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Targeting molecular pathways with camptothecin as novel therapy for gastric cancer
D A Litvak1, H T Papaconstantinou, B M Evers
1Department of Surgery, The University of Texas Medical Branch, Galveston, TX 77555-0527, USA.
Abstract:
Novel chemotherapeutic agents are needed to treat gastric cancer for which the prognosis remains dismal. The antitumor alkaloid camptothecin (CPT) may be useful in the treatment of certain solid tumors; however, its effects on gastric cancer are largely undefined. The purpose of our study was to characterize the effects of CPT on human gastric tumors in vivo and to determine the cellular mechanisms involved in CPT-mediated inhibition. Two human gastric cancers, WIL and TOR, were transplanted subcutaneously into athymic nude mice. After tumors reached 50 to 100 mm(2), mice were randomized into three groups to receive injections of either low-dose CPT (5 mg/kg), high-dose CPT (10 mg/kg), or vehicle (control) intraperitoneally 3 days a week for 3 weeks. Tumors were measured and weighed, and protein levels of the cell cycle inhibitor, p21Waf1/Cip1, and the antiapoptotic protein, Bcl-2, were assessed. Both dosages of CPT significantly inhibited growth of WIL and TOR gastric tumors. CPT (10 mg/kg) reduced tumor size compared to baseline, establishing this as a tumoricidal dosage. Treatment with CPT was associated with increased levels of p21Waf1/Cip1 and decreased levels of Bcl-2. CPT effectively kills human gastric cancers associated with increased levels of p21Waf1/Cip1 and decreased levels of Bcl-2. By activating cell cycle withdrawal and cell death through induction of p21Waf1/Cip1 and downregulation of Bcl-2, CPT may be an effective agent for gastric cancer.
Insights
Camptothecin (CPT) effectively inhibits human gastric cancer growth in mice. This novel chemotherapeutic agent increases cell cycle inhibitor p21Waf1/Cip1 and decreases antiapoptotic protein Bcl-2, offering a potential new treatment strategy.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Gastric cancer has a poor prognosis, necessitating novel chemotherapeutic agents.
- The efficacy of camptothecin (CPT), an antitumor alkaloid, in gastric cancer treatment is largely unexplored.
Purpose of the Study:
- To investigate the effects of CPT on human gastric tumors in vivo.
- To elucidate the cellular mechanisms underlying CPT's inhibitory action on gastric cancer growth.
Main Methods:
- Human gastric cancer cell lines (WIL and TOR) were xenografted into athymic nude mice.
- Mice received low-dose (5 mg/kg) or high-dose (10 mg/kg) CPT, or vehicle control, intraperitoneally for 3 weeks.
- Tumor growth was monitored, and protein levels of p21Waf1/Cip1 and Bcl-2 were assessed.
Main Results:
- Both low and high doses of CPT significantly inhibited the growth of WIL and TOR gastric tumors.
- The high dose (10 mg/kg) of CPT demonstrated tumoricidal effects, reducing tumor size.
- CPT treatment led to increased levels of the cell cycle inhibitor p21Waf1/Cip1 and decreased levels of the antiapoptotic protein Bcl-2.
Conclusions:
- CPT demonstrates significant antitumor activity against human gastric cancer xenografts in vivo.
- CPT exerts its effects by inducing cell cycle arrest via p21Waf1/Cip1 upregulation and promoting apoptosis through Bcl-2 downregulation.
- CPT represents a promising therapeutic agent for gastric cancer, warranting further clinical investigation.