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Investigation into the Efficacy of Val-SN-38, a Valine-Ester Prodrug of the Anti-Cancer Agent SN-38.

Kwak EY, Choi MK, Yang SG, Shim CK, Shim WS - Biomol Ther (Seoul) (2012)

Bottom Line: However, it turned out that Val-SN-38 had poor stability compared with SN-38, which resulted in a decrease in beneficial efficacy for Val-SN-38.Overall, the present study showed that a valine-added prodrug approach could be advantageous provided that the stability of the compound can be ensured.We believe this is a noteworthy study that unravels the discrepancy between intracellular accumulation and efficacy of valine-added prodrug.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Seoul National University, Seoul 151-742.

ABSTRACT
We recently reported that Val-SN-38, a novel valine ester prodrug of SN-38, had greatly improved the intracellular accumulation of SN-38 in MCF-7 cell line, probably through enhanced uptake via amino acid transporters. In the present study, the efficacy of Val-SN-38 was further investigated both in vitro and in vivo. It was found that the in vitro cytotoxic effect of Val-SN-38 was similar to that of SN-38. Moreover, Val-SN-38 exhibited an equal potency to that of SN-38 in survival experiments in vivo. Because these results seemed to be contrary to the previous finding, further investigation was performed to find out the underlying cause of the contradiction. As only the lactone form is known to have cytotoxic activity, the proportion of lactone in Val-SN-38 and SN-38 was determined, but no differences were found. However, it turned out that Val-SN-38 had poor stability compared with SN-38, which resulted in a decrease in beneficial efficacy for Val-SN-38. Overall, the present study showed that a valine-added prodrug approach could be advantageous provided that the stability of the compound can be ensured. We believe this is a noteworthy study that unravels the discrepancy between intracellular accumulation and efficacy of valine-added prodrug.

No MeSH data available.


Related in: MedlinePlus

Survival rates of mice administered SN-38 (filled circle), Val-SN-38 (empty square), and irinotecan (gray diamond).
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Figure 003: Survival rates of mice administered SN-38 (filled circle), Val-SN-38 (empty square), and irinotecan (gray diamond).

Mentions: To further test if Val-SN-38 has an in vivo anti-cancer effect, colon cancer-induced mice were used and their survival rates were investigated. As shown in Fig. 3, the survival rate of the irinotecan-administered group was the worst of the 3 compounds, since all mice in the group failed to live 28 days (n=4). Otherwise, mice administered Val-SN-38 (n=4) and SN-38 (n=4) survived longer than the irinotecan-administered group by at least 2 weeks, suggesting both Val-SN-38 and SN-38 exhibited a stronger in vivo anti-tumor effect than iri-notecan. Otherwise, the survival rate between Val-SN-38 and SN-38 was indistinguishable. This appears to be in line with the aforementioned in vitro cytotoxicity results (Fig. 1, 2), suggesting


Investigation into the Efficacy of Val-SN-38, a Valine-Ester Prodrug of the Anti-Cancer Agent SN-38.

Kwak EY, Choi MK, Yang SG, Shim CK, Shim WS - Biomol Ther (Seoul) (2012)

Survival rates of mice administered SN-38 (filled circle), Val-SN-38 (empty square), and irinotecan (gray diamond).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3794531&req=5

Figure 003: Survival rates of mice administered SN-38 (filled circle), Val-SN-38 (empty square), and irinotecan (gray diamond).
Mentions: To further test if Val-SN-38 has an in vivo anti-cancer effect, colon cancer-induced mice were used and their survival rates were investigated. As shown in Fig. 3, the survival rate of the irinotecan-administered group was the worst of the 3 compounds, since all mice in the group failed to live 28 days (n=4). Otherwise, mice administered Val-SN-38 (n=4) and SN-38 (n=4) survived longer than the irinotecan-administered group by at least 2 weeks, suggesting both Val-SN-38 and SN-38 exhibited a stronger in vivo anti-tumor effect than iri-notecan. Otherwise, the survival rate between Val-SN-38 and SN-38 was indistinguishable. This appears to be in line with the aforementioned in vitro cytotoxicity results (Fig. 1, 2), suggesting

Bottom Line: However, it turned out that Val-SN-38 had poor stability compared with SN-38, which resulted in a decrease in beneficial efficacy for Val-SN-38.Overall, the present study showed that a valine-added prodrug approach could be advantageous provided that the stability of the compound can be ensured.We believe this is a noteworthy study that unravels the discrepancy between intracellular accumulation and efficacy of valine-added prodrug.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Seoul National University, Seoul 151-742.

ABSTRACT
We recently reported that Val-SN-38, a novel valine ester prodrug of SN-38, had greatly improved the intracellular accumulation of SN-38 in MCF-7 cell line, probably through enhanced uptake via amino acid transporters. In the present study, the efficacy of Val-SN-38 was further investigated both in vitro and in vivo. It was found that the in vitro cytotoxic effect of Val-SN-38 was similar to that of SN-38. Moreover, Val-SN-38 exhibited an equal potency to that of SN-38 in survival experiments in vivo. Because these results seemed to be contrary to the previous finding, further investigation was performed to find out the underlying cause of the contradiction. As only the lactone form is known to have cytotoxic activity, the proportion of lactone in Val-SN-38 and SN-38 was determined, but no differences were found. However, it turned out that Val-SN-38 had poor stability compared with SN-38, which resulted in a decrease in beneficial efficacy for Val-SN-38. Overall, the present study showed that a valine-added prodrug approach could be advantageous provided that the stability of the compound can be ensured. We believe this is a noteworthy study that unravels the discrepancy between intracellular accumulation and efficacy of valine-added prodrug.

No MeSH data available.


Related in: MedlinePlus