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Volume 118, Issue 1, Pages (January 2000)

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Presentation on theme: "Volume 118, Issue 1, Pages (January 2000)"— Presentation transcript:

1 Volume 118, Issue 1, Pages 81-89 (January 2000)
Pyrrolidinedithiocarbamate increases the therapeutic index of 5-fluorouracil in a mouse model  Simon P. Bach, Rebecca Chinery, Sarah T. O'Dwyer, Christopher S. Potten, Robert J. Coffey, Alastair J.M. Watson  Gastroenterology  Volume 118, Issue 1, Pages (January 2000) DOI: /S (00) Copyright © 2000 American Gastroenterological Association Terms and Conditions

2 Fig. 1 (A, C, E, and G) Apoptotic cell index percentages and (B, D, F, and H) mitotic cell index percentages in large (A-D) and small intestinal crypts (E-H) of BDF 1 mice 6 hours (A, B, E, and F) or 24 hours (C, D, G, and H) after 1 dose of 40 mg/kg 5-FU alone (solid lines) or 40 mg/kg 5-FU plus 250 mg/kg PDTC (dashed lines). Control untreated values are shown for comparison (dotted lines; A, B, E, and F). Six animals were used in each data group, counting 50 half-crypts per mouse. Data lines are smoothed over 3 positions. Gastroenterology  , 81-89DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

3 Fig. 1 (A, C, E, and G) Apoptotic cell index percentages and (B, D, F, and H) mitotic cell index percentages in large (A-D) and small intestinal crypts (E-H) of BDF 1 mice 6 hours (A, B, E, and F) or 24 hours (C, D, G, and H) after 1 dose of 40 mg/kg 5-FU alone (solid lines) or 40 mg/kg 5-FU plus 250 mg/kg PDTC (dashed lines). Control untreated values are shown for comparison (dotted lines; A, B, E, and F). Six animals were used in each data group, counting 50 half-crypts per mouse. Data lines are smoothed over 3 positions. Gastroenterology  , 81-89DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

4 Fig. 1 (A, C, E, and G) Apoptotic cell index percentages and (B, D, F, and H) mitotic cell index percentages in large (A-D) and small intestinal crypts (E-H) of BDF 1 mice 6 hours (A, B, E, and F) or 24 hours (C, D, G, and H) after 1 dose of 40 mg/kg 5-FU alone (solid lines) or 40 mg/kg 5-FU plus 250 mg/kg PDTC (dashed lines). Control untreated values are shown for comparison (dotted lines; A, B, E, and F). Six animals were used in each data group, counting 50 half-crypts per mouse. Data lines are smoothed over 3 positions. Gastroenterology  , 81-89DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

5 Fig. 1 (A, C, E, and G) Apoptotic cell index percentages and (B, D, F, and H) mitotic cell index percentages in large (A-D) and small intestinal crypts (E-H) of BDF 1 mice 6 hours (A, B, E, and F) or 24 hours (C, D, G, and H) after 1 dose of 40 mg/kg 5-FU alone (solid lines) or 40 mg/kg 5-FU plus 250 mg/kg PDTC (dashed lines). Control untreated values are shown for comparison (dotted lines; A, B, E, and F). Six animals were used in each data group, counting 50 half-crypts per mouse. Data lines are smoothed over 3 positions. Gastroenterology  , 81-89DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

6 Fig. 2 Time course of small intestinal (A) apoptotic cell index percentage and (B) mitotic cell index percentage after a dose of 40 mg/kg 5-FU alone or 40 mg/kg 5-FU plus 250 mg/kg PDTC. Six animals were used at each time point, counting 50 half crypts per mouse. Data combined from cell positions Arrow indicates a significant difference between treatment groups (P < 0.001). Gastroenterology  , 81-89DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

7 Fig. 2 Time course of small intestinal (A) apoptotic cell index percentage and (B) mitotic cell index percentage after a dose of 40 mg/kg 5-FU alone or 40 mg/kg 5-FU plus 250 mg/kg PDTC. Six animals were used at each time point, counting 50 half crypts per mouse. Data combined from cell positions Arrow indicates a significant difference between treatment groups (P < 0.001). Gastroenterology  , 81-89DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

8 Fig. 3 Time course for large intestinal apoptotic cell index percentage in (A) the stem cell zone (cell positions 1-3), (B) the late transit cell zone (cell positions 10-12), and (C) cell positions 1-18, inclusive, after a dose of 40 mg/kg 5-FU alone or 40 mg/kg 5-FU plus 250 mg/kg PDTC. Six animals were used at each time point, counting 50 half crypts per mouse. Arrows indicate a significant difference between treatment groups (P < 0.001). Gastroenterology  , 81-89DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

9 Fig. 3 Time course for large intestinal apoptotic cell index percentage in (A) the stem cell zone (cell positions 1-3), (B) the late transit cell zone (cell positions 10-12), and (C) cell positions 1-18, inclusive, after a dose of 40 mg/kg 5-FU alone or 40 mg/kg 5-FU plus 250 mg/kg PDTC. Six animals were used at each time point, counting 50 half crypts per mouse. Arrows indicate a significant difference between treatment groups (P < 0.001). Gastroenterology  , 81-89DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

10 Fig. 3 Time course for large intestinal apoptotic cell index percentage in (A) the stem cell zone (cell positions 1-3), (B) the late transit cell zone (cell positions 10-12), and (C) cell positions 1-18, inclusive, after a dose of 40 mg/kg 5-FU alone or 40 mg/kg 5-FU plus 250 mg/kg PDTC. Six animals were used at each time point, counting 50 half crypts per mouse. Arrows indicate a significant difference between treatment groups (P < 0.001). Gastroenterology  , 81-89DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

11 Fig. 4 Time course for large intestinal mitotic cell index percentage in (A) the stem cell zone (cell positions 1-3), (B) the late transit cell zone (cell positions 10-12), and (C) cell positions 1-18, inclusive, after a dose of 40 mg/kg 5-FU alone or 40 mg/kg 5-FU plus 250 mg/kg PDTC. Six animals were used at each time point, counting 50 half crypts per mouse. Arrow indicates a significant difference between treatment groups (P < 0.001). Gastroenterology  , 81-89DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

12 Fig. 5 (A) Colonic epithelium 6 days after administration of 5-FU, 500 mg/kg, in 2 doses 6 hours apart. Arrow indicates a single regenerating crypt containing several mitotic figures (original magnification 400×). (B) Normal murine colonic epithelium (400×). (C) Apoptotic body (thick arrow) and mitotic figure (thin arrow) in colonic epithelium 24 hours after administration of 40 mg/kg 5-FU (1000×). (D) Apoptotic body stained using the TUNEL technique (thick arrow). Note the apoptotic body, which remains unstained (thin arrow; 1000×). Gastroenterology  , 81-89DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

13 Fig. 6 (A) Crypt survival curves obtained from the large intestine of BDF 1 mice 6 days after treatment with 5-FU ( mg/kg) alone or 5-FU ( mg/kg) plus PDTC (500 mg/kg), administered as 2 divided doses 6 hours apart. The fraction of surviving colonic crypts is higher when 5-FU was administered with PDTC (P < 0.001, F test). (B) Corresponding data from the small intestine of BDF 1 mice viewed 5 days after treatment described in A. The fraction of surviving crypts is not altered by pretreatment with PDTC (P = 0.62, F test). Gastroenterology  , 81-89DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions


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