Fiona Mackay

A potent cytotoxic photoactivated platinum complex

We show by x-ray crystallography that the complex trans, trans, trans-[Pt(N3)2(OH)2(NH3)(py)] (1) contains an octahedral PtIV center with almost linear azido ligands. Complex 1 is remarkably stable in the dark, even in the presence of cellular reducing agents such as glutathione, but readily undergoes photoinduced ligand substitution and photoreduction reactions. When 1 is photoactivated in cells, it is highly toxic: 13–80 x more cytotoxic than the PtII anticancer drug cisplatin, and ca. 15 x more cytotoxic toward cisplatin-resistant human ovarian cancer cells. Cisplatin targets DNA, and DNA platination levels induced in HaCaT skin cells by 1 were similar to those of cisplatin. However, cisplatin forms mainly intrastrand cis diguanine cross-links on DNA between neighboring nucleotides, whereas photoactivated complex 1 rapidly forms unusual trans azido/guanine, and then trans diguanine PtII adducts, which are probably mainly intrastrand cross-links between two guanines separated by a third base. DNA interstrand and DNA–protein cross-links were also detected. Importantly, DNA repair synthesis on plasmid DNA platinated by photoactivated 1 was markedly lower than for cisplatin or its isomer transplatin (an inactive complex). Single-cell electrophoresis experiments also demonstrated that the DNA damage is different from that induced by cisplatin or transplatin. Cell death is not solely dependent on activation of the caspase 3 pathway, and, in contrast to cisplatin, p53 protein did not accumulate in cells after photosensitization of 1. The trans diazido PtIV complex 1 therefore has remarkable properties and is a candidate for use in photoactivated cancer chemotherapy.

A Potent Trans‐Diimine Platinum Anticancer Complex Photoactivated by Visible Light

Activating platinum with light: An inert platinum(IV) diazido complex trans, trans,trans-[Pt(N3)2(OH)2(py)2] becomes potently cytotoxic to cancer cells when activated by low doses of visible light.

New Institutionalism Through a Gender Lens: Towards a Feminist Institutionalism?

New institutionalism (NI) may no longer qualify as being ‘new’, but since re-emphasizing institutions as a central explanatory variable in political analysis over two decades ago, it continues to provide scholars with a useful perspective through which to analyse political dynamics and outcomes that shape everyday life. The renewed focus on institutions has rebalanced the structure/agency scales back toward the former without losing important insights about the role and impact of political actors. NI has allowed for greater understanding about the co-constitutive nature of politics: the various ways in which actors bring about or resist change in institutions; and the way institutions shape the nature of actors’ behaviour through the construction of rules, norms and policies.

Gender and Political Representation in the UK: The State of the ‘Discipline’

Who governs is a traditional question in the study of politics: who is absent and who is present in the domains of public power? Feminist political scientists have taken and transformed this conventional question by focusing on the intractable problem of the relative exclusion of women. In so doing, the under-representation of women in parliaments and in national, local and regional assemblies has moved from the footnotes of political science to the focus of a flourishing international sub-field of scholarly inquiry. Academic interest has mirrored and paralleled growing political activism and advocacy around the issue by actors in local, national and international arenas. Despite global trends towards transformations in gender roles, such processes do not translate in a straightforward way into opportunities for political leadership (Inglehart and Norris 2003). During the 1980s and 1990s the political under-representation of women was reframed as a serious problem for democracy and human development, which was seen to raise awkward and crucial questions about the distribution of power. Governments and political parties were placed under increasing pressure to counter women’s chronic minority status in political institutions through affirmative action such as gender candidate quotas.

Photocytotoxic trans-Diam(m)ine Platinum(IV) Diazido Complexes More Potent than Their cis Isomers

The photocytotoxicity of a series of anticancer trans-dihydroxido [Pt(N(3))(2)(OH)(2)(NH(3))(X)] (X = alkyl or aryl amine) platinum(IV) diazido complexes has been examined, and the influence of cis-trans isomerism has been investigated. A series of photoactivatable Pt(IV)-azido complexes has been synthesized: The synthesis, characterization, and photocytotoxicity of six mixed-ligand ammine/amine Pt(IV) diazido complexes, cis,trans,cis-[Pt(N(3))(2)(OH)(2)(NH(3))(X)] where X = propylamine (4c), butylamine (5c), or pentylamine (6c) and aromatic complexes where X = pyridine (7c), 2-methylpyridine (8c), or 3-methylpyridine (9c) are reported. Six all-trans isomers have also been studied where X = methylamine (2t), ethylamine (3t), 2-methylpyridine (8t), 4-methylpyridine (10t), 3-methylpyridine (9t), and 2-bromo-3-methylpyridine (11t). All of the complexes exhibit intense azide-to-Pt(IV) LMCT bands (ca. 290 nm for trans and ca. 260 nm for cis). When irradiated with UVA light (365 nm), the Pt(IV) complexes undergo photoreduction to Pt(II) species, as monitored by UV-vis spectroscopy. The trans isomers of complexes containing aliphatic or aromatic amines were more photocytotoxic than their cis isomers. One of the cis complexes (9c) was nonphotocytotoxic despite undergoing photoreduction. Substitution of NH(3) ligands by MeNH(2) or EtNH(2) results in more potent photocytotoxicity for the all-trans complexes. The complexes were all nontoxic toward human keratinocytes (HaCaT) and A2780 human ovarian cancer cells in the dark, apart from the 3-methylpyridine (9t), 2-bromo-3-methylpyridine (11t), and 4-methylpyridine (10t) derivatives.

Nested Newness, Institutional Innovation, and the Gendered Limits of Change

Opportunities for innovation are created by broad restructuring processes and by the chance to be in at the start of new or substantially revised political institutions. These intuitions have animated the efforts of womens movement activists and their allies in processes of political transition and constitutional or institutional “engineering” (and reengineering) with the aim of embedding gender rights and freedoms (Banaszak, Beckwith, and Rucht 2003; Dobrowolsky and Hart 2003). Institutional theory supports these intuitions. Reformers—including feminist change agents—may take advantage of the “permissive” stage of institutional creation. By successfully intervening to insert new actors, new values, and new rules into new institutions, reformers may profoundly influence the future developments of an institution (Goodin 1996; Pierson 2004). By “locking in” elements that promote gender equality and gender justice at the stage of institutional design, the goal is to set off fledgling institutions along progressive paths, thus counteracting historic gender bias and gendered power imbalances found in most traditional political institutions.

Formation of platinated GG cross-links on DNA by photoactivation of a platinum(IV) azide complex

Platinum(II) diam(m)ine complexes such as cisplatin are effective anticancer drugs but have accompanying side effects. We are exploring the design of platinum complexes with low toxicity that could be photoactivated selectively at the target site. We show here that the Pt(IV) azide complex cis,trans-[Pt(en)(N3)2(OH)2] is unreactive towards DNA until irradiated with visible light. Transcription mapping studies of a 212-bp fragment of pSP73KB plasmid DNA treated with cis,trans-[Pt(en)(N3)2(OH)2] and irradiated with visible light showed that the platination sites were similar to those observed for cisplatin, and were mainly in GG sequences. HPLC analysis of enzymatic digests of an irradiated sample of a 40-bp DNA duplex treated with the same complex also revealed preferential formation of GG cross-links. Since such DNA lesions are thought to be responsible for the induction of apoptosis in cancer cells by platinum drugs, the use of unreactive photoactivatable platinum pro-drugs may become an effective strategy for the design of a new generation of platinum anticancer complexes.

Women's Representation in the Scottish Parliament and National Assembly for Wales: Party Dynamics for Achieving Critical Mass

The new Scottish Parliament and National Assembly for Wales elected in May 1999 were notable for the high levels of womens representation amongst their membership. This article examines the decisions taken by the main political parties about candidate selection and specifically the promotion of women candidates, exploring some of the inter and intra party dynamics influencing this result. The most significant changes were achieved in those parties that adopted rigid policies of positive action in favour of women. The decisions to adopt such systems were influenced by party ideology, degree of centralised leadership control and presence of women in positions of power within party elites. The environment in which such measures were considered was also highly influenced by the new electoral system and the presence of women activists in the design of the new institutions, particularly in Scotland. Together, these factors made womens representation a central feature in party competition.

Already Doin' It for Ourselves? Skeptical Notes on Feminism and Institutionalism

Let us first lay our cards on the table: We are both invested in the “feminist institutionalist project” and have highlighted the potential benefits of such a synthesis in earlier interventions (Kenny 2007; Lovenduski 1998; Mackay and Meier 2003; see also Lovenduski 1998). However, in this essay we sound a cautionary note and urge a more skeptical approach. We pose the questions: Why does feminism need new institutionalism? What do neoinstitutionalist approaches contribute to feminist scholarship on political institutions, broadly defined? When considering the potential for intellectual “borrowing” between feminism and new institutionalism, it is important to consider whether new institutional theory is “an enabling framework—or an intellectual strait-jacket” for feminist scholarship (Mackay and Meier 2003, 6). The question, then, is not only what the new institutionalism can contribute to feminist research but also what scope there is to “gender” the new institutionalism.

Introduction: Gender, Politics, and Institutions

Gender, Politics, and Institutions – and the international network of scholars involved in this collaborative enterprise1 – is animated by the desire to find new tools and analytical frameworks to help us to answer some of the big questions and real-world puzzles about gendered power inequalities in public and political life. For example, how are formal structures and informal ‘rules of the game’ gendered? How do political institutions affect the daily lives of women and men, respectively? By what processes and mechanisms are such institutions produced, both reflecting and reproducing social systems, including gendered power relations? How do institutions constrain actors, ideas, and interests? Finally, what is the gendered potential for institutional innovation, reform, and change in pursuit of gender justice, and what are its limits?