The Impossibility of Criminal Justice Ethics: Toward a Phenomenology of the Possible.

Regardless the specific theoretical perspective, all ethical formulations for criminal justice practice in some way construct the ontological character of the offender, which, in turn, situates both epistemology and method. How this ethical process ultimately constructs the offender will likely help to establish the degree of ethical worth such an individual is deemed worthy to receive. Whether based upon the seriousness of the crime or based upon the specific configuration of the architecture of incarceration, the very possibility of legitimate ethical practice is greatly compromised.

The therapeutic encounter within the event of forensic psychotherapy: a phenomenological hermeneutic of the givenness of the other within the therapeutic relationship.

In this article, we draw upon the works of Jean-Luc Marion and Claude Romano to offer a phenomenological hermeneutic of clinical forensics. We introduce Marion's description of givenness and the event, and apply these ideas to clinical forensics. First, we describe Romano's conceptualization of the transformative effect of the event, relative to the "openness" of the participants to this encounter.

Agnew's general strain theory reconsidered: a phenomenological perspective.

Since its inception, strain theory has attempted to explore the dynamic evoked between the process of goal identification and the process of goal acquisition as this relates to subsequent criminal behavior. Over the years of its development, strain theorists have attempted to broaden the initial scope of this perspective. Robert Agnew with his general strain theory has sought to introduce a variety of other factors relative to the experience of strain and the capacity they represent concerning subsequent criminal activity.

A novel 9-aza-anthrapyrazole effective against human prostatic carcinoma xenografts.

Objectives: Systematic investigation of a novel series of intercalating agents, 9-aza-anthrapyrazoles, has led to the identification of a promising analogue, BBR 3438. This study describes the antitumour efficacy of the novel compound in human prostate carcinoma models and the molecular/cellular basis of its activity.

Methods And Results: The novel 9-aza-anthrapyrazole BBR 3438 was significantly more effective than doxorubicin and losoxantrone (DuP-941) in two of the three tested prostate carcinoma models.

Molecular mechanisms of resistance to taxanes and therapeutic implications.

The mechanism of resistance to taxanes has not been fully elucidated. Since Taxol is a substrate for P-glycoprotein, overexpression of this transport system is recognized as a relevant mechanism of resistance. Additional mechanisms include changes of microtubule structure and/or composition resulting in reduced drug binding to the target.

A role for loss of p53 function in sensitivity of ovarian carcinoma cells to taxanes.

Loss of p53 function has been linked to increased responsiveness to taxane treatment of ovarian carcinoma in clinical studies. We recently reported that the acquisition of cisplatin resistance in an ovarian carcinoma cell line (IGROV-1) was associated with mutation of p53 and collateral sensitivity to paclitaxel. The increased sensitivity to paclitaxel of the cisplatin-resistant subline appeared to be pharmacologically relevant since it was reflected in an in vivo sensitization to taxanes.

Activation of the orphan nuclear receptor RORalpha induces growth arrest in androgen-independent DU 145 prostate cancer cells.

Background: RORalpha is a transcription factor which belongs to the family of orphan nuclear receptors. The regulatory functions of this receptor are still poorly understood. However, response elements for RORalpha are present on the promoter of cell cycle-related genes suggesting that it might be involved in the control of cell proliferation.

Tissue distribution, antitumour activity and in vivo apoptosis induction by MEN10755 in nude mice.

MEN10755 is a disaccharide analogue of doxorubicin (DXR) endowed with a broader spectrum of activity compared with DXR in a panel of human tumour xenografts. In an attempt to investigate the pharmacological basis of the improvement of therapeutic efficacy of the analogue, a comparative pharmacokinetic (tissue and tumour distribution) and pharmacodynamic (antitumoral activity and ability to induce apoptosis) study of MEN10755 and DXR was performed in athymic nude mice bearing a human ovarian carcinoma xenograft (A2780). Drug level was quantified by high performance liquid chromatography (HPLC) with fluorimetric detection after a single intravenous (i.

Role of apoptosis and apoptosis-related genes in cellular response and antitumor efficacy of anthracyclines.

Cellular resistance to anthracyclines is a major limitation of their clinical use in the treatment of human tumors. Resistance to doxorubicin is described as a multifactorial phenomenon involving the overexpression of defense factors and alterations in drug-target interactions. Such changes do not account for all manifestations of drug resistance, in particular intrinsic resistance of solid tumors.

Differential gene expression in p53-mediated G(1) arrest of human fibroblasts after gamma-irradiation or N-phosphoacetyl-L-aspartate treatment.

In human fibroblasts, N:-phosphoacetyl-L-aspartate (PALA) and gamma-radiation induce reversible and irreversible p53-mediated G(1) cell cycle arrest, respectively. By coupling the premature chromosome condensation technique to fluorescence in situ hybridization, we found no evidence of DNA damage after PALA treatment. We used representational difference analysis (cDNA-RDA) to study changes in gene expression after PALA treatment and gamma-radiation in normal human fibroblasts.

BBR 3464: a novel triplatinum complex, exhibiting a preclinical profile of antitumor efficacy different from cisplatin.

Multinuclear platinum complexes represent a new class of anticancer agents, distinct in terms of DNA binding features and the profile of antitumor activity from their mononuclear counterparts, in particular cisplatin. Among complexes of this class, BBR 3464, a trinuclear platinum compound has been selected for preclinical development. In the present study, we describe the preclinical evaluation of BBR 3464 in a series of human tumor cell lines and tumor xenografts, with special emphasis on tumor types known to be resistant to cisplatin.

Oral efficacy and bioavailability of a novel taxane.

A novel taxane (IDN 5109), originally selected for its ability to overcome P-glycoprotein-mediated drug resistance, is characterized by an improved preclinical profile in terms of efficacy and tolerability. Because P-glycoprotein may critically influence intestinal absorption and oral bioavailability of taxanes, the purpose of the study was to evaluate the bioavailability, the pharmacokinetic behavior, and the antitumor activity of the new taxane after oral administration. A comparative study of antitumor activity of Taxol and IDN 5109 given orally was performed in a human breast carcinoma model, MX-1, which is highly responsive to i.

Bcl-2 phosphorylation in a human breast carcinoma xenograft: a common event in response to effective DNA-damaging drugs.

A variety of cytotoxic agents effective as antitumor drugs are known to kill tumor cells through induction of apoptosis as the most relevant modality of cell death. A specific role for the protein Bcl-2 in the cell death pathway induced by antimicrotubule agents has been proposed, because Bcl-2 phosphorylation occurs in response to microtubule damage. In this study, we compared efficacy, apoptosis, and Bcl-2 phosphorylation in the Bcl-2-overexpressing MX-1 human breast carcinoma xenograft after treatment with cytotoxic agents characterized by different mechanisms of action.

Clavilactones, a novel class of tyrosine kinase inhibitors of fungal origin.

Targeting of deregulated protein tyrosine kinases has been proposed as a new approach in the therapeutic intervention against pathological processes including proliferative disorders and cancer. Using a screening approach based on a comparative evaluation of antiproliferative effects in a panel of tumor cells with differential expression of protein tyrosine kinases, three benzoquinoid macrolidic fungal metabolites produced by Clitocybe clavipes, clavilactones A, B, and D (CA, CB, and CD) and two semisynthetic derivatives of these products, diacetyl-CA and dimethyl-CA, were identified as inhibitors of protein tyrosine kinases. Naturally occurring CA, CB, and CD showed inhibitory activity in kinase assays against the Ret/ptc1 and epidermal growth factor receptor (EGF-R) tyrosine kinases, while being less effective against the v-Abl tyrosine kinase and p34(cdc2) serine/threonine kinase (IC(50) 2.

A novel charged trinuclear platinum complex effective against cisplatin-resistant tumours: hypersensitivity of p53-mutant human tumour xenografts.

Multinuclear platinum compounds were rationally designed to bind to DNA in a different manner from that of cisplatin and its mononuclear analogues. A triplatinum compound of the series (BBR 3464) was selected for preclinical development, since, in spite of its charged nature, it was very potent as cytotoxic agent and effective against cisplatin-resistant tumour cells. Anti-tumour efficacy studies were performed in a panel of human tumour xenografts refractory or poorly responsive to cisplatin.

A novel taxane with improved tolerability and therapeutic activity in a panel of human tumor xenografts.

Clinically available taxanes represent one of the most promising class of antitumor agents, despite several problems with their solubility and toxicity. In an attempt to improve the pharmacological profile of taxanes, a new series of analogues was synthesized from 14beta-hydroxy-10-deacetylbaccatin III and tested in a panel of human tumor cell lines. On the basis of the pattern of cytotoxicity and lack of cross-resistance in tumor cell lines expressing the typical multidrug-resistant phenotype, a compound (IDN5109) was selected for preclinical development.

Improved efficacy and enlarged spectrum of activity of a novel anthracycline disaccharide analogue of doxorubicin against human tumor xenografts.

On the basis of a structure-activity study of a new series of anthracycline disaccharides, we recently identified a doxorubicin analogue (MEN 10755) with a promising antitumor activity. In the present study, to better support the pharmacological interest of MEN 10755, we extended the preclinical evaluation of antitumor efficacy to a large panel of 16 human tumor xenografts, which originated from different clinicopathological types. Tumors with typical multidrug-resistant phenotype were excluded because MEN 10755 was found unable to overcome resistance mediated by transport systems.

Growth-inhibitory effects of luteinizing hormone-releasing hormone (LHRH) agonists on xenografts of the DU 145 human androgen-independent prostate cancer cell line in nude mice.

Experiments have been performed to clarify whether LHRH agonists might decrease growth of hormone-unresponsive prostate cancer in vivo. Male nude mice were injected s.c.

Stimulation of the apoptotic response as a basis for the therapeutic synergism of lonidamine and cisplatin in combination in human tumour xenografts.

The pharmacological interest in lonidamine is related to its ability to enhance the cytotoxic effects of several DNA-damaging anti-tumour agents. This study was undertaken to better understand the in vivo interaction between lonidamine and cisplatin in the treatment of human tumour xenografts, including three carcinoma models characterized by a different responsiveness to cisplatin, in spite of the presence of a wild-type p53 gene in all tumours. The drug combination was more effective in tumour growth inhibition than cisplatin alone against MX-1 breast carcinoma and A2780 ovarian carcinoma, both highly responsive to cisplatin, whereas no influence of ionidamine was observed on anti-tumour activity of cisplatin in the treatment of the relatively resistant IGROV-1 ovarian carcinoma.

P1GF-saporin fusion protein: a potential anti-angiogenic agent.

Vascularization is an important step in tumor growth and metastasis. Tumor neovascularization can be considered, therefore, as a good target for antineoplastic therapy. In order to target saporin, a powerful plant toxin, in proximity of the tumor we fused the saporin coding sequence to that for placental growth factor-2 (P1GF-2).

Doxorubicin disaccharide analogue: apoptosis-related improvement of efficacy in vivo.

Background: Although doxorubicin remains one of the most effective agents for the treatment of solid tumors, there is an intensive effort to synthesize doxorubicin analogues (compounds with similar chemical structures) that may have improved antitumor properties. We have synthesized a novel doxorubicin disaccharide analogue (MEN 10755) and have characterized some of its relevant biochemical, biologic, and pharmacologic properties.

Methods: The antitumor activity of this compound (MEN 10755) was studied in a panel of human tumor xenografts, including xenografts of A2780 ovarian tumor cells, MX-1 breast carcinoma cells, and POVD small-cell lung cancer cells.