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Platinum drug effects on the expression of genes in the polyamine pathway: time-course and concentration-effect analysis based on Affymetrix gene expression profiling of A2780 ovarian carcinoma cells

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Abstract

Purpose

As a follow-up to our previous findings that platinum drugs induce a key enzyme in polyamine catabolism, gene expression profiling and mathematical modeling were used to define the effects of cisplatin and oxaliplatin on the expression of polyamine metabolic pathway genes in A2780 human ovarian carcinoma cells.

Methods

Time-course and concentration–effect experiments were each carried out with cisplatin or oxaliplatin in two separate experiments and cells subjected to gene expression profiling using Affymetrix array technology. Time-course data were modeled using exponential increase and decrease models. Concentration–effect data were modeled using a four parameter Hill model.

Results

Gene expression profiling of human ovarian carcinoma A2780 cells after exposure to either cisplatin or oxaliplatin indicates that the expression of several genes involved in polyamine pathway is affected by the platinum drugs. Mathematical/Statistical modeling of the data from time-course and concentration–effect experiments of gene expression from nine polyamine pathway genes represented on the HGU95Av2 chip, indicates that three biosynthetic pathway genes (SAMDC, ODC1 and SRM) are down-regulated and one catabolic pathway gene (SSAT) is up-regulated. Expression changes were similar for different probesets for a given gene on the array. Studies on the induction of SSAT by platinum drugs suggested by the Affymetrix data have been previously validated from this laboratory (Hector et al. in Mol Cancer Ther 3:813–822, 2004). Here, the effects of oxaliplatin exposure on SAMDC and ODC observed by Affymetix are validated with real time QRT-PCR.

Conclusion

The data indicate a concerted effect of platinum drugs on the polyamine metabolic pathway with down-regulation in the expression of several enzyme genes involved in biosynthesis and many-fold up-regulation in expression of SSAT, an acetylating enzyme gene that is critically involved in polyamine catabolism and export.

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Abbreviations

Put:

Putrescine

Spd:

Spermidine

Spm:

Spermine

ODC1:

Ornithine decarboxylase

SAMDC:

S-adenosylmethionine decarboxylase

SSAT:

Spermidine/spermine N 1-acetyltransferase (also known as SSAT-1)

SMS:

Spermine synthase

SRM:

Spermidine synthase

SMOX:

Spermine oxidase

OAZ:

Ornithine decarboxylase antienzyme

OAZIN:

Ornithine decarboxylase antienzyme inhibitor

MTA:

Methylthioadenosine

AcCoA:

Acetylcoenzyme A

DENSPM:

N 1 N 11-diethylnorspermine

QRT-PCR:

Quantitative RT-PCR

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Acknowledgment

This Research was supported by NIH CA109619, NIH RR10742 and CA-16056.

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Authors and Affiliations

  1. Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Ram Varma & William R. Greco

  2. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Suzanne Hector, Kimberly Clark & Lakshmi Pendyala

  3. Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Lesleyann Hawthorn

  4. Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Carl Porter

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  1. Ram Varma
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  2. Suzanne Hector
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  3. William R. Greco
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  4. Kimberly Clark
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  7. Lakshmi Pendyala
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Correspondence to Lakshmi Pendyala.

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Varma, R., Hector, S., Greco, W.R. et al. Platinum drug effects on the expression of genes in the polyamine pathway: time-course and concentration-effect analysis based on Affymetrix gene expression profiling of A2780 ovarian carcinoma cells. Cancer Chemother Pharmacol 59, 711–723 (2007). https://doi.org/10.1007/s00280-006-0325-3

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  • DOI: https://doi.org/10.1007/s00280-006-0325-3

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