Further evaluation of uPA and PAI-1 as biomarkers for prostatic diseases.

Purpose: To assay for uPA and PAI-1 in prostate tissue from 40 patients with prostatic disease and to examine the robustness of the correlation of the uPA/PAI-1 ratio with benign prostatic hyperplasia (BPH) and prostate cancer (PCa), previously identified in a different cohort of 62 patients.

Methods: uPA and PAI-1 were extracted from liquid N2 frozen homogenised prostate tissue with TRIS/Triton pH 8.5 buffer and measured by ELISA (FEMTELLE).

uPA/PAI-1 ratios distinguish benign prostatic hyperplasia and prostate cancer.

Purpose: Urokinase plasminogen activator (uPA) and its inhibitor type 1 (PAI-1) are associated with tumour metabolism and are widely considered to be informative for the identification of cancer. We have analysed prostate tissue resections from patients with prostate cancer (PCa) and with benign prostatic hyperplasia (BPH) for protein levels of uPA and PAI-1, and searched for distinctions between these two clinical manifestations.

Methods: Prostate tissue was deep frozen in liquid N2 and homogenized in a stainless steel punch homogenizer.

In vitro radiosensitization by pentoxifylline does not depend on p53 status.

Purpose: The mode by which the xanthine derivative, pentoxifylline, induces a radiosensitizing effect in cell cultures is a key and controversial radiobiological issue and requires further elucidation.

Materials And Methods: Six human glioblastoma cell lines were tested for the effect of pentoxifylline treatment at maximum G2/M block on the basis of cell survival, mitotic activity, and micronucleus formation after exposure to gamma radiation. Cell survival was measured by the colony-forming assay.

Cytogenetic analyses of Azadirachtin reveal absence of genotoxicity but marked antiproliferative effects in human lymphocytes and CHO cells in vitro.

In this work we have examined the genotoxic potential of the bioinsecticide Azadirachtin A (AZA) and its influence on cell proliferation on human lymphocytes and Chinese Hamster ovary (CHO) cells. AZA genotoxicity was assessed by the analysis of chromosomal aberrations and sister chromatid exchanges (SCEs) in the absence and presence of rat liver S9 metabolism. Primary DNA damage was also investigated by means of the comet assay.

Differential effects of novel tumour-derived p53 mutations on the transformation of NIH-3T3 cells.

The p53 tumour suppressor gene is frequently mutated in human tumours and different tumour-derived mutations have varying effects on cells. The effect of a novel tumour-derived p53 mutation and two recently described mutations from South African breast cancer patients on the growth rate, colony formation, cell cycle arrest after irradiation and response to chemotherapeutic drugs was investigated. None of the p53 mutations had any significant effect on the inherent growth rate of the cells; however, contact inhibition of growth in two of the mutants was lost.

Inhibition of homologous recombination repair with Pentoxifylline targets G2 cells generated by radiotherapy and induces major enhancements of the toxicity of cisplatin and melphalan given after irradiation.

The presentation reviews the modus operandi of the dose modifying drug Pentoxifylline and the dose enhancement factors which can be achieved in different cell types. Preclinical and clinical data show that Pentoxifylline improves the oxygenation of hypoxic tumours and enhances tumour control by irradiation. In vitro experiments demonstrate that Pentoxifylline also operates when oxygen is not limiting and produces dose modifying factors in the region of 1.

Radiosensitization of CHO cells by two novel rhodium complexes under oxic and hypoxic conditions.

Background: Tumour hypoxia severely limits the success of radiotherapy. Radiosensitization of hypoxic tumour cells by drugs is thus an important clinical issue.

Materials And Methods: Two novel ferrocene-containing beta-diketonato complexes of the transition metals rhodium and iridium were examined for their cytotoxic activity against Chinese hamster ovary (CHO) cells by MTT and clonogenic assays.

Tumor radiosensitizers--current status of development of various approaches: report of an International Atomic Energy Agency meeting.

Purpose: The International Atomic Energy Agency (IAEA) held a Technical Meeting of Consultants to (1) discuss a selection of relatively new agents, not those well-established in clinical practice, that operated through a variety of mechanisms to sensitize tumors to radiation and (2) to compare and contrast their tumor efficacy, normal tissue toxicity, and status of development regarding clinical application. The aim was to advise the IAEA as to which developing agent or class of agents would be worth promoting further, by supporting additional laboratory research or clinical trials, with the eventual goal of improving cancer control rates using radiotherapy, in developing countries in particular.

Results: The agents under discussion included a wide, but not complete, range of different types of drugs, and antibodies that interfered with molecules in cell signaling pathways.

Influence of p53 and bcl-2 on chemosensitivity in benign and malignant prostatic cell lines.

The administration of cancer chemotherapeutic agents results in an increase in the apoptotic cells in the tumor: therefore, it has been assumed that anticancer drugs exhibit their cytotoxic effects via apoptotic signaling pathways. Characteristics that confer sensitivity to drug-induced apoptosis are, a functional p53 protein and expression of the apoptosis-promoting protein, bax. The role of p53 and bax/bcl-2 in drug-induced apoptosis was assessed in six prostate cell lines, 1532T, 1535T, 1542T, 1542N, BPH-1 and LNCaP using TD(50) concentrations of etoposide, vinblastine and estramustine.

Cytotoxicity and cell death pathways invoked by two new rhodium-ferrocene complexes in benign and malignant prostatic cell lines.

Background: Apoptotic propensity is currently viewed as an important parameter in drug-induced toxicity. But other cell death pathways exist e.g.

Changes in G1-phase populations in human glioblastoma and neuroblastoma cell lines influence p66/Be neutron-induced micronucleus yield.

Some photon resistant tumours are sensitive to neutrons but no predictive methods exist which could identify such tumours. In a recent study addressing this clinically important issue, we demonstrated that relative biologic effectiveness (RBE) values for p(66)/Be neutrons estimated from micronucleus (MN) data correlate positively with RBE values obtained from conventional clonogenic survival data. However, not all photon-resistant cell lines showed high RBE values when the MN endpoint was used.

Pentoxifylline enhances tumor oxygenation and radiosensitivity in rat rhabdomyosarcomas during continuous hyperfractionated irradiation.

Purpose: To examine the influence of the hemorrheologic agent pentoxifylline (PTX) on tumor oxygenation and radiosensitivity.

Material And Methods: Tumor oxygenation in rat rhabdomyosarcomas R1H after PTX administration (50 mg/kg body weight) was measured using interstitial pO(2) probes (Licox CMP system and Eppendorf pO(2)-Histograph). Tumors were irradiated with (60)Co gamma-irradiation using single doses (15 and 30 Gy), conventional fractionation (60 Gy/30 fractions/6 weeks), and continuous hyperfractionation (54 Gy/36 fractions/18 days) in combination with PTX or an equivalent volume of physiological saline.

Inhibition of DNA repair by Pentoxifylline and related methylxanthine derivatives.

The methylxanthine drug Pentoxifylline is reviewed for new properties which have emerged only relatively recently and for which clinical applications can be expected. After a summary on the established systemic effects of Pentoxifylline on the microcirculation and reduction of tumour anoxia, the role of the drug in the treatment of vasoocclusive disorders, cerebral ischemia, infectious diseases, septic shock and acute respiratory distress, the review focuses on another level of drug action which is based on in vitro observations in a variety of cell lines. Pentoxifylline and the related drug Caffeine are known radiosensitizers especially in p53 mutant cells.

Micronucleus response of human glioblastoma and neuroblastoma cells toward low-LET photon and high-LET p(66)/Be neutron irradiation.

The identification of photon resistant tumors that are sensitive to neutrons is still an unresolved problem, and no radiobiological criteria have been developed that could help the selection of patients for neutron therapy. The micronucleus (MN) assay has been evaluated for this purpose in a panel of human glioblastoma and neuroblastoma cell lines spanning a wide range of photon sensitivities defined by mean inactivation doses ([Latin capital letter D with macron above][gamma]) of 1.25-3.

Studies on the influence of DNA repair on radiosensitivity in prostate cell lines.

The relationship between radiosensitivity and DNA repair was investigated in six human prostate cell lines, 1542-NPTX, BPH-1, 1542-CP(3)TX, 1532-CP(2)TX, 1535-CP(1)TX and LNCaP. Except for LNCaP, these cell lines are new and were derived from primary prostate tumours and normal non-tumourigenic prostate tissue. Cell survival was assessed by clonogenic assay.

Drug resistance in prostate cancer cell lines is influenced by androgen dependence and p53 status.

Chemotherapeutic drug resistance remains a significant obstacle in the control of prostate cancer. The influence of p53 and androgen status on the drug response of new cell lines from normal, benign and primary tumour epithelium was investigated. The prostate cell lines 1542-NPTX, BPH-1, 1542-CP(3)TX, 1532-CP(2)TX, 1535-CP(1)TX and LNCaP were exposed to TD(50) doses of etoposide, vinblastine and estramustine for a period of 24 h and re-incubated for a further 4 days before measuring the cell viability by crystal violet vital dye staining assay.