Abstract | PURPOSE: 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 >IC(50) concentrations and antagonism at <IC(50). 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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Authors | Suzanne Hector, Ramakumar Tummala, Nicholas D Kisiel, Paula Diegelman, Slavoljub Vujcic, Kimberly Clark, Marwan Fakih, Debora L Kramer, Carl W Porter, Lakshmi Pendyala |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 62
Issue 3
Pg. 517-27
(Aug 2008)
ISSN: 0344-5704 [Print] Germany |
PMID | 17987291
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Organoplatinum Compounds
- Polyamines
- Oxaliplatin
- N(1),N(11)-diethylnorspermine
- Spermine
- Oxidoreductases Acting on CH-NH Group Donors
- polyamine oxidase
- Acetyltransferases
- diamine N-acetyltransferase
- Fluorouracil
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Topics |
- Acetyltransferases
(genetics, metabolism)
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology, therapeutic use)
- Blotting, Western
- Cell Line, Tumor
- Colonic Neoplasms
(drug therapy, metabolism, pathology)
- Drug Synergism
- Fluorouracil
(pharmacology, therapeutic use)
- Gene Expression
(drug effects)
- Humans
- Organoplatinum Compounds
(pharmacology, therapeutic use)
- Oxaliplatin
- Oxidoreductases Acting on CH-NH Group Donors
(genetics, metabolism)
- Polyamines
(metabolism)
- Rectal Neoplasms
(drug therapy, metabolism, pathology)
- Spermine
(analogs & derivatives, pharmacology, therapeutic use)
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