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Antitumor activity of KF22678, a novel thioester derivative of leinamycin
T Ashizawa1, K Kawashima, Y Kanda
1Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co Ltd, Shizuoka-Ken, Japan.
Abstract:
KF22678, a novel thioester derivative of leinamycin with the 1-oxo-1,2-dithiolane-3-one moiety, was examined for anti-tumor activity, toxicity in mice and activation mechanism. KF22678 showed a broad antitumor spectrum against human carcinoma xenografts (lung, colon, ovary and prostate). The efficacy of KF22678 was significantly higher than that of cisplatin. KF22678 exhibited low cross-resistance against various drug-resistant cell lines of MDR1 or MRP overexpressing human tumors, and, in addition, exhibited more potent antitumor activity in vivo than ADM against A2780/ADM and KB/MRP xenograft. DL-Buthionine sulfoximine (BSO) pretreatment significantly reduced intracellular glutathione (GSH) level in human lung carcinoma A549 cells, leading to decrease in the cytotoxicity of KF22678, whereas the cytotoxicity of melphalan was augmented by BSO pretreatment. DNA single-strand breaks (SSB) were observed in A549 cells treated with KF22678 and bleomycin. DNA SSB induced by KF22678 was greatly reduced in the presence of BSO in the cells, whereas DNA SSB induced by bleomycin was not. In addition, the antitumor activity of KF22678 against BSO-pretreated human lung carcinoma PC-9 tumor was significantly decreased. These results suggest that the activation of KF22678 by intracellular GSH might be important for DNA SSB and antitumor activity in vitro and in vivo.
Insights
KF22678, a novel leinamycin derivative, demonstrates broad antitumor activity against various human carcinomas, outperforming cisplatin. Its efficacy relies on intracellular glutathione (GSH) for DNA damage and anti-cancer effects.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- Leinamycin derivatives are investigated for anti-cancer properties.
- Drug resistance remains a significant challenge in cancer therapy.
Purpose of the Study:
- To evaluate the anti-tumor activity, toxicity, and activation mechanism of KF22678.
- To compare KF22678 efficacy against existing chemotherapeutics and resistant cell lines.
Main Methods:
- In vitro and in vivo studies using human carcinoma xenografts.
- Assessment of cytotoxicity in drug-resistant cell lines (MDR1, MRP).
- Investigation of activation mechanism using DL-Buthionine sulfoximine (BSO) to modulate intracellular glutathione (GSH) levels and DNA single-strand breaks (SSB) analysis.
Main Results:
- KF22678 exhibited broad-spectrum anti-tumor activity against lung, colon, ovary, and prostate xenografts, exceeding cisplatin efficacy.
- KF22678 showed low cross-resistance in multidrug-resistant cell lines and potent in vivo activity against resistant xenografts.
- Reduced intracellular GSH levels via BSO pretreatment decreased KF22678 cytotoxicity and antitumor activity, suggesting GSH-dependent activation and DNA SSB induction.
Conclusions:
- KF22678 is a potent anti-cancer agent with broad efficacy and low cross-resistance.
- Intracellular glutathione (GSH) plays a crucial role in KF22678 activation, DNA single-strand break induction, and overall anti-tumor effect.