In vitro antitumour activity and cellular pharmacological properties of the platinum-iminoether complex trans-[PtCl2[E-HN=C(OMe)Me]2].

The platinum complex trans-[PtCl2¿E-HN=C(OMe)Me¿2] was compared to cisplatin for cytotoxicity towards tumour cells, and for cellular pharmacological properties in A2780 and cisplatin-resistant A2780/Cp8 ovarian cancer cells. Trans-[PtCl2¿E-HN=C(OMe)Me¿2] was comparably cytotoxic to cisplatin (mean IC50 after 72 h exposure = 6. 1 microM and 7 microM, respectively) and did not show cross-resistance in A2780/Cp8 cells (resistance factor = 0.9). Cellular accumulation measurements after treatment with equimolar drug concentrations showed that trans-[PtCl2¿E-HN=C(OMe)Me¿2] entered both A2780 and A2780/Cp8 cells much more efficiently than cisplatin, whose accumulation was reduced in A2780/Cp8 cells. Unlike cisplatin, trans-[PtCl2¿E-HN=C(OMe)Me¿2] induced rapidly cell death and cell cycle modifications of treated cells, thus indicating substantially different mechanistic properties.

In vitro and in vivo antitumour activity and cellular pharmacological properties of new platinum-iminoether complexes with different configuration at the iminoether ligands.

In order to widen our knowledge on antitumour trans-[PtCl2(iminoether)2] complexes, we have synthesised two new derivatives, trans-[PtCl2¿E-HN = C(OEt)Me¿2] (1) and trans-[PtCl2¿Z-HN = C(OEt)Me¿2] (2), which differ in the configuration of the iminoether ligands. Isomer 1 showed an in vitro cytotoxicity similar to that of cisplatin in a panel of human tumour cell lines (mean IC50 = 8 and 7.7 microM, respectively), whereas isomer 2 showed a lower activity (IC50 = 14.3 microM). Both 1 and 2 isomers overcame cisplatin resistance of ovarian cancer cell line A2780/Cp8. In agreement with the n-octanol/saline partition ratios, intracellular platinum content (and DNA platination) after a 2-h exposure to equimolar drug concentrations was in the order 1 > 2 >> cisplatin, thus indicating that substitution of imminoethers for ammines determines a major lipophilicity and cellular uptake of the platinum drug. Both 1 and 2 showed a major toxic effect towards an excision repair-defective Drosophila strain, thus indicating cellular DNA as cytotoxic target. Finally, both 1 and 2 were active in vivo against the murine P388 system, but, contrary to the in vitro activity, isomer 2 was slightly more active than 1. On the whole, the results confirm the antitumour activity of trans-[PtCl2(iminoether)2] complexes, and indicate that the configuration of the iminoether ligands may affect the pharmacological properties of this class of complexes.

Anti-leukaemic action of RuCl2 (DMSO)4 isomers and prevention of brain involvement on P388 leukaemia and on P388/DDP subline.

Two ruthenium(II) complexes, characterised by the presence of dimethylsulphoxide ligands, were investigated in comparison to cisplatin on mouse P388 leukaemia and on a subline made resistant to cisplatin (P388/DDP). Both cis- and trans-RuCl2(DMSO)4 significantly prolonged the survival time of leukaemic mice, independently of the tumour line used. Unlike cisplatin, the prolongation of life-span of tumour-bearing hosts caused by ruthenium complexes was not supported by a parallel inhibition of the number of tumour cells in the treated hosts, as evidenced by tumour cell count in the peritoneal cavity and by vivo-vivo bioassays of blood samples and of whole brains. Thus, cis- and trans-RuCl2(DMSO)4 appear capable of preventing leukaemic spread into the central nervous system also when the number of tumour cells in the peritoneal cavity and in the blood stream is as high as in untreated controls. When the drug-induced DNA damage was investigated by modifying double stranded DNA and identifying the lesions able to inhibit DNA synthesis in vitro, trans-RuCl2(DMSO)4 and, to a lesser extent, cis-RuCl2(DMSO)4 formed blocking lesions at the same sites of cisplatin; nevertheless, the mechanism of antitumour activity of ruthenium complexes appears to be different from that of cisplatin for the absence of any relationship between cytotoxicity and prevention of leukaemic dissemination into the central nervous system. These data indicate that the activity of cis- and trans-RuCl2(DMSO)4 on the P388 leukaemia is characterised by the lack of cross-resistance with cisplatin and by the alteration of the metastasising behaviour of leukaemic cells which lose their natural capacity to invade the central nervous system.

Reduction of tumor-associated fibrinolytic-activity by antimetastatic dosages of 2 ru(ii)-dmso complexes in mice bearing lewis lung-carcinoma.

Some Ru(II)-DMSO complexes have antimetastatic properties in experimental tumors. Since plasminogen activators are thought to play an important role in the expression of cancer cell metastatic capacity, we evaluated the effect of two Ru(II)-DMSO complexes on the fibrinolytic activity of Lewis lung carcinoma. Tumor-bearing mice were given daily, for 14 days, an i.p. injection of antimetastatic dosages of cis-RuCl2(DMSO)4 (700 mg/kg/die) or trans-RUCl2(DMSO)4 (37 mg/kg/die), or vehicle. Tumor extracts obtained on day 15 from treatment groups had significantly lower (plasminogen-dependent) fibrinolytic activity than extracts from control animals (p<0.001). Urokinase inhibitor activity in tumor extracts did not differ among groups and did not correlate with plasminogen activator activity, Fibrin autography of control tumor extracts revealed the presence of a main fibrinolytic band co-migrating with urinary plasminogen activator (urokinase-type) and of minor bands with a higher molecular weight. In samples from animals treated with either Ru(II)-DMSO complex the most striking finding was a reduction of the band corresponding to free urokinase. These findings suggest that ruthenium complexes decrease the fibrinolytic activity of tumor cells by reducing urokinase production rather than by enhancing inhibitor production. Treatment of tumor-bearing mice with cis-RuCl2(DMSO)4 at a dosage equimolar to the trans isomer, neither reduced metastasis formation nor decreased plasminogen activator activity of tumor extracts. The depression of tumor-associated proteolytic activity could contribute to the antimetastatic properties of ruthenium complexes.

Interaction of RuCl2 (dimethylsulphoxide)4 isomers with DNA.

A wide series of restriction enzymes with a range of specificities was used to investigate the interaction with DNA of Ru(II)-DMSO complexes with anticancer activity. While cis-RuCl2 (DMSO)4 was almost completely inactive, treatment of pBR 322 DNA with trans-RuCl2 (DMSO)4 protected G rich sequences from cutting of specific restriction endonucleases, indicating a preferential interaction with adjacent guanines.

Synthesis, mutagenicity, binding to pBR 322 DNA and antitumour activity of platinum(II) complexes with ethambutol.

Platinum complexes with N,N'-bis(1-hydroxybut-2-yl)ethylenediamine, [PtCl2(ethambutol)] were prepared and the biological activity of three isomers [with (-), (+) and (+/-) ethambutol, respectively] investigated. All species interact with the Bam HI and Ava I recognition sequences showing a binding preference for GC rich sequences of DNA. The complex which showed the greatest interaction with adjacent guanines, [PtCl2[+/-)ethambutol)] was also found to be the most mutagenic of the three. On the other hand, only [PtCl2[+)ethambutol)] had a considerable antitumour activity against both P388 leukaemia and Lewis lung carcinoma, and this was not correlated either with restriction enzyme blocking activity or with mutagenicity.

Patient requests in primary health care settings: development and validation of a research instrument.

The development of the Primary Care Patient Request Scale and factor analytic and validation data from four diverse clinic samples are reported. The factor analysis yielded five plausible request dimensions: Treatment of Psychosocial Problems, Medical Explanation, Supportive Communication, Test Results, and Ventilation and Legitimation. The construct validity of the instrument was tentatively supported by the ability of the factor scales to discriminate consistently among the nature of the presenting complaint, the type of primary care clinic, and the marital status of the patient. Establishment of the clinical and research utility of the Primary Care Patient Request Scale awaits further efforts at cross-validation.

Keeping the faith: Psychosocial correlates of activism persistence into middle adulthood.

This study was conducted to determine certain ideological, personological, lifestyle, and familial correlates of activism persistence into middle adulthood. Almost 15 years following their arrest for participation in the Free Speech Movement, 30 former Berkeley activists responded to a political activity scale and measures selected to tap variables in each of the contextual domains. Although persisters did not differ from nonpersisters with respect to most lifestyle dimensions, they were distinguished by more radical beliefs, stronger repudiation of Protestant ethic values, and a stronger family legacy of social concern. The results provide more support for theories of activists' adult development based on notions of generational continuity, rather than generational rebellion.

Transition or transformation? Personal and political development of former Berkeley Free Speech Movement activists.

Former Berkeley Free Speech Movement activists' sociopolitical status, self and ideal self constructions, perceptions of parents' child-rearing practices and moral reasoning were compared with an assessment made 11 years earlier following the Berkeley Sproul Hall sit-in. Activists were found to be less politically active, more tempered in their political radicalism, more pragmatic and personally reactive in their self and ideal self conceptualizations, more critical in their perceptions of parental relationships, and stable in their level of moral development. While activists appear to have made some important life transitions, an argument is made for their continued distinctiveness as a generational cohort both politically and psychosocially.

Community control or control of the community? The case of the community mental health center.

This paper analyzes the powerful professional and social forces arrayed against community control. True community control is seen to be in danger of being compromised and co-opted by the mental health establishment. A radical and untried proposition, the implementation of community control, awaits broader institutional and political reform.

Community control in the hands of the liberal reformer: a reply.

Community control has been criticized as being quixotic, reductionistic, and incompatible with the demands of an industrial society. Alternatively, liberal reformers seek to ameliorate the ills of the mental health system through existing political channels, enlightened administrators, and an informed public. Although heralded as a more balanced and therefore more comprehensive critique, the liberal analysis employs an equilibrium model which ultimately favors the conventional power structure. Despite the potential vulnerability of community control, less radical approaches ultimately guard rather than seriously dispute professional hegemony.