Table 4.
Impact of experimental design on critical colorectal cancer endpoints.
| Animal model | Carcinogen | CRC-specific endpoints measured |
|---|---|---|
| Studies demonstrating beneficial effects of folate on critical colorectal cancer endpoints | ||
| Rat Sprague-Dawley Male [83] |
DMH 44 mg/kg body weight Weekly × 15 weeks |
Percent of rats with colonic tumors: 70% (0 mg/kg folate) 40% (2 mg/kg folate) 10% (8 mg/kg folate) 42% (40 mg/kg folate) (Similar results for # tumors/rat) |
|
| ||
| Rat Fisher 344 Male [15] |
5-week diet prior to DMH ENU 100mg/kg |
Mutant frequency: 8-fold increase (0 mg/kg folate, no antibiotics) 6-fold increase (0 mg/kg folate, with antibiotics) 5-fold increase (2 mg/kg folate) |
|
| ||
| Rat Fisher 344 Male [85] |
DMH 25 mg/kg body weight 2 weekly injections |
Colonic aberrant crypts/aberrant crypt foci: ~150 aberrant crypts, 50 foci (2 mg/kg folate) ~250 aberrant crypts, 75 foci (0 mg/kg folate) |
|
| ||
| Rat Albino Male [86] |
3-week diet prior to DMH 8-week diet after DMH AOM 30 mg/kg body weight |
Aberrant crypt foci: ~65 aberrant crypts (2 mg/kg folate) ~58 aberrant crypts (8 mg/kg folate) ~30 aberrant crypts (40 mg/kg folate) (note: no deficient group) |
|
| ||
| Mice Balb/cAnNCrlBR Wildtype (from 129) Backcrossed >10 generations into Balb/c Sex: not stated [81] |
None, diet only |
Percent mice with duodenal tumors: 0% (2 mg/gk folate) 12.5% (0.3 mg/kg folate) (2/16 mice; adenoma versus adenocarcinoma not specified) |
|
| ||
| Mice C57bl/6 Apc1638N, BAT-LacZ (Wnt reporter mouse) No. of generations backcrossed N/A Sex: not stated [84] |
None, diet and genotype only (Note: diet includes multiple B vitamin manipulations: Riboflavin, B6, B12, and folate) |
Gastrointestinal tumor incidence and multiplicity; aberrant crypt foci: 50% incidence (2 mg/kg folate, adequate Bvitamins) 91% incidence (0 mg/kg folate, B vitamin deficient) ~1.7 tumors/animal (2 mg/kg folate, adequate Bvitamins) ~2.7 tumors/animal (0 mg/kg folate, B vitamin deficient) ~2 aberrant crypts (2 mg/kg folate, adequate Bvitamins) ~2.5 aberrant crypts (0 mg/kg folate, B vitamin deficient) |
|
| ||
| Mice C57bl/6 Apc1638N No. of generations backcrossed N/A Sex: both [78] |
None, diet and genotype only (Note: diet includes multiple B vitamin manipulations: Riboflavin, B6, B12, and folate; dietary intervention in dams and offspring) |
Gastrointestinal tumor incidence (percent) and multiplicity: ~55% incidence (0.5 mg/kg folate, B vitamin deficient) ~58% incidence (2.0 mg/kg folate, Bvitamin adequate) ~20% incidence (8.0 mg/kg folate, B vitamin supplemented) ~0.6 tumors/animal (0.5 mg/kg folate, B vitamin deficient) ~0.6 tumors/animal (2.0 mg/kg folate, Bvitamin adequate) ~0.25 tumors/animal (8.0 mg/kg folate, B vitamin supplemented) (Note: tumor invasiveness significantly worse in deficient group compared to control group) |
|
| ||
| Mice C57bl/6 Apcmin >10 generations backcrossed Sex: not stated [68] |
None, diet and genotype only Shmt heterozygous and null genotypes crossed onto Apcmin Note: choline altered as well as folate |
Gastrointestinal tumor number and tumor load (total tumor area/mouse): Impact of diet seen only in Shmt heterozygous model: ~32 small intestinal tumors (2 mg/kg folate, 2.5 g/kg choline) ~60 small intestinal tumors (0 mg/kg folate, 0 g/kg choline) ~40 mm 2 tumor load (2 mg/kg folate, 2.5 g/kg choline) ~80 mm2 tumor load (0 mg/kg folate, 0 g/kg choline) |
|
| ||
| Mice C57bl/6 DNA polymerase β +/− >10 generations Sex: Male [59] |
DMH 30 mg/kg body weight Weekly for 6 weeks Killed after 12 weeks |
Total aberrant crypt foci: ~15 aberrant crypts (2 mg/kg folate, wildtype) ~38 aberrant crypts (0 mg/kg folate, wildtype) (Note: this work presents data both in support of protective and detrimental roles for folate; protective presented here, detrimental presented below) |
|
| ||
| Rat Sprague-Dawley Male [72] |
AOM 15 mg/kg Weekly for 3 weeks Killed after 8 weeks |
Total aberrant crypt foci: ~300 aberrant crypts (8 mg/kg folate) ~200 aberrant crypts (0 mg/kg folate + abx post-AOM) (Note: no “standard” control group of 2 mg/kg folate) |
|
| ||
| Rat Sprague-Dawley Male [73] |
AOM 15 mg/kg/week Weekly for 3 weeks Killed after 22 weeks |
Number of colon adenocarcinomas: 13 (8 mg/kg folate, no abx) 12 (8 mg/kg folate, with abx) 4 (0 mg/kg folate, no abx) 3 (0 mg/kg folate, abx before AOM) 4 (0 mg/kg folate, abx after AOM) (Note: no “standard” control group of 2 mg/kg folate) |
|
| ||
| Rat Sprague-Dawley Male [76] |
AOM 2 weekly exposures (total dosing unclear) Diet begun 6 weeks post- AOM |
Aberrant crypt foci and tumor size (tumor diameter/tumor-bearing animal, cm)
84.6 aberrant crypts (0 mg/kg folate) 93.4 aberrant crypts (2 mg/kg folate) 108.1 aberrant crypts (5 mg/kg folate) 137.9 aberrant crypts (8 mg/kg folate) 0.5 cm (0 mg/kg folate) 1.2 cm (2 mg/kg folate) 1.3 cm (5 mg/kg folate) 1.6 cm (8 mg/kg folate) |
|
| ||
| Mice C57bl/6 APCmin No. of generations backcrossed N/A Sex: not stated [77] |
None, diet and genotype only Two timepoints: 3 and 6 months |
Aberrant crypt foci and ileal adenomas: At 3 months: 1.3 aberrant crypts (0 mg/kg folate) 0.27 aberrant crypts (2 mg/kg/folate) 0.20 aberrant crypts (8 mg/kg folate) 0.00 aberrant crypts (20 mg/kg folate) 11.0 ileal adenomas (0 mg/kg folate) 7.36 ileal adenomas (2 mg/kg folate) 7.30 ileal adenomas (8 mg/kg folate) 2.36 ileal adenomas (20 mg/kg folate) At 6 months: 1.67 ileal adenomas (0 mg/kg folate) 7.09 ileal adenomas (2 mg/kg folate) 5.33 ileal adenomas (8 mg/kg folate) 4.38 ileal adenomas (20 mg/kg folate) |
|
| ||
| Mice C57bl/6 DNA polymerase β +/− >10 generations Sex: male [59] |
DMH 30 mg/kg body weight Weekly for 6 weeks Killed after 12 weeks |
Total aberrant crypt foci:
~33 aberrant crypts (2 mg/kg folate, heterozygote) ~20 aberrant crypts (0 mg/kg folate, heterozygote) (Note: this work presents data both in support of protective and detrimental roles for folate; detrimental presented here, protective presented above.) |
~indicates values are approximated from graphical data; N/A: not available; Shmt: serine hydroxyl methyl transferase.