Clinical and experimental study of oxaliplatin in treating human gastric carcinoma.
OBJECTIVE
To evaluate the therapeutic effectiveness of oxaliplatin on human gastric carcinoma and to explore its mechanisms.


METHODS
Twenty-two cases of stage IV gastric carcinoma received 4-6 (mean 4.6) cycles of first line combined chemotherapy with oxaliplatin (oxaliplatin 85 mg/m(2), iv, gtt, 1 h, d 1; leukovorin 200 mg/m(2), iv, gtt, 1 h, d 1 and d 2; 5-FU 300 mg/m(2),iv, d 1 and d 2, 5-FU, continuous iv, gtt, 48 h; 1 cycle/2 wk). Response rate, progression-free survival (PFS), total survival time, toxic side effects were evaluated. The inhibitory effect of oxaliplatin on human gastric cell line SGC-7901 was detected and IC(50) was calculated by MTT. Transmission electron microscopy, flow cytometry and TUNEL were performed to evaluate the apoptosis of cell line induced by the drug. The expression of Caspase-3 m-RNA was detected by RT-PCR. AC-DEVD-CHO, a Caspase-3 specific inhibitor, was used to elucidate the role of activated Caspase-3 in the process of apoptosis induced by oxaliplatin.


RESULTS
Total response (complete and partial) occurred in 9 (40.9%) patients. Mean PFS was 4.2 mo and mean total survival time was 7.2 mo. Cumulative neurotoxicity (all grade I-II), vomiting and diarrhea, myelosuppression appeared in 93.5%, 20%, 32.9% patients, respectively. IC(50) was calculated to be 0.71 mg/L by MTT assay. A maximal inhibitory rate reached 85.3%. Apoptosis index was elevated after incubated with 1 mmol/L oxaliplatin for 30 min, but without statistic significance (P>0.05). However it could be detected at a much higher degree both by flowcytometry and by TUNEL with a statistical significance (68.47+/-7.92% and 8.23+/-2.67%, respectively, P<0.05) after incubated with 1 mmol/L oxaliplatin for 2 d. By means of RT-PCR, we detected an enhancement of Caspase-3 m-RNA expression induced by oxaliplatin which was also in positive correlation with the apoptotic level. AC-DEVD-CHO, a Caspase-3 specific inhibitor, could significantly inhibit and delay apoptosis induced by oxaliplatin.


CONCLUSIONS
Oxaliplatin is effective and well-tolerated in patients with advanced gastric carcinoma. Oxaliplatin could significantly inhibit the growth of human gastric cell line SGC-7901. The induction of Caspase-3 m-RNA expression, activation of Caspase-3 and promotion of apoptosis may be some of the therapeutic mechanisms of oxaliplatin on gastric carcinoma. Annexin-V-fluorescein labeling flow cytometry is much more sensitive than TUNEL in detecting early stage apoptosis.
Lin
Wan-Long
WL
Department of Gastroenterology, Affiliated Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China. linwanlong155@sohu.com
Li
Ding-Guo
DG
Chen
Qiang
Q
Lu
Han-Ming
HM
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009842:Oligopeptides / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure
D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D009944:Organoplatinum Compounds; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D000077150:Oxaliplatin