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Characterization of sequence-dependent synergy between ZD1839 ("Iressa") and oxaliplatin
Jian-Ming Xu1, Amalia Azzariti, Montemuro Severino
1Beijing 307 Hospital Cancer Center, Beijing 100039, China.
Unlabelled:
ZD1839 ("Iressa"), a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is currently undergoing preclinical and clinical evaluation in several solid tumors. The present study aimed to assess the effect of ZD1839 in combination with oxaliplatin in the colon cancer cell lines HT-29 and LoVo. For in vitro chemosensitivity testing, cells were treated with serial dilutions of each drug sequentially at a fixed ratio of doses that corresponded to 1/20, 1/10, 1/5, 1/2, 1, 1.5 and 2 times the individual IC(50) values. Oxaliplatin followed by ZD1839 produced a synergistic effect. In contrast, oxaliplatin following ZD1839 exhibited an additive effect at best. Mass spectrometry examination revealed that ZD1839 modestly enhanced cellular oxaliplatin accumulation and platinum-DNA (Pt-DNA) adducts (P>0.05). In additional studies, high-performance liquid chromatography revealed that oxaliplatin had no effect on ZD1839 accumulation. In contrast, ZD1839 markedly inhibited removal of Pt-DNA adducts (P<0.05). With oxaliplatin treatment (1 day) followed by ZD1839 (1 day), then incubation with drug-free medium (1 day), 90% of Pt-DNA adducts remained. Apoptosis examination revealed that oxaliplatin-induced apoptosis was prolonged by sequential oxaliplatin followed by ZD1839 treatment compared with oxaliplatin alone. Further experiments revealed that ZD1839 decreased cellular gamma-glutamyltransferase activity.
Conclusions:
The above observations provide a mechanistic explanation for the synergy of oxaliplatin followed by ZD1839, and suggest that this treatment combination warrants further preclinical and clinical investigation.
Insights
Combining oxaliplatin with ZD1839 (Iressa) shows synergistic effects in colon cancer cells. This sequential treatment enhances platinum-DNA adducts and prolongs apoptosis, warranting further investigation.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- ZD1839 (Iressa) is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) evaluated for solid tumors.
- Oxaliplatin is a common chemotherapy agent used in cancer treatment.
Purpose of the Study:
- To investigate the combined effects of ZD1839 and oxaliplatin in colon cancer cell lines.
- To determine the optimal sequence for drug administration to achieve synergistic effects.
Main Methods:
- In vitro chemosensitivity testing using serial dilutions of ZD1839 and oxaliplatin.
- Mass spectrometry and high-performance liquid chromatography to assess drug accumulation and DNA adducts.
- Apoptosis assays to evaluate cell death induction.
Main Results:
- Sequential treatment of oxaliplatin followed by ZD1839 demonstrated a synergistic effect in colon cancer cells.
- ZD1839 enhanced oxaliplatin accumulation and significantly inhibited the removal of platinum-DNA adducts.
- The combination therapy prolonged oxaliplatin-induced apoptosis compared to oxaliplatin alone.
Conclusions:
- The sequential administration of oxaliplatin followed by ZD1839 offers a mechanistic basis for synergy.
- This combination therapy warrants further preclinical and clinical research for colon cancer treatment.