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01-08-2008 | Original Article

Polyamine catabolism in colorectal cancer cells following treatment with oxaliplatin, 5-fluorouracil and N ¹ , N ¹¹ diethylnorspermine

Authors: Suzanne Hector, Ramakumar Tummala, Nicholas D. Kisiel, Paula Diegelman, Slavoljub Vujcic, Kimberly Clark, Marwan Fakih, Debora L. Kramer, Carl W. Porter, Lakshmi Pendyala

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2008

Abstract

Purpose

Our previous studies showed that combined treatment of oxaliplatin and N ¹ , N ¹¹diethyl-norspermine (DENSPM) results in massive induction of spermidine/spermine N ¹-acetyltransferase (SSAT) mRNA and activity. Since oxaliplatin and 5-fluorouracil (5FU) are used clinically in treatment of colorectal cancers, this study examines the effect of adding DENSPM to oxaliplatin/5FU combination on SSAT and spermine oxidase (SMO) in HCT-116 cells.

Methods

HCT-116 cells were treated with clinically relevant concentrations of drugs for 20 h followed by 24 h in drug free medium. SSAT and SMO mRNA and protein were assayed by QRT-PCR and Westerns respectively; polyamine pools were measured by HPLC. SSAT and SMO mRNA in tumor biopsies from patients with rectal cancer receiving oxaliplatin, capecitabine and radiation were measured by QRT-PCR.

Results

Oxaliplatin + 5FU + DENSPM produced significantly higher levels of SSAT and SMO mRNA, protein and activity than those seen with oxaliplatin+5FU with a significant depletion of cellular spermine and spermidine pools. Oxaliplatin/DENSPM was superior to 5FU/DENSPM in SSAT induction but similar for SMO. Oxaliplatin + DENSPM revealed synergistic growth inhibition at >IC₅₀ concentrations and antagonism at <IC₅₀. SMO and SSAT induction occurred in 60 and 30% of the patient samples examined.

Conclusions

These studies demonstrated that combining DENSPM with oxaliplatin + 5FU provides an added benefit by aiming at the clinically relevant therapeutic target, the polyamine catabolism. Further, we show for the first time, that SMO and SSAT induction could be measured in tumor biopsies in patients receiving chemo-radiation. Optimization of treatment conditions in vivo should facilitate a clinical evaluation of the three drug combination.

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Title: Polyamine catabolism in colorectal cancer cells following treatment with oxaliplatin, 5-fluorouracil and N 1 , N 11 diethylnorspermine
Authors: Suzanne Hector
Ramakumar Tummala
Nicholas D. Kisiel
Paula Diegelman
Slavoljub Vujcic
Kimberly Clark
Marwan Fakih
Debora L. Kramer
Carl W. Porter
Lakshmi Pendyala
Publication date: 01-08-2008
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2008
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-007-0633-2

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