Targeting of tumour cells with polyamine-drug conjugates

Cullis, Paul M.; Green, Ruth E.; Malone, Mark E.; Merson-Davies, Louise; Weaver, Richard J.

doi:10.1042/bst022402s

Cited by 7 publications

(9 citation statements)

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“…[60][61][62] Polyamines linked to DNA interacting moieties have also been used in attempts to target cytotoxics to cancer cells. 63 Notably a chlorambucil-polyamine combination was significantly more cytotoxic than the simple alkylating agent reminiscent of the situation with 1´. 64 In this sense the platinumpolyamines described here represent another class of these "chimeric" molecules with potential for dual biological activity -the polyamine conjugate contributes to the target reaction, without affecting the final outcome, in this case formation of {Pt,Pt} interstrand crosslinks.…”

Section: Discussionmentioning

confidence: 99%

Chimeric Platinum-Polyamines and DNA Binding. Kinetics of DNA Interstrand Cross-Link Formation by Dinuclear Platinum Complexes with Polyamine Linkers

Ruhayel

Langner

Oke³

et al. 2012

J. Am. Chem. Soc.

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The first observation of a polyamine-DNA interaction using 2D [(1)H, (15)N] HSQC NMR spectroscopy allows study of the role of the linker in polynuclear platinum-DNA interactions and a novel "anchoring" of the polyamine by Pt-DNA bond formation allows examination of the details of conformational B → Z transitions induced by the polyamine. The kinetics and mechanism of the stepwise formation of 5'-5' 1,4-GG interstrand cross-links (IXLs) by fully (15)N-labeled [{trans-PtCl((15)NH(3))(2)}(2){μ-((15)NH(2)(CH(2))(6)(15)NH(2)(CH(2))(6)(15)NH(2))}](3+) (1,1/t,t-6,6, 1) and [{trans-PtCl((15)NH(3))(2)}(2){μ-((15)NH(2)(CH(2))(6)(15)NH(2)(CH(2))(2)(15)NH(2)(CH(2))(6)(15)NH(2))}](4+) (1,1/t,t-6,2,6, 1') with the self-complementary oligonucleotide 5'-{d(ATATGTACATAT)(2)} (duplex I) are compared to the analogous reaction with 1,0,1/t,t,t (BBR3464) under identical conditions (pH 5.4, 298 K). Initial electrostatic interactions with the DNA are delocalized and followed by aquation to form the monoaqua monochloro species. The rate constant for monofunctional adduct formation, k(MF), for 1 (0.87 M(-1) s(-1)) is 3.5 fold higher than for 1,0,1/t,t,t (0.25 M(-1) s(-1); the value could not be calculated for 1' due to peak overlap). The evidence suggests that several conformers of the bifunctional adduct form, whereas for 1,0,1/t,t,t only two discrete conformers were observed. The combined effect of the conformers observed for 1 and 1' may play a crucial role in the increased potency of these novel complexes compared to 1,0,1/t,t,t. Treated as a single final product, the rate of formation of the 5'-5' 1,4-GG IXL, k(CH), for 1 (k(CH) = 4.37 × 10(-5) s(-1)) is similar to that of 1,0,1/t,t,t, whereas the value for 1' is marginally higher (k(CH) = 5.4 × 10(-5) s(-1)).

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Section: Discussionmentioning

confidence: 99%

Chimeric Platinum-Polyamines and DNA Binding. Kinetics of DNA Interstrand Cross-Link Formation by Dinuclear Platinum Complexes with Polyamine Linkers

Ruhayel

Langner

Oke³

et al. 2012

J. Am. Chem. Soc.

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“…Of great surprise, however, is the lack of specificity demonstrated by this transporter. A very wide range of polyamine-based compounds, some containing very complex side chains, have been shown to rely upon this transporter for their entrance into cells [9][10][11]. This has led to the design and testing of novel strategies for delivery of various toxic, fluorescent or growth-regulatory agents to targeted cells [9,12,13].…”

Section: The Polyamine Transportermentioning

confidence: 99%

“…A very wide range of polyamine-based compounds, some containing very complex side chains, have been shown to rely upon this transporter for their entrance into cells [9][10][11]. This has led to the design and testing of novel strategies for delivery of various toxic, fluorescent or growth-regulatory agents to targeted cells [9,12,13]. Although the physiology of the polyamine transporter has been extensively studied, very little is actually known about the biochemical components involved in the mammalian transporter and there remain diverse models for the uptake mechanisms [14][15][16].…”

Section: The Polyamine Transportermentioning

confidence: 99%

Unusual aspects of the polyamine transport system affect the design of strategies for use of polyamine analogues in chemotherapy

Mitchell

Thane

Sequeira

et al. 2007

Biochemical Society Transactions

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One strategy for inhibiting tumour cell growth is the use of polyamine mimetics to depress endogenous polyamine levels and, ideally, obstruct critical polyamine-requiring reactions. Such polyamine analogues make very unusual drugs, in that extremely high intracellular concentrations are required for growth inhibition or cytotoxicity. Cells exposed to even sub-micromolar concentrations of such analogues can achieve effective intracellular levels because these compounds are incorporated by the very aggressive polyamine uptake system. Once incorporated to these levels, many of these analogues induce the synthesis of a regulatory protein, antizyme, which inhibits both polyamine synthesis and the transporter they used to enter the cell. Thus this feedback system allows steady-state maintenance of effective cellular doses of such analogues. Accordingly, effective cellular levels of polyamine analogues are generally inversely related to their capacity to induce antizyme. Antizyme activity is down-regulated by interaction with several binding partners, most notably antizyme inhibitor, and at least a few tumour tissues exhibit deficiencies in antizyme expression. Our studies explore the role of antizyme induction by several polyamine analogues in their physiological response and the possibility that cell-to-cell differences in antizyme expression may contribute to variable sensitivities to these agents.

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“…La 2,2difluoroputrescine a été initialement utilisée dans un modèle expérimental : après injection de ce composé à des animaux porteurs d'une tumeur de Lewis recevant de la DFMO, l'accumulation maximale de difluorospermidine et de difluorospermine se produit dans le tissu tumoral et l'intestin grêle ; dans ces conditions expérimentales, les autres tissus de l'organisme contiennent en effet moins de 25 % de la quantité de difluoropolyamines accumulées par la tumeur [35]. Afin de favoriser l'accumulation de composés cytotoxiques par le tissu tumoral, des molécules anticancéreuses ont également été substituées par des polyamines ; ce fut par exemple le cas du chlorambucil-spermidine et spermine (figure 7) [36]. Bien qu'assez récente, cette approche thérapeutique permet d'envisager de réduire dans le futur les effets secondaires toxiques de certains médicaments anticancéreux usuels.…”

Section: Vectorisation Tumorale De Médicaments Anticancéreux Par Des unclassified

Les polyamines présentent-elles actuellement un intérêt dans le traitement du cancer

Seiler¹,

Moulinoux²

1996

Med Sci (Paris)

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L ' i m p o r t a n c e b i o l o g i q u e d'amines telles que la putrescine, la spermidine et la spermine (figure 1), communément appelées « polyamines », provient du fait qu'il s'agit d'ingrédients universels de toute cellule eucaryote. Les polyamines remplissent de multiples fonctions dans les cellules eucaryotes. La plupart d'entre elles sont dues aux interactions électrostatiques qu'engagent ces polycations organiques avec des sites anioniques présents au niveau des acides nucléiques (ADN, ARN), des protéines, des membranes cellulaires. Les polyamines se comportent ainsi comme des cations métalliques tels le Na + , le K + , le Ca 2+ , le Mg 2+ … mais à la différence de ces derniers, dont la source est par définition extracellulaire, non ADRESSES N. Seiler : docteur ès sciences, professeur associé.

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Targeting of tumour cells with polyamine-drug conjugates

Abstract: 402s Biochemical SocietvTransactions (1 994) 22 DNA crosslinking Ki for plymine uptake in ADJK6 cells Targeting of tumour cells with polyamine-drug conjugates 3 o m 0.01 na 2 m

Cited by 7 publications

References 0 publications

Chimeric Platinum-Polyamines and DNA Binding. Kinetics of DNA Interstrand Cross-Link Formation by Dinuclear Platinum Complexes with Polyamine Linkers

Chimeric Platinum-Polyamines and DNA Binding. Kinetics of DNA Interstrand Cross-Link Formation by Dinuclear Platinum Complexes with Polyamine Linkers

Unusual aspects of the polyamine transport system affect the design of strategies for use of polyamine analogues in chemotherapy

Les polyamines présentent-elles actuellement un intérêt dans le traitement du cancer

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