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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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Circadian patterns of abcc2 mRNA expression in the ileum mucosa of mice, according to genetic background and sex.Mean (± SEM) as a function of Zeitgeber Time (ZT), with ZT0 as light onset. (A) male and female B6D2F1; (B) male and female B6CBAF1. Mean abcc2 expression increased six-fold from ZT0 (trough) to ZT12 (peak) for B6D2F1 males and ZT0 (trough) to ZT9 (peak) for B6D2F1 females (ANOVA, p = 0.04; Cosinor, p = 0.0023 for B6D2F1 males and ANOVA, p = 0.0008; Cosinor, p = 0.0023 for B6D2F1 females). Similar three- to four-fold circadian variations were found in male and female B6CBAF1, with highest values occurring from ZT9 to ZT15, and a trough at ZT0 (ANOVA, p = 0.004 in male; p = 0.003 in female). The rhythm was validated by cosinor for B6CBAF1 (p = 0.00026 and p = 0.00012 in male and female, respectively).
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pone-0020393-g002: Circadian patterns of abcc2 mRNA expression in the ileum mucosa of mice, according to genetic background and sex.Mean (± SEM) as a function of Zeitgeber Time (ZT), with ZT0 as light onset. (A) male and female B6D2F1; (B) male and female B6CBAF1. Mean abcc2 expression increased six-fold from ZT0 (trough) to ZT12 (peak) for B6D2F1 males and ZT0 (trough) to ZT9 (peak) for B6D2F1 females (ANOVA, p = 0.04; Cosinor, p = 0.0023 for B6D2F1 males and ANOVA, p = 0.0008; Cosinor, p = 0.0023 for B6D2F1 females). Similar three- to four-fold circadian variations were found in male and female B6CBAF1, with highest values occurring from ZT9 to ZT15, and a trough at ZT0 (ANOVA, p = 0.004 in male; p = 0.003 in female). The rhythm was validated by cosinor for B6CBAF1 (p = 0.00026 and p = 0.00012 in male and female, respectively).

Mentions: In study 2, mean mRNA expression of abcc2 also varied six-fold over the 24 h, with a peak at ZT12 and a nadir at ZT0 in male B6D2F1 (ANOVA, p = 0.04) (Figure 2A), Cosinor analysis further confirmed a sinusoidal pattern (p = 0.0023). The circadian amplitude was 72% of the mesor (35 to 110), and the acrophase was localized at ZT10∶20 (8∶20 to 12∶25). Thus, both studies 1 and 2 demonstrated a circadian rhythm with similar characteristics for the abcc2 mRNA expression in the ileum mucosa of male B6D2F1 mice.


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 mucosa of mice, according to genetic background and sex.Mean (± SEM) as a function of Zeitgeber Time (ZT), with ZT0 as light onset. (A) male and female B6D2F1; (B) male and female B6CBAF1. Mean abcc2 expression increased six-fold from ZT0 (trough) to ZT12 (peak) for B6D2F1 males and ZT0 (trough) to ZT9 (peak) for B6D2F1 females (ANOVA, p = 0.04; Cosinor, p = 0.0023 for B6D2F1 males and ANOVA, p = 0.0008; Cosinor, p = 0.0023 for B6D2F1 females). Similar three- to four-fold circadian variations were found in male and female B6CBAF1, with highest values occurring from ZT9 to ZT15, and a trough at ZT0 (ANOVA, p = 0.004 in male; p = 0.003 in female). The rhythm was validated by cosinor for B6CBAF1 (p = 0.00026 and p = 0.00012 in male and female, respectively).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020393-g002: Circadian patterns of abcc2 mRNA expression in the ileum mucosa of mice, according to genetic background and sex.Mean (± SEM) as a function of Zeitgeber Time (ZT), with ZT0 as light onset. (A) male and female B6D2F1; (B) male and female B6CBAF1. Mean abcc2 expression increased six-fold from ZT0 (trough) to ZT12 (peak) for B6D2F1 males and ZT0 (trough) to ZT9 (peak) for B6D2F1 females (ANOVA, p = 0.04; Cosinor, p = 0.0023 for B6D2F1 males and ANOVA, p = 0.0008; Cosinor, p = 0.0023 for B6D2F1 females). Similar three- to four-fold circadian variations were found in male and female B6CBAF1, with highest values occurring from ZT9 to ZT15, and a trough at ZT0 (ANOVA, p = 0.004 in male; p = 0.003 in female). The rhythm was validated by cosinor for B6CBAF1 (p = 0.00026 and p = 0.00012 in male and female, respectively).
Mentions: In study 2, mean mRNA expression of abcc2 also varied six-fold over the 24 h, with a peak at ZT12 and a nadir at ZT0 in male B6D2F1 (ANOVA, p = 0.04) (Figure 2A), Cosinor analysis further confirmed a sinusoidal pattern (p = 0.0023). The circadian amplitude was 72% of the mesor (35 to 110), and the acrophase was localized at ZT10∶20 (8∶20 to 12∶25). Thus, both studies 1 and 2 demonstrated a circadian rhythm with similar characteristics for the abcc2 mRNA expression in the ileum mucosa of male B6D2F1 mice.

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