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Strain- and sex-dependent circadian changes in abcc2 transporter expression: implications for irinotecan chronotolerance in mouse ileum.

Okyar A, Piccolo E, Ahowesso C, Filipski E, Hossard V, Guettier C, La Sorda R, Tinari N, Iacobelli S, Lévi F - PLoS ONE (2011)

Bottom Line: Irinotecan was also best tolerated in males (p = 0.05) and in B6CBAF(1) (p = 0.0006).Strain- and sex-dependent circadian patterns in abcc2 expressions displayed robust relations with the chronotolerance of ileum mucosa for irinotecan.This finding has strong potential implications for improving the intestinal tolerability of anticancer drugs through circadian delivery.

View Article: PubMed Central - PubMed

Affiliation: INSERM, U776 Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, France.

ABSTRACT

Background: ATP-binding cassette transporter abcc2 is involved in the cellular efflux of irinotecan. The drug is toxic for mouse ileum, where abcc2 is highly expressed. Here, we investigate whether circadian changes in local abcc2 expression participate in the circadian rhythm of irinotecan toxicity for ileum mucosa, and further assess whether genetic background or sex modify this relation.

Methodology/principal findings: Ileum mucosa was obtained every 3-4 h for 24 h in male and female B6D2F(1) and B6CBAF(1) mice synchronized with light from Zeitgeber Time (ZT)0 to ZT12 alternating with 12 h of darkness. Irinotecan (50 mg/kg i.v. daily for 4 days) was administered at the sex- and strain-specific times corresponding to least (ZT11-15) or largest drug-induced body weight loss (ZT23-03-07). Abcc2 expression was determined with qRT-PCR for mRNA and with immunohistochemistry and confocal microscopy for protein. Histopathologic lesions were graded in ileum tissues obtained 2, 4 or 6 days after treatment. Two- to six-fold circadian changes were demonstrated for mRNA and protein mean expressions of abcc2 in mouse ileum (p<0.05). ZT12 corresponded to high mRNA and protein expressions, with circadian waveforms differing according to genetic background and sex. The proportion of mice spared from ileum lesions varied three-fold according to irinotecan timing, with best tolerability at ZT11-15 (p = 0.00003). Irinotecan was also best tolerated in males (p = 0.05) and in B6CBAF(1) (p = 0.0006).

Conclusions/significance: Strain- and sex-dependent circadian patterns in abcc2 expressions displayed robust relations with the chronotolerance of ileum mucosa for irinotecan. This finding has strong potential implications for improving the intestinal tolerability of anticancer drugs through circadian delivery.

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Related in: MedlinePlus

Circadian patterns of abcc2 mRNA expression in the ileum of male B6D2F1 mice.Mean (± SEM) in mucosa and in serosa as a function of Zeitgeber Time (ZT), with ZT0 as light onset. Statistically significant differences according to ZT were validated for mucosa with ANOVA (p = 0.02). A statistically significant 24 h rhythm was confirmed for mucosa with cosinor (p = 0.0011).
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pone-0020393-g001: Circadian patterns of abcc2 mRNA expression in the ileum of male B6D2F1 mice.Mean (± SEM) in mucosa and in serosa as a function of Zeitgeber Time (ZT), with ZT0 as light onset. Statistically significant differences according to ZT were validated for mucosa with ANOVA (p = 0.02). A statistically significant 24 h rhythm was confirmed for mucosa with cosinor (p = 0.0011).

Mentions: Mean mRNA expression of abcc2 in ileum mucosa varied three-fold over the 24 h in male B6D2F1 mice, according to results from Study 1. Highest values were found in the first half of the dark span, with a peak at ZT12, while the nadir occurred at ZT0 (ANOVA, p = 0.02) (Figure 1). A sinusoidal pattern in abcc2 expression was further confirmed with cosinor (p = 0.0011). The circadian amplitude was 55% of the mesor (95% Confidence Limits, CL: 30 to 80), and the acrophase was located at ZT13∶35 (11∶50 to 15∶25). Conversely, there was barely any mRNA expression in ileum serosa (Figure 1), without any significant rhythm detection (cosinor, p = 0.07).


Strain- and sex-dependent circadian changes in abcc2 transporter expression: implications for irinotecan chronotolerance in mouse ileum.

Okyar A, Piccolo E, Ahowesso C, Filipski E, Hossard V, Guettier C, La Sorda R, Tinari N, Iacobelli S, Lévi F - PLoS ONE (2011)

Circadian patterns of abcc2 mRNA expression in the ileum of male B6D2F1 mice.Mean (± SEM) in mucosa and in serosa as a function of Zeitgeber Time (ZT), with ZT0 as light onset. Statistically significant differences according to ZT were validated for mucosa with ANOVA (p = 0.02). A statistically significant 24 h rhythm was confirmed for mucosa with cosinor (p = 0.0011).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3108586&req=5

pone-0020393-g001: Circadian patterns of abcc2 mRNA expression in the ileum of male B6D2F1 mice.Mean (± SEM) in mucosa and in serosa as a function of Zeitgeber Time (ZT), with ZT0 as light onset. Statistically significant differences according to ZT were validated for mucosa with ANOVA (p = 0.02). A statistically significant 24 h rhythm was confirmed for mucosa with cosinor (p = 0.0011).
Mentions: Mean mRNA expression of abcc2 in ileum mucosa varied three-fold over the 24 h in male B6D2F1 mice, according to results from Study 1. Highest values were found in the first half of the dark span, with a peak at ZT12, while the nadir occurred at ZT0 (ANOVA, p = 0.02) (Figure 1). A sinusoidal pattern in abcc2 expression was further confirmed with cosinor (p = 0.0011). The circadian amplitude was 55% of the mesor (95% Confidence Limits, CL: 30 to 80), and the acrophase was located at ZT13∶35 (11∶50 to 15∶25). Conversely, there was barely any mRNA expression in ileum serosa (Figure 1), without any significant rhythm detection (cosinor, p = 0.07).

Bottom Line: Irinotecan was also best tolerated in males (p = 0.05) and in B6CBAF(1) (p = 0.0006).Strain- and sex-dependent circadian patterns in abcc2 expressions displayed robust relations with the chronotolerance of ileum mucosa for irinotecan.This finding has strong potential implications for improving the intestinal tolerability of anticancer drugs through circadian delivery.

View Article: PubMed Central - PubMed

Affiliation: INSERM, U776 Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, France.

ABSTRACT

Background: ATP-binding cassette transporter abcc2 is involved in the cellular efflux of irinotecan. The drug is toxic for mouse ileum, where abcc2 is highly expressed. Here, we investigate whether circadian changes in local abcc2 expression participate in the circadian rhythm of irinotecan toxicity for ileum mucosa, and further assess whether genetic background or sex modify this relation.

Methodology/principal findings: Ileum mucosa was obtained every 3-4 h for 24 h in male and female B6D2F(1) and B6CBAF(1) mice synchronized with light from Zeitgeber Time (ZT)0 to ZT12 alternating with 12 h of darkness. Irinotecan (50 mg/kg i.v. daily for 4 days) was administered at the sex- and strain-specific times corresponding to least (ZT11-15) or largest drug-induced body weight loss (ZT23-03-07). Abcc2 expression was determined with qRT-PCR for mRNA and with immunohistochemistry and confocal microscopy for protein. Histopathologic lesions were graded in ileum tissues obtained 2, 4 or 6 days after treatment. Two- to six-fold circadian changes were demonstrated for mRNA and protein mean expressions of abcc2 in mouse ileum (p<0.05). ZT12 corresponded to high mRNA and protein expressions, with circadian waveforms differing according to genetic background and sex. The proportion of mice spared from ileum lesions varied three-fold according to irinotecan timing, with best tolerability at ZT11-15 (p = 0.00003). Irinotecan was also best tolerated in males (p = 0.05) and in B6CBAF(1) (p = 0.0006).

Conclusions/significance: Strain- and sex-dependent circadian patterns in abcc2 expressions displayed robust relations with the chronotolerance of ileum mucosa for irinotecan. This finding has strong potential implications for improving the intestinal tolerability of anticancer drugs through circadian delivery.

Show MeSH
Related in: MedlinePlus