The influence of tumour microenvironmental factors on the efficacy of cisplatin and novel platinum(IV) complexes

Mellor, Howard R.; Snelling, Sarah; Hall, '; Modok, Szabolcs; Jaffar, Mohammed; Hambley, Trevor W.; Callaghan, Richard

doi:10.1016/j.bcp.2005.07.016

Cited by 48 publications

(36 citation statements)

References 37 publications

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“…The effects of simulated hypoxia and the use of models like spheroids, which mimic the tumor microenvironment, have been examined to predict the behavior of compounds in solid tumors. For example, a spheroid-based tumor model revealed that Pt(IV) complexes, although active, were unable to display selectivity for hypoxic cells [33]. …”

Section: Platinummentioning

confidence: 99%

Redox activation of metal-based prodrugs as a strategy for drug delivery

Graf

Lippard

2012

Advanced Drug Delivery Reviews

460

335

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This review provides an overview of metal-based anticancer drugs and drug candidates. In particular, we focus on metal complexes that can be activated in the reducing environment of cancer cells, thus serving as prodrugs. There are many reports of Pt and Ru complexes as redox-activatable drug candidates, but other d-block elements with variable oxidation states have a similar potential to serve as prodrugs in this manner. In this context are compounds based on Fe, Co, or Cu chemistry, which are also covered. A trend in the field of medicinal inorganic chemistry has been toward molecularly targeted, metal-based drugs obtained by functionalizing complexes with biologically active ligands. Another recent activity is the use of nanomaterials for drug delivery, exploiting passive targeting of tumors with nanosized constructs made from Au, Fe, carbon, or organic polymers. Although complexes of all of the above mentioned metals will be described, this review focuses primarily on Pt compounds, including constructs containing nanomaterials.

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Section: Platinummentioning

confidence: 99%

Redox activation of metal-based prodrugs as a strategy for drug delivery

Graf

Lippard

2012

Advanced Drug Delivery Reviews

460

335

View full text Add to dashboard Cite

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“…The conditions in the tumor microenvironment such as hypoxia, increased glycolysis, and other metabolic changes are conducive for metastasis [3]. While solid tumors are rich in quiescent cells, developing tumors contain proliferating cells [4, 5]. Additionally, the tissue architecture of tumors shows a great variation from its normal counterparts in tissue integrity and exhibit differential genetic programming [6-8].…”

Section: Introductionmentioning

confidence: 99%

Tumor microsomal metabolism of the food toxicant, benzo(a)pyrene, in Apc Min mouse model of colon cancer

et al. 2012

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The present study was conducted to investigate whether colon tumors were capable of metabolizing benzo (a)pyrene (BaP), and fluoranthene (FLA), two toxicants that belong to the polycyclic aromatic hydrocarbon family of compounds. Microsomes were isolated from the colon tumors of ApcMin mice that received subchronic doses of 50 μg/kg BaP and incubated with either BaP or FLA (3 μM each) alone or in combination and appropriate control groups that received nothing. Subsequent to incubation, samples were extracted with ethyl acetate and analyzed for BaP and FLA metabolites by reverse-phase HPLC equipped with fluorescence detection. Microsomes from tumor tissues were found to metabolize BaP to a greater extent than those from the non-tumor tissues. The rate of BaP metabolism (picomoles of metabolite per minute per milligram of protein) was found to be more when microsomes from BaP-pretreated mice were exposed to BaP alone and FLA in combination with BaP, compared to controls. The microsomes from BaP-preexposed mice generated greater proportion of BaP 7,8-diol and BaP 3,6- and 6,12-diones compared to other experimental groups. Additionally, microsomes from BaP-pretreated mice produced greater proportion of FLA 2, 3-diol and 2, 3 D FLA when microsomes were incubated with FLA alone or a combination of BaP and FLA. Our studies revealed that the tumor microsomes were competent to metabolize BaP and FLA either singly or in combination. The biotransformation of BaP and FLA as a consequence of prior and simultaneous exposure to BaP may influence the growth of tumors. Our findings may have relevance to human long-term dietary intake of these toxicants and the consequent acceleration of the colon carcinogenesis process.

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“…The reduction potential of platinum(IV) complexes can be tuned and we have established parameters for doing so, and in particular for making them highly resistant to reduction (Hambley et al, 1999). However, it has not been established whether their properties can be tuned such that they are selectively reduced in hypoxic environments Mellor et al, 2005).…”

Section: Introductionmentioning

confidence: 99%