– 50 µg/ml, and AGS cells (0.1– 50 µg/ml). When bound to an appropriate carrier to deliver the compound directly to neoplastic cells, their use as anti-neoplastic substances cannot be excluded.

The effect of maternal treatment with diclofenac sodium and thymoquinone on testicular parameters in rat offspring

Introduction and objectiveDiclofenac sodium (DS) can have toxic effects on various tissues and organs, as well as causing foetal and new-born malformations. Thymoquinone (TQ), the basic bioactive compound of black seed oil, is an antioxidant and antineoplastic substance. The aim of our study was to explore the effects of DS and TQ exposure during gestation on offspring rat testicular histology. Materials and methodsMother pregnant rats were divided into five groups: control, saline, DS, TQ and DS plus TQ (DS+TQ) four animals for each group. They were then treated as follows between day of 5 and 15 of gestation: the control group received no treatment. The saline group received physiological saline (1mg/kg/d) via the intraperitoneal (IP) route; the DS group received an intramuscular (IM) injection of DS (6.1mg/kg/d); the TQ group received TQ (5mg/kg/d) dissolved in drinking water; and the DS+TQ group received DS (6.1mg/kg/d) and TQ (5mg/kg/d) dissolved in water. After birth, the male rats were fed for four weeks, and at the end of this period offspring were sacrificed. Stereological methods, physical disector and Cavalieri principle were used for particle counting and volume estimation respectively. ResultsThe results revealed a significant decrease in the total number of Sertoli and Leydig cells in 4-week-old rats in the DS group (p<0.05), and TQ not have provide protection against this adverse effect of DS. ConclusionsIn this study, DS at a dose of 6.1mg/kg, equivalent to a dose of 1mg/kg in humans, decreased the number of Sertoli and Leydig cells, and TQ did not have a protective effect against the adverse effect of DS during the gestation period. These results show that new dose depend studies on TQ and DS interaction are requested to see protective effect of TQ.

Minocycline Prevents the Development of Mechanical Allodynia in Mouse Models of Vincristine-Induced Peripheral Neuropathy.

Vincristine is an antineoplastic substance that is part of many chemotherapy regimens, used especially for the treatment of a variety of pediatric cancers including leukemias and brain tumors. Unfortunately, many vincristine-treated patients develop peripheral neuropathy, a side effect characterized by sensory, motoric, and autonomic symptoms. The sensory symptoms include pain, in particular hypersensitivity to light touch, as well as loss of sensory discrimination to detect vibration and touch. The symptoms of vincristine-induced neuropathy are only poorly controlled by currently available analgesics and therefore often necessitate dose reductions or even cessation of treatment. The aim of this study was to identify new therapeutic targets for the treatment of vincristine-induced peripheral neuropathy (VIPN) by combining behavioral experiments, histology, and pharmacology after vincristine treatment. Local intraplantar injection of vincristine into the hind paw caused dose- and time-dependent mechanical hypersensitivity that developed into mechanical hyposensitivity at high doses, and lead to a pronounced, dose-dependent infiltration of immune cells at the site of injection. Importantly, administration of minocycline effectively prevented the development of mechanical hypersensitivity and infiltration of immune cells in mouse models of vincristine induce peripheral neuropathy (VIPN) based on intraperitoneal or intraplantar administration of vincristine. Similarly, Toll-like receptor 4 knockout mice showed diminished vincristine-induced mechanical hypersensitivity and immune cell infiltration, while treatment with the anti-inflammatory meloxicam had no effect. These results provide evidence for the involvement of Toll-like receptor 4 in the development of VIPN and suggest that minocycline and/or direct Toll-like receptor 4 antagonists may be an effective preventative treatment for patients receiving vincristine.

Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle—leading to cell death and tumor degradation—and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches.

Chemotherapy-induced peripheral neuropathy and neuropathic pain

The perception of the media is that chemotherapy is mainly associated with nausea, vomiting and hair loss. In the longer term the development of peripheral neuropathy, i.e. chemotherapy-induced peripheral neuropathy (CIPN) is often more important for patients. The CIPN represents a side effect of many antineoplastic substances with severe functional impairment and its prevention and treatment is an important task. In addition to many interventions, which have been shown to be ineffective, physiotherapeutic measures and possibly the prophylactic application of cold are helpful for prevention. Randomized studies on the treatment of painful CIPN provided positive data for duloxetine and to a lesser extent for venlafaxine.

Single Versus Double Ring Structure: Search for Best Anti-Neoplastic Driver in Colon and Pancreatic Cancer Cells-Taurultam or Taurolidine?

Background: Since the molecular mechanism of the well-known anti-infective and antineoplastic substance Taurolidine (TRD) is still unknown, we sought to analyze the anti-neoplastic capacity of its main metabolite Taurultam (TAU) in malignant human cell lines derived from pancreatic cancer (AsPC-1, BxPC-3, HPAF II, MiaPaca-2, Panc-1) and colon cancer (SW-480, HT-29 and HCT-116) in vitro. Methods: Cell lines were incubated with TAU or TRD in increasing concentrations for 24h and 48h. Comprehensive analyses were performed to quantify the anti-neoplastic activity of TAU: Analysis of cytotoxicity via MTT-assay, inhibition of proliferation via BrdU and induction of apoptosis and necrosis via FACS-analysis. Furthermore, cell growth was monitored using a real-time cell analyzer. Results: TAU revealed a significant cytotoxic and anti-proliferative effect on all pancreatic and colon cancer cell-lines as well in MTT- and BrdU- assays as in the real-time cell analyzer. Furthermore, FACS analyses were characterized by a significant apoptotic and necrotic response upon stimulation with TAU. In contrast to TRD antineoplastic effects were noticeable lower. Conclusion: It could be demonstrated for the first time, that TAU provides antineoplastic effects operating through mechanisms like its parent compound TRD. However, our results show clearly that TAU is not the only anti-neoplastic active metabolite of TRD. Hence, our data suggest that the efficiency of TRD against cancer cells is rather based on the methylol-containing species released during hydrolysis. These promising results are the first step towards the development of a novel substance combining the high anti-neoplastic capacity of TRD with better molecular properties of TAU, like a higher solubility in aqueous solution.

Isolation of Human Cancer Cell Growth Inhibitory, Antimicrobial Lateritin from a Mixed Fungal Culture

The purpose of this study was to attempt the reproducible coculture of more than two fungi for biosynthesis of potential antineoplastic substances. Five different fungi were simultaneously inoculated into broth cultures and grown for two weeks. Cancer cell line bioassay-guided fractionation, NMR, and mass spectroscopy led to the isolation and characterization of lateritin. Lateritin inhibited the growth of a mini-panel of human cancer cell lines, gram-positive bacteria, and Candida albicans. Individually, the five fungi did not synthesize detectable levels of lateritin. This study adds to the small but growing body of evidence that mixed fermentation is a viable avenue for natural product drug discovery. In addition, this is the first report of the reproducible coculture of more than two microbes for natural product biosynthesis, and the first report of the human solid tumor cell line and antimicrobial activities of lateritin.

Influence of the department on the resection rate in palliative treatment of metastatic colorectal cancer (CRC)

13528 Background: During the last years due to the application of Irinotecan, Oxaliplatin and “biologicals” for the first- and secondline treatment of CRC in palliative situation the efficacy of palliative treatment has considerably improved with an acceptable toxicity. The achievements of secondary metastatic resection after downsizing by palliative treatment have increasingly become the focus of interest in palliative patients and opened up new ways in terms of curative options (Folprecht et al. 2005; Wein et al. 2001). Here, we analyse the influence of different departments on the resection rate after palliative treatment. Methods: A prospective phase III trial in metastatic CRC with systemic treatment by 5-FU/sodium FA as a 24h-infusion (AIO) versus AIO plus Oxaliplatin followed by secondary metastatic resection. Trial start: 2000; end of trial: 2005. Randomized patients: n = 240 by 5 centers experienced in clinical trials. In order to achieve a homogeneous patient group, non-resectability of distant metastases was required according to pre-defined criteria. Stratification characteristics: In accordance to the participating departments; ECOG index 0.1 vs 2. Involvement of the hepatic tumour extension 25% vs other localisation; organ manifestation 1 vs &gt; 1. Inclusion criteria: Definitively non-resectable metastases. Palliative first-line treatment: Histologically proven adenocarcinoma of the colon or rectum, unambiguous enlargement of metastatic masses in objective imaging procedures. At least one bidimensionally measurable tumour lesion. Age: &gt; 18, &lt; 75 years. Exclusion criteria: Concomitant treatment with other anti-neoplastic substances. Sensoric neuropathy. Results: Resected/randomized patients of 176 currently evaluable patients, both treatment groups combined: department (dep.) 01: 0/26 (0%), dep. 02: 10/27 (37.0%), dep. 03: 21/68 (30.9%), dep. 04: 8/43 (18.6%), dep. 05: 1/12 (8.3%), total: 40/176 (22.7%). Although in the total population, a remarkable resection rate could be achieved, the variation between the departments is high (p=.0043 for differences between departments). Conclusions: The resection rate after palliative CRC treatment essentially depends on the department. No significant financial relationships to disclose.

Ex vivo analysis of antineoplastic agents in precision‐cut tissue slices of human origin: effects of cyclooxygenase‐2 inhibition in hepatocellular carcinoma

Cultures of precision-cut tissue slices allow the investigation of substance effects on human tissues under in vivo-like conditions over a limited time span. We have adapted the model for direct analyses of antineoplastic substances on tumor tissues. We have recently demonstrated that selective cyclooxygenase-2 (COX-2) inhibitors strongly suppress growth of human hepatocellular carcinoma (HCC) cells in vitro and nude mouse HCC implants by inducing apoptosis and reducing proliferation. We have now analyzed the effects of COX-2 inhibition on human tumor tissue. Three hundred micrometer slices of tumorous and non-tumorous liver tissue from three surgically resected HCCs were cultured with increasing concentrations of the selective COX-2 inhibitor Meloxicam (20-200 microM) for 6, 12, 24, and 48 h. The cultured tissue slices were analysed morphologically and by immunohistology for proliferation (Ki-67), apoptosis (M30), and COX-2 expression. COX-2 was expressed in all HCCs and in the non-tumorous liver tissue. Cytoplasmic COX-2 immunoreactivity in HCCs increased during culturing time. In two of three cases, COX-2 inhibition significantly increased tumor cell apoptosis in HCCs, whereas the low basal apoptosis rate in the non-tumorous liver parenchyma did not change. Tumor cell proliferation was mildly reduced, but the changes did not reach statistical significance. These results demonstrate that the precision-cut tissue slice culture model is a useful tool to analyze directly drug-dependent antitumorous or unwanted organ-specific effects. The analysis of COX-2 inhibition lends further support to the antineoplastic effects previously demonstrated in vitro and in animal models.

Chemical occupational risks identified by nurses in a hospital environment

Hospital nursing workers are exposed to occupational chemical risks. This quantitative study aimed to identify what chemical substances nurses have contact with in their activities, what substances cause health problems and what alterations correspond to possible problems caused by the chemical products they mention. A self-administered data collection instrument was answered by 53 nurses, who mentioned exposure mainly to antibiotics and benzene (100%), iodine (98.1%) and latex-talc (88.7%); the main problem-causing substances mentioned were antineoplastic substances (86.7%), glutaraldehyde (79.2%) and ethylene oxide (75.5%); the described health alterations were: eye watering; allergic reactions; nausea and vomiting, while other health problems that can be caused by the above listed products were not mentioned. These workers need further information on occupational chemical risks, which they could have received in undergraduate or permanent education courses.

Phosphoramidon, a novel matrix metalloproteinase inhibitor, inhibits significantly tumor growth independently of the application route (intraperitoneal [i.p.] versus intravenous [i.v.]) in a rat model of peritoneal carcinomatosis

Introduction: Occurrence of peritoneal carcinomatosis remains still an unsolved problem in gastrointestinal cancer. Over the last years, novel antineoplastic substances such as matrix metalloproteinase (MMP) inhibitors have been investigated in animal models to achieve a decrease of tumor growth. The aim of the study was to determine whether i) Phosphoramidon, an MMP inhibitor, can prevent or diminish i.p. tumor growth, and ii) whether direct i.p. administration of Phosphoramidon is superior to the i.v. route.

Valproic acid and interferon-α synergistically inhibit neuroblastoma cell growth in vitro and in vivo

Valproic acid (VPA) as a differentiation inducing anti-neoplastic substance is currently tested in solid tumour and leukaemia patients. Previously, we were able to show that the anti-cancer activity of VPA was synergistically increased by interferon-alpha (IFN-alpha) in Be(2)-C neuroblastoma (NB) cells. Now, we studied the effects of VPA in combination with IFN-alpha on two other NB cell lines. UKF-NB-2 and UKF-NB-3 cell growth was synergistically inhibited by VPA and IFN-alpha. Cell cycle investigations revealed massive accumulation of cells in G0/G1-phase after a combined treatment with VPA and IFN-alpha. The VPA-induced accumulation of acetylated histones in NB cell nuclei that indicates inhibition of histone deacetylases was not further enhanced by the combination treatment with IFN-alpha. Most strikingly, VPA plus IFN-alpha synergistically inhibited growth of UKF-NB-3 xenograft tumours in nude mice and induced complete cures in two out of six animals, while single treatment merely inhibited tumour growth. The results of this study together with our previous report strongly encourage the clinical evaluation of VPA and IFN-alpha for NB patients.

Proteasome inhibitors and their combination with antiandrogens: effects on apoptosis, cellular proliferation and viability of prostatic adenocarcinoma cell cultures.

The 26S proteasome is a ubiquitin-dependent proteolytic system that has been implicated in the regulation of cell cycle progression and apoptosis. We investigated the effects of the proteasome inhibitors MG115 and PSI alone or in combination with different concentrations of the antiandrogen hydroxyflutamide on the cellular proliferation, apoptosis and viability of 10 prostatic adenocarcinoma cell cultures. Treatment with both proteasome inhibitors resulted in apoptosis induction, whereas the combinations with hydroxyflutamide generally did not, with the exception of MG115 combined with 10(-7) M hydroxyflutamide. MG115 caused a significant decrease in cellular proliferation, as did the combinations of both proteasome inhibitors with hydroxyflutamide, whereas hydroxyflutamide alone was only effective at a concentration of 10(-5) M. Cellular viability was significantly reduced when both proteasome inhibitors were combined with 10(-5) M hydroxyflutamide. Although the results varied among different cell lines, we conclude that proteasome inhibitors are able to induce apoptosis and reduce cellular proliferation. They might prove effective as antineoplastic substances in prostatic adenocarcinoma alone or in combination with antiandrogens.

Subpopulations of mononuclear leukocytes associated with inhibition of Ehrlich ascites tumor growth by treatment with Bothrops jararaca venom.

Snake venoms have been used as antineoplastic substances in several experimental models. We demonstrated in previous studies that Bothrops jararaca venom (BjV) induces inhibition of Ehrlich ascites tumor (EAT) growth accompanied by an increase of mononuclear (MN) leukocytes in all groups inoculated with EAT and/or venom. The objective of the present study was to characterize the subpopulations of MN leukocytes involved in the inhibition of EAT growth by treatment with BjV. Swiss mice were inoculated with 1.0x10(3) EAT cells by the intraperitoneal route and treated with 0.4 mg/kg of BjV by the same route (Group TV). Treatment was started 24 h after tumor cell inoculation and consisted of five intraperitoneal injections performed at 72 h intervals. After 2, 8 and 14 days, groups of animals were sacrificed and the number of B, TCD4 and TCD8 lymphocytes, macrophages and natural killer cells present in the peritoneal cavity was determined by flow cytometry. The control group consisted of animals inoculated with EAT and treated with 0.1 ml of saline under the same conditions as the experimental group (Group T). Two additional control groups consisted of animals not inoculated with EAT and treated with saline or venom. Data were analyzed statistically by the Kruskal-Wallis non-parametric test for independent samples. On the 2nd and 8th day we observed a difference between groups T and TV (group T > group TV) for all cell types, except natural killer cells, that only differed on the 2nd day. However, on the 14th day there was no difference in MN cells among groups. These data suggest that the inhibition of EAT is related to the toxic action of BjV on tumor cells and/or to the proteolytic effect of the venom on the mediators produced by the cells for growth modulation.

Optimization and validation of an analytical procedure by high-performance liquid chromatography for the quantification of peroxisomicines and isoperoxisomicines

Peroxisomicine A1 is a potential antineoplastic substance extracted from plants of the genus Karwinskia. An RP-HPLC–DAD method was developed and validated for the separation and quantification of four isomers of this compound. These isomers coelute in the preparative procedure and are present at a proportion ranging between 3 and 5% in the peroxisomicine A1 purified in the laboratory. The desirability coefficient of the method described here was enhanced 140% with respect to the previously reported method.

Teratogenicity of Edoferon Kappa A, a Molecule Derived from Salicylate, in Cultured Rat Embryos: Differences from Salicylate and Interaction with Free Oxygen Radical Scavenging Enzymes

The effect of edoferon kappa A (E-KA), a non-specific immunomodulatory and anti-neoplastic chemical substance derived from the methyl form of salicylate (acetyl salicylic acid; ASA), on mammalian embryos was studied and compared to the effects of ASA. Rat embryos were cultured in vitro from 9.5 days of gestation for 48 h. E-KA (0.1-12.8 mg/ml) and ASA (0.1-0.6 mg/ml) were added to the whole rat serum. To investigate the interaction of these molecules with antioxidant agents, the lowest effective concentrations of E-KA (0.6 mg/ml) and ASA (0.3 mg/ml) for all parameters were added to the culture media in the presence of superoxide dismutase (SOD) (30 U/ml) or glutathione (0.5 mumol/ml). The growth and development of embryos was compared and each embryo was evaluated for the presence of any malformations. E-KA and ASA decreased growth and development in a concentration-responsive manner. There was also a concentration-related increase in overall dysmorphology (haematoma in the yolk sac and neural system, open neural tube, abnormal tail torsion and the absence of fore limb bud). There were no statistically significant differences between the control and embryos grown in the presence of 0.1-0.4 mg/ml E-KA, although the effects of ASA started at a concentration of 0.2 mg/ml. Embryos showed significant growth retardation in all scoring criteria and severe malformations when 0.5-3.2 mg/ml E-KA and 0.3-0.6 mg/ml ASA were added. When SOD was added, there was a significant decrease in the incidence of malformations and growth and developmental parameters were increased but this decrease never reached the control level. We concluded that E-KA has direct toxic effects on the developing embryo but at much higher concentrations than ASA, and the teratogenic effects of these molecules might be related to free oxygen radicals.

Inhibition of proteasome function induces programmed cell death in proliferating endothelial cells.

Proteolysis mediated by the ubiquitin-proteasome system has been implicated in the regulation of programmed cell death. Here we investigated the differential effects of proteasomal inhibitors on the viability of proliferating and quiescent primary endothelial cells in vitro and in vivo. Subconfluent, proliferating cells underwent carbobenzoxy-L-isoleucyl-gamma-t-butyl-L-glutamyl-L-alanyl-L-leucinal (PSI) -induced apoptosis at low concentrations (EC(50)=24 nM), whereas at least 340-fold higher concentrations of PSI were necessary to obtain the same effect in confluent, contact-inhibited cells. PSI-mediated cell death could be blocked by a caspase-3 inhibitor (Ac-DEVD-H), but not by a caspase-1 inhibitor (Ac-YVAD-H), suggesting that a caspase-3-like enzyme is activated during PSI-induced apoptosis. When applied to the embryonic chick chorioallantoic membrane, a rapidly expanding tissue, PSI induced massive apoptosis also in vivo. PSI treatment of the CAM led to the formation of areas devoid of blood flow due to the induction of apoptosis in endothelial and other cells and to the collapse of capillaries and first order vessels. Our results demonstrate that proteasomal inhibitors such as PSI may prove effective as novel anti-angiogenic and anti-neoplastic substances.

Intraperitoneale Therapie des Ovarialkarzinoms über Portsysteme mit Zytostatika und Zytokinen

Das Ovarialkarzinom ist charakterisiert durch eine initiale Tumorausbreitung über Lymphspalten im Bereich der oberflächlichen Peritonealschichten. Der Tumor ist damit auf die peritoneale Höhle beschränkt, erst in der Folge kommt es zur Penetration und Metastasierung in die umgebenden Organe. Diesem Pathomechanismus versucht man bei der intraperitonealen Therapie mit Zytostatika und Zytokinen gerecht zu werden. Die Zielvorstellung ist, durch eine intraperitoneale Applikation von antineoplastischen Substanzen eine hohe lokale Wirksamkeit bei gleichzeitig geringer systemischer Toxizität zu erreichen. Voraussetzung ist jedoch eine geringe Tumormasse, da nur in diesen Fällen eine ausreichende Penetration und Resorption durch das Peritoneum gewährleistet ist unter Berücksichtigung einer geringen Eindringtiefe. Deshalb bestehen nur bestimmte Indikationen, die eine intraperitoneale Therapie sinnvoll erscheinen lassen. Der größte Benefit scheint demnach einer Salvage-Therapie zuzukommen bei kleinen Resttumoren nach Primärtherapie mit nur mikroskopischem Nachweis oder einem maximalen Tumordurchmesser der Einzelläsion von weniger als 0,5 cm. Eine weitere Indikation, allerdings ohne Tumormeßparameter, stellt die Konsolidierungstherapie bei Patientinnen mit fortgeschrittenem Ovarialkarzinom und chirurgisch erreichter kompletter Remission dar. Neben der operativen Technik der Portanlage, wobei das Hauptinteresse endoskopischen Verfahren gilt, kann über die Erfahrung mit verschiedenen Zytostatika und Zytokinen bei der IP-Verabreichung berichtet werden. Zum Einsatz kommen hierbei generell Substanzen, wie Cisplatin, Carboplatin, aber auch Mitoxantron und Paclitaxel. Von Interesse und als sehr hoffnungsvoll erweisen sich neue Substanzen, wie Topotecan. Eigene Ergebnisse bei der Anwendung von rekombinanten Tumornekrosefaktor Alpha mit Interferon Alpha oder Gamma konnten in Abhängigkeit der Tumorrestmenge eine gute Wirksamkeit gegenüber minimalen soliden Tumorrestanteilen (<0,2cm) in Abhängigkeit der Dosierung zeigen. Voraussetzung für eine IP-Therapie sind jeweils ein ausreichender intraperitonealer Verteilungsraum ohne Nachweis von Adhäsionen sowie der Einsatz ausreichender Verteilungsvolumina. Zur Bestätigung der genannten Indikationsstellungen zur IP-Therapie ist die Durchführung weiterer klinischer, randomisierter Studien anzustreben. Bei Einsatz einer IP-Therapie sind die genannten pathoanatomischen und pharmakokinetischen Voraussetzungen zu berücksichtigen. Darüber hinaus sollten Erfahrungen bei der systemischen Anwendung von Zytostatika und Zytokinen bestehen.

アクリル樹脂骨セメントからの塩酸ドキソルビシンの放出性

Doxorubicin hydrochloride (ADR) is an antineoplastic substance which has a wide therapeutic range against human solid tumors, lymphomas, and acute leukemias. However ADR has the risk of cardiotoxicity and marrow dipression as side effects. Acrylic bone cement conteining ADR (ADR-bone cement) has been used for filling the bony defect and for controlling local recurrences after excision of malignant tumors in our hospital. We investigate the release of ADR from ADR-bone cement in vitro and in vivo elution studies for assessing usefullness of ADR-bone cement as drug delivery system. The release of ADR from ADR-bone cement has two phases. First phase of the release was supposed to occur a very high discharge from the external-surface of the cement, and secondary from the pores of the cement. In vitro elution studies, the release of ADR from ADR-bone cement was eluted slowly during over 12 weeks. 50 percentage of the total released ADR was eluted within 1 hour, 90 percentage within 1 week. During 12 weeks 0.6-1.6 percentage of the total ADR implanted was released. The concentration of ADR in drain fluid of the patient implanted ADR-bone cement is higher than the serum concentration of ADR of the patient dosed 30 mg ADR intravenously. However, the patient implanted ADR-bone cement has no symptoms like general side effects, necrosis, dead spase fluid and infection by local high concentration of ADR. Our studies show the possibility of long and local administration of ADR by ADR-bone cement. This topical administration decrease general side effects and is a useful drug delivery system.

Application of alpha-aminoisobutyric acid, L-methionine, thymidine and 2-fluoro-2-deoxy-D-glucose to monitor effects of chemotherapy in a human colon carcinoma cell line.

Up to 4 h after treatment of human SW 707 colon carcinoma cells with the antineoplastic drug 4-amino-N-(2'-aminophenyl)-benzamide (GOE 1734, dinaline), the effects of tumour cell metabolism and proliferation were examined in vitro. Four tracers which can be labelled with isotopes suitable for positron emission tomography (PET) were used for this purpose: alpha-aminoisobutyric acid (AIB) and methionine to study changes in amino acid transport and protein synthesis, thymidine to observe changes in tumour proliferation and 2-fluoro-2-deoxy-D-glucose (FDG) to estimate glucose metabolism. Dinaline showed an inhibition of the sodium-dependent and -independent uptake of AIB. The methionine uptake was found to increase shortly after therapy. Thymidine incorporation into DNA was impaired and the FDG uptake showed a maximally 2.2-fold enhancement. Inhibition of AIB uptake suggests changes in amino acid transport, whereas increased uptake of methionine and FDG points to an enhancement of protein synthesis and glycolysis caused by repair mechanisms. The cytostatic and antiproliferative effect of dinaline, observed in cell growth curves, could be demonstrated by the impaired thymidine incorporation into DNA. This study demonstrates that in vitro screening with radiotracers suitable for PET can help to clarify effects of new antineoplastic substances on tumour cell metabolism. These data may be applied to choose the appropriate time schedule for monitoring therapeutic effects on tumour tissue.