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Base excision repair as a therapeutic target in colon cancer
Lili Liu1, Yoko Nakatsuru, Stanton L Gerson
1Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Abstract:
Base excision repair (BER) is a fundamental cellular process used to reduce the cytotoxicity of alkylating agent chemotherapy. Heretofore, no therapeutic agents have targeted this DNA repair pathway. Methoxyamine (MX), which binds abasic sites, acting as an inhibitor of BER, was evaluated in combination with the methylating agent temozolomide (TMZ). Three human colon cancer cell lines were used, SW480 cells, which are wild-type for mismatch repair genes and have mutated p53, HCT116 cells, which are mutant in hMLH1 and wild-type for p53, and HCT15 cells, which are mutant in hMSH6 and mutant in p53 as well. Nude mice carrying these tumors received TMZ alone or in combination with MX or O(6)-benzylguanine (BG), an inhibitor of O(6)-alkylguanine DNA-alkyltransferase, daily i.p. for 5 consecutive days. At the highest tolerable dose of TMZ (120 mg/kg), a tumor growth delay of approximately 9.3 +/- 1.2 days was noted in SW480. Addition of BG resulted in a tumor growth delay of 25 +/- 2.4 days accompanied by significant weight loss (23%) and severe myelosuppression. In contrast, SW480 tumor-bearing mice treated with MX + TMZ had cessation of tumor growth for 50 +/- 13 days and very slow regrowth, yielding tumor growth delays of >70 +/- 14 days (P < 0.002) without additive systemic toxicity. HCT116 and HCT15 xenografts were completely resistant to treatment with TMZ alone or in combination with BG. However, treatment with MX + TMZ induced significant tumor growth delays (20 +/- 1.4 days in HCT116 and 14 +/- 3.1 days in HCT15 xenografts, P < 0.05). These studies demonstrate that a significant enhancement of the antitumor effect of TMZ by MX was observed in human colon cancer xenografts with mismatch repair proficiency and deficiency. DNA BER may be a useful pharmacological target through which tumor cells can be sensitized to alkylating therapeutic agents.
Insights
Methoxyamine (MX) combined with temozolomide (TMZ) significantly enhances colon cancer treatment by inhibiting base excision repair (BER). This combination therapy shows potent antitumor effects without increased toxicity, unlike other agents.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Base excision repair (BER) is a critical DNA repair pathway that mitigates the cytotoxic effects of alkylating chemotherapy agents.
- Targeting DNA repair pathways, specifically BER, presents a novel therapeutic strategy to enhance cancer treatment efficacy.
- Methoxyamine (MX) inhibits BER by binding to abasic sites, while temozolomide (TMZ) is a methylating agent used in chemotherapy.
Purpose of the Study:
- To evaluate the efficacy of combining Methoxyamine (MX), a BER inhibitor, with temozolomide (TMZ), an alkylating agent, in human colon cancer xenografts.
- To assess the impact of MX + TMZ therapy on tumor growth delay and systemic toxicity in different colon cancer cell lines.
- To investigate the potential of targeting the BER pathway as a pharmacological strategy to sensitize tumors to alkylating agents.
Main Methods:
- Three human colon cancer cell lines (SW480, HCT116, HCT15) with varying mismatch repair and p53 statuses were used.
- Nude mice bearing these xenografts were treated with TMZ alone, TMZ + O(6)-benzylguanine (BG), or TMZ + Methoxyamine (MX).
- Tumor growth delay and systemic toxicity (e.g., weight loss, myelosuppression) were monitored to evaluate treatment efficacy and safety.
Main Results:
- MX + TMZ significantly extended tumor growth delay in SW480 xenografts (>70 days) without additive toxicity, outperforming TMZ + BG which caused severe side effects.
- HCT116 and HCT15 xenografts, resistant to TMZ or TMZ + BG, showed significant tumor growth delays (20 and 14 days, respectively) when treated with MX + TMZ.
- The combination of MX and TMZ demonstrated enhanced antitumor effects in both mismatch repair-proficient and deficient human colon cancer xenografts.
Conclusions:
- The combination of Methoxyamine (MX) and temozolomide (TMZ) is a highly effective strategy for enhancing antitumor activity in colon cancer xenografts.
- Targeting the base excision repair (BER) pathway with MX represents a promising approach to sensitize cancer cells to alkylating chemotherapy.
- MX + TMZ offers a potentially superior therapeutic option with reduced systemic toxicity compared to other combination strategies.