[Treatment of Chronic Functional Constipation during Pregnancy and Lactation].

Natural fibres (bulk-forming agents), docusate sodium (stool-softener), mineral oils (lubricant laxatives), macrogol (polyethylene glycol, PEG), sugars and sugar alcohols (osmotic laxatives) and anthraquinones and diphenolic laxatives (stimulant laxatives) seem to be safe medicaments regarding teratogenicity and lactation. The US Food and Drug Administration (FDA) risk categories for these substances taken during pregnancy and lactation are often the result of the lack of studies than of evidence-based information. So risk categories do not help in the decision-making for the right laxative.

Studies on the mechanism of action of benzamide riboside: a novel inhibitor of IMP dehydrogenase.

Benzamide is a well known inhibitor of poly(ADP-ribose)polymerase, an enzyme involved in DNA repair. However, benzamide exhibited neuotoxicity in animals and hence, in the hope of overcoming this problem, benzamide riboside (BR) was synthesized. Our mechanism of action studies on BR suggested that the agent was being metabolized to its 5'-monophosphate and then to its NAD analogue (BAD, benzamide adenine dinucleotide) that inhibits Inosine 5'-monophosphate dehydrogenase (IMPDH).

Sensitizing human colon carcinoma HT-29 cells to cisplatin by cyclopentenylcytosine, in vitro and in vivo.

Cyclopentenylcytosine (CPEC) is cytotoxic to HT-29 cells in vitro and in vivo. Treatment with CPEC resulted in sensitizing HT-29 cells to cisplatin (CDDP), as evidenced by synergistic cytotoxicity. CPEC exhibits potent cytotoxicity to HT-29 cells in vitro, 2 and 24 h exposure providing an LC50 of 2.

Photodynamic action of meta-tetrahydroxyphenylchlorin (mTHPC) on an ovarian cancer cell line.

Meta-tetrahydroxyphenylchlorin (mTHPC) exhibits significant cytotoxicity against a variety of human cells in culture in combination with light, but also in dark reaction. The ovarian cancer cell line SK-OV3 was incubated with various concentrations of mTHPC and in comparison with Taxol and Cisplatin: then the effect on cell growth was determined. mTHPC exhibited an IC50 of 0.

5-aminolevulinic acid-mediated photodynamic therapy of intraepithelial neoplasia and human papillomavirus of the uterine cervix--a new experimental approach.

The aim of this study was to treat patients for ectocervical dysplasia [cervical intraepithelial neoplasia (CIN) grades 1 and 2] and associated human papilloma virus (HPV) infections with photodynamic therapy (PDT). In 20 patients, 5-aminolevulinic acid (5-ALA, 12% w/v) was applied topically with a cervical cap 8 h prior to illumination. A thermal light source (150 W halogen lamp) emitting a broadband red light (total energy: 100 J/cm2, fluence rate: 90 mW/cm2) was used for superficial illumination of the portio.

Studies on the antitumor activity and biochemical actions of cyclopentenyl cytosine against human colon carcinoma HT-29 in vitro and in vivo.

Cyclopentenyl cytosine (CPEC) is cytotoxic to several tumor cell lines. CPEC inhibits CTP synthesis resulting in depletion of cytidylate pools. The aim of this study was to examine CPEC's cytotoxic and antitumor activity in vitro and in vivo against human colon carcinoma HT-29, and to relate its action on CTP synthesis.

Modulation of the cytotoxicity of 3'-azido-3'-deoxythymidine and methotrexate after transduction of folate receptor cDNA into human cervical carcinoma: identification of a correlation between folate receptor expression and thymidine kinase activity.

Cervical carcinoma is an AIDS-defining illness. The expression of folate receptors (FRs) in cervical carcinoma (HeLa-IU1) cells was modulated by stable transduction of FR cDNA encapsidated in recombinant adeno-associated virus-2 in the sense and antisense orientation (sense and antisense cells, respectively). Although sense cells proliferated slower than antisense or untransduced cells in vivo and in vitro in 2% (but not 10%) FCS, [methyl-3H]thymidine incorporation into DNA was significantly increased in sense cells in 10% serum; therefore, the basis for this discrepancy was investigated.

Does the in-vitro efficiency of meso-tetrahydroxy-phenyl-chlorin depend on pre-treatment of sensitizer?

The efficiency of a new photosensitizer of the second generation, meso-tetra-hydroxyphenyl-chlorin (mTHPC), which has a strong absorption at 652 nm, was investigated by oxygen consumption measurements and membrane integrity testing. The experiments proved a great increase in the efficiency of mTHPC after preincubation at 37 degrees C for 24 hours. From these findings it can be assumed that tumor cells can be treated in an optimal way with PDT after a longer delay following drug administration.

Clinical effect of meso-tetrahydroxyphenylchlorine based photodynamic therapy in recurrent carcinoma of the ovary: preliminary results.

This article addresses the use of meso-tetrahydroxyphenylchlorin-based photodynamic therapy (m-THPC-PDT) to treat recurrent gynaecologic malignancies of the ovary. Photodynamic therapy is an experimental approach in the treatment of neoplasms and results indicate it is a highly tissue selective, relatively simple intervention with few side effects, therefore reducing the overall burden on the patient. Of the three patients involved in the initial study, two were treated solely with photodynamic therapy by laparoscopy, and one underwent additional palliative debulking surgery of metastatic tumours.

Studies on the mechanism of action of 1-beta-D-arabinofuranosyl-5-azacytosine (fazarabine) in mammalian lymphoblasts.

Fazarabine has shown activity in the panel of 60 cultured human tumor lines of the National Cancer Institute. COMPARE analyses relating correlation coefficients of other anticancer drugs with those of fazarabine suggest that this agent operates through a similar mode of action to that of cytarabine. Studies have been carried out both in culture and in vivo to examine the mechanism of action of fazarabine in P388 murine and Molt-4 human lymphoblasts.

A new approach to cancer therapy due to appropriate uptake and retention kinetics of meta-tetrahydroxy-phenylchlorin in a human fibroblast cell line.

Studies have shown that meta-tetrahydroxy-phenylchlorin is an efficient tumor targeting agent for laser photodynamic therapy. The effectiveness of this approach for cancer treatment depends on drug concentration, incubation time and extracellular protein. We studied uptake and retention kinetics of mTHPC in a human fibroblast cell line.

Synergistic growth inhibitory and differentiating effects of trimidox and tiazofurin in human promyelocytic leukemia HL-60 cells.

Increased ribonucleotide reductase (RR) activity has been linked with malignant transformation and tumor cell growth. Therefore, this enzyme is considered to be an excellent target for cancer chemotherapy. We have examined the effects of a newly patented RR inhibitor, trimidox (3,4,5-trihydroxybenzohydroxamidoxime).

Comparison of biochemical parameters of benzamide riboside, a new inhibitor of IMP dehydrogenase, with tiazofurin and selenazofurin.

The biochemical and cytotoxic activities of the IMP dehydrogenase (IMPDH) inhibitors benzamide riboside, tiazofurin, and selenazofurin were compared. These three C-nucleosides exert their cytotoxicity by forming an analogue of NAD, wherein nicotinamide is replaced by the C-nucleoside base. The antiproliferative activities of these three agents were compared in a panel of 60 human cancer cell lines.

p210 bcr-abl confers overexpression of inosine monophosphate dehydrogenase: an intrinsic pathway to drug resistance mediated by oncogene.

The p210 bcr-abl fusion protein tyrosine kinase oncogene has been implicated in the pathogenesis of chronic granulocytic leukemia (CGL). Specific intracellular functions performed by p210 bcr-abl have recently been delineated. We considered the possibility that p210 bcr-abl may also regulate the abundance of inosine 5'-monophosphate dehydrogenase (IMPDH) which is a rate-limiting enzyme for de novo guanylate synthesis.

Cytotoxicity and characterization of an active metabolite of benzamide riboside, a novel inhibitor of IMP dehydrogenase.

Benzamide riboside exhibits significant cytotoxicity against a variety of human tumor cells in culture. On the basis of metabolic studies, the primary target of this drug's action appears to be IMP dehydrogenase (IMPDH). Incubation of human myelogenous leukemia K562 cells with an IC50 concentration of benzamide riboside resulted in an expansion of IMP pools (5.

Biochemical and antitumor activity of trimidox, a new inhibitor of ribonucleotide reductase.

Trimidox (3,4,5-trihydroxybenzamidoxime), a newly synthesized analog of didox (N,3,4-trihydroxybenzamide) reduced the activity of ribonucleotide reductase (EC 1.17.4.

Synergistic action of tiazofurin with hypoxanthine and allopurinol in human neuroectodermal tumor cell lines.

The activity of IMP dehydrogenase (EC 1.2.1.

Role of p21 RAS in p210 bcr-abl transformation of murine myeloid cells.

The p21 RAS product has been implicated as part of the downstream signaling of certain nonreceptor tyrosine kinase oncogenes and several growth factor receptor-ligand interactions. We have reported that the chronic myelogenous leukemia oncogene p210 bcr-abl transforms a growth-factor-dependent myeloid cell line NFS/N1.H7 to interleukin-3 (IL-3) independence.

Cytotoxicity, differentiating activity and metabolism of tiazofurin in human neuroblastoma cells.

The IMP dehydrogenase inhibitor, tiazofurin (TR)-2-beta-D-ribofuranosylthiazole-4-carboxamide, which exhibited oncolytic activity in patients with chronic myelogenous leukaemia (CML) in blast crisis was found to inhibit the growth of human neuroblastoma SK-N-SH cells with an IC50 of 4.2 microM. TR treatment of cells perturbed nucleic acid and catecholamine pathways.

GM-CSF: modulation of biochemical and cytotoxic effects of tiazofurin in HL-60 cells.

Cytokines, such as granulocyte macrophage colony stimulating factor (GM-CSF) or interleukin-3 (IL-3) recruit quiescent cells into the cell cycle and sensitize these cells towards cell cycle specific chemotherapeutic agents. We examined the in vitro effects of GM-CSF on HL-60 cells and tested its modulatory influence on biochemical and cytotoxic effects seen with tiazofurin, a potent and specific inhibitor of IMP dehydrogenase. Incubation of HL-60 cells with 500 U/ml GM-CSF for 4 d enhanced cell proliferation, which was accompanied by a significant increase in IMP dehydrogenase activity (from 2.

Biochemical consequences of resistance to tiazofurin in human myelogenous leukemic K562 cells.

Tiazofurin exhibits antitumor activity in murine and human tumor cells. In a recent phase I/II trial in patients with end-stage leukemia, tiazofurin showed good response; however, repeated treatment resulted in clinical resistance to the drug. To elucidate the mechanisms of resistance in human leukemic cells, two variants of human myelogenous leukemia K652 cells resistant to tiazofurin were developed by drug-selection pressure.

Cytotoxicity of a new IMP dehydrogenase inhibitor, benzamide riboside, to human myelogenous leukemia K562 cells.

COMPARE computer program suggested that benzamide riboside, BR, 3-(1-deoxy-beta-D-ribofuranosyl)benzamide, should have a similar mechanism of action as that of tiazofurin, an inhibitor of IMP dehydrogenase (IMPDH). This hypothesis was tested in K562 cells in culture. BR was cytotoxic to K562 cells with an IC50 of 2 microM.