Pharmacokinetics, metabolism and tumour disposition of 8-chloroadenosine 3',5'-monophosphate in breast cancer patients and xenograft bearing mice

Cummings, Jeffrey L.; Langdon, Simon P.; Ritchie, Alison; Burns, David J.; Mackay, James; Stockman, Paul K.; Leonard, Robert; Miller, William R.

doi:10.1093/oxfordjournals.annonc.a010574

Cited by 18 publications

(8 citation statements)

References 13 publications

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“…Based on these findings, many researchers have been trying to adopt 8-Cl-cAMP as a new therapeutic agent against cancer and phase I clinical test has been accomplished (Cummings et al, 1996;Propper et al, 1999). However, the mechanisms through which 8-Cl-cAMP induces growth inhibition and cell death are still unclear and under debate.…”

Section: Discussionmentioning

confidence: 99%

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8‐Cl‐cAMP and its metabolite, 8‐Cl‐adenosine induce growth inhibition in mouse fibroblast DT cells through the same pathways: Protein kinase C activation and cyclin B down‐regulation

Ahn

Jung

Hong

2004

Journal Cellular Physiology

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8-Chloro-cyclic AMP (8-Cl-cAMP) is known to be most effective in inducing growth inhibition and differentiation of a number of cancer cells. Also, its cellular metabolite, 8-Cl-adenosine was shown to induce growth inhibition in a variety of cell lines. However, the signaling mechanism that governs the effects of 8-Cl-cAMP and/or 8-Cl-adenosine is still uncertain and it is not even sure which of the two is the key molecule that induces growth inhibition. In this study using mouse fibroblast DT cells, it was found that adenosine kinase inhibitor and adenosine deaminase could reverse cellular growth inhibition induced by 8-Cl-cAMP and 8-Cl-adenosine. And 8-Cl-cAMP could not induce growth inhibition in the presence of phosphodiesterase (PDE) inhibitor, but 8-Cl-adenosine could. We also found that protein kinase C (PKC) inhibitor could restore this growth inhibition, and both the 8-Cl-cAMP and 8-Cl-adenosine could activate the enzymatic activity of PKC. Besides, after 8-Cl-cAMP and 8-Cl-adenosine treatment, cyclin B was down-regulated and a CDK inhibitor, p27 was up-regulated in a time-dependent manner. These results suggest that it is not 8-Cl-cAMP but 8-Cl-adenosine which induces growth inhibition, and 8-Cl-cAMP must be metabolized to exert this effect. Furthermore, there might exist signaling cascade such as PKC activation and cyclin B down-regulation after 8-Cl-cAMP and 8-Cl-adenosine treatment.

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Section: Discussionmentioning

confidence: 99%

“…As mentioned above, 8-Cl-cAMP and 8-Cl-adenosine are undergoing phase I clinical test against human cancers (Cummings et al, 1996;Propper et al, 1999). However, the debate is still going on as to whether 8-ClcAMP is a prodrug for its metabolite, 8-Cl-adenosine.…”

Section: -Cl-camp-induced Growth Inhibitionmentioning

confidence: 99%

8‐Cl‐cAMP and its metabolite, 8‐Cl‐adenosine induce growth inhibition in mouse fibroblast DT cells through the same pathways: Protein kinase C activation and cyclin B down‐regulation

Ahn

Jung

Hong

2004

Journal Cellular Physiology

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“…Its development was initiated because of the cytotoxicity profile of cAMP analogues, including 8-Cl-cAMP, which has shown pre-clinical toxicity in many tumour types [79][80][81]. Its development was initiated because of the cytotoxicity profile of cAMP analogues, including 8-Cl-cAMP, which has shown pre-clinical toxicity in many tumour types [79][80][81].…”

Section: Purine Analogues In Therapy: Clinical Activity and Mechanismmentioning

confidence: 99%

The Role of Nucleoside Transport in the Antineoplastic Activity of Purine Nucleoside Chemotherapeutic Agents

King¹

2008

CCTR

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Purine nucleoside analogues are extensively used in the treatment of malignancies and viral diseases. For example, cladribine and fludarabine are two purine nucleoside analogues that have activity in the treatment of chronic lymphocytic leukemias. These chemotherapeutic agents exert their cytotoxic actions through interactions with intracellular targets. Due to their hydrophilic nature, many purine nucleoside analogues do not readily diffuse across cell membranes at therapeutic concentrations. The presence or absence of mediated transport systems will therefore have an impact on their pharmacological activities.There are two families of nucleoside transporters with members in human (h) cells and tissues: the equilibrative nucleoside transporters (hENTs) and the concentrative nucleoside transporters (hCNTs). These transporter proteins mediate the uptake of both physiologic nucleosides and nucleoside analogue chemotherapeutic agents. It has been documented that permeant specificity, tissue distribution and cellular localization of these transporters contribute to the antineoplastic activity of the purine nucleoside analogues. This article will review current knowledge of the role of nucleoside transport proteins in the cytotoxic actions of purine nucleoside analogues.

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“…On the one side, 8-Cl-cAMP exerts its growth-inhibitory effect by binding to PKA in a competitive manner against cAMP (Rohlff et al, 1993;Noguchi et al, 1998) and on the other side, the effect of 8-Cl-cAMP is at least in part due to its metabolite 8-Cl-adenosine. Furthermore, the anticancer effect of 8-Cl-cAMP has been suggested to be independent of residual activity of PKA or concentration of cAMP (Lange-Carter et al, 1993;Cummings et al, 1996;Langefeld et al, 1997;Halgren et al, 1998;Carlson et al, 2001;Yin et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Genome-wide expression profiling of 8-chloroadenosine- and 8-chloro-cAMP-treated human neuroblastoma cells using radioactive human cDNA microarray

Park

Choe²,

Choo³

et al. 2002

Exp Mol Med

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Previous reports raised question as to whether 8-chloro-cyclic adenosine 3,5-monophosphate (8-ClcAMP) is a prodrug for its metabolite, 8-Cl-adenosine which exerts growth inhibition in a broad spectrum of cancer cells. The present study was carried out to clarify overall cellular affects of 8-Cl-cAMP and 8-Cl-adenosine on SK-N-DZ human neuroblastoma cells by systematically characterizing gene expression using radioactive human cDNA microarray.

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Pharmacokinetics, metabolism and tumour disposition of 8-chloroadenosine 3',5'-monophosphate in breast cancer patients and xenograft bearing mice

Abstract: The fate of 8-Cl-cAMP in human tumours is characterised by extensive metabolism to products which are not generally observed in plasma. These data raise the possibility that 8-Cl-cAMP is a prodrug for a product of its metabolism in human tumours.

Cited by 18 publications

References 13 publications

8‐Cl‐cAMP and its metabolite, 8‐Cl‐adenosine induce growth inhibition in mouse fibroblast DT cells through the same pathways: Protein kinase C activation and cyclin B down‐regulation

8‐Cl‐cAMP and its metabolite, 8‐Cl‐adenosine induce growth inhibition in mouse fibroblast DT cells through the same pathways: Protein kinase C activation and cyclin B down‐regulation

The Role of Nucleoside Transport in the Antineoplastic Activity of Purine Nucleoside Chemotherapeutic Agents

Genome-wide expression profiling of 8-chloroadenosine- and 8-chloro-cAMP-treated human neuroblastoma cells using radioactive human cDNA microarray

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