Table 3.
Clinical alterations and the toxicity of cisplatin in mice.
|
strain (breeder) |
age sex, N |
R | cisplatin dose | TP |
BUN mg/dl |
Cr mg/dl |
end | M | histology and other comments | Ref. |
|---|---|---|---|---|---|---|---|---|---|---|
| BALB/c | MTD | iv | D2-4 | ns | ns | D10 | 0% | Histology: proximal tubular epithelial necrosis observed not earlier than D6 - D10; D4: ↓GFR; Urine: ↑proteins, glycosuria, |
[55] | |
| female | 7 mg/kg | D6 | ns | ns | ||||||
| N=3-8 | D10 | ns | ns | |||||||
|
| ||||||||||
| BALB/c | female | ip | 8 mg/kg | D4 | ns | ns | D4 | 0% | Histology: not evaluated D4:↓GFR |
[56] |
|
| ||||||||||
| C57BL/6J | 20-25g | ip | 10 mg/kg | D1 | 24 ±17 ns | 1.4 ± 0.5 ns | D4 | 0% | Histology: D2 rare changes, D3-D4 evident loss of brush border, pyknotic nuclei, vesicles, Ultrastructure: changes in mitochondria from D1 | [44] |
| Jax | male | D2 | 44 ±10 ns | 1.9 ± 0.9 ns | ||||||
| N=6 | D3 | 105 ±9 | 12.7 ±1.2 | |||||||
| D4 | 228 ± 18 | 22.4 ±1.8 | ||||||||
|
| ||||||||||
| C57BL/6 Harlan, UK |
male N=6 |
ip | 7.5 mg/kg | D4 | 1.6x ns | 1.2x ns | D4 | 0% | ↓BW (4.4±5%); histology: not evaluated | [103] |
| 10 mg/kg | D4 | ↑4x | ↑3.1x | D4 | 0% | ↓BW (15.3±11%), histology: moderate ATN: degradation of the brush border, loss of cell-cell adhesion, cellular vacuolation and sloughing of cellular material into lumen | ||||
| 12.5mg/kg | D4 | ↑5x | ↑3.6x | D4 | HEP | BW (↓27±1%)∗, systemic toxicity | ||||
|
| ||||||||||
| C57BL/6 | 8-12 wk | ip | 15 mg/kg | D5 | n.a. | 4.7 ± 0.5 | D5 | 12% | Histology: all survived mice (7/8) had severe ATN although one had normal Cr levels (6/7); survived mice: ↓BW (19.5%), lack of grooming, lethargy, high morbidity, ↓WBC |
[114] |
| USA | female | (6/7) | (1/8) | |||||||
| N=8 | ||||||||||
|
| ||||||||||
| C57BL/6 | male | ip | 15 mg/kg | D5 | ↑4x | n.a. | D5 | 55% | ↓BW (24%), histology: severe ATN: extensive tubular necrosis, loss of the epithelial brush- border, presence of protein casts in the lumen mice began dying on day 3 |
[115] |
| Harlan | 6-8 wk | (6/11) | ||||||||
| N=11 | ||||||||||
|
| ||||||||||
| C57BL/6 | 11-15wk | ip | 15 mg/kg | D2 | ns | n.a. | D10 | 100% | Histology: not evaluated D4:↓BW (20-30%); mice began dying on day 5 |
[41] |
| Japan | male | D3 | 4x | 2x | ||||||
| N=5-6 | ||||||||||
|
| ||||||||||
| Swiss | Male | ip | D3 | ↑3x | ↑10x | D3 | 0% | Histology: not evaluated Kidney:↓SOD, CAT, GPx, ↓GSH, ↑MDA |
[116] | |
| albino | 6-7wks | 10 mg/kg | ||||||||
| (India) | N=6 | |||||||||
|
| ||||||||||
| Swiss | female | ip | 12 mg/kg | D3 | ↑4x | ↑4x | D3 | 0% | Histology: severe ATN; marked necrosis in proximal tubules Kidney:↓SOD, CAT, GPx; ↓GSH, ↑MDA |
[117] |
| albino | 6wks | |||||||||
| (India) | N=6 | |||||||||
|
| ||||||||||
| ICR Thailand |
25-30g male N=8 |
ip | 7.5 mg/kg | D3-5 | ↑ns | ns | 0 | Preliminary experiment to determine cisplatin dose | [118] | |
| 10 mg/kg | D3 D5 |
31.7±2.9 ns 53.8 ± 4.2 |
0.88±0.02 ns 1.74 ± 0.43 ns |
D5 | 0 | dose- and time-dependent elevation of BUN and Cr | ||||
| 12.5mg/kg | D3 D4 D5 |
52.2 ± 8.3 88.9 ± 18.8 131.8 ± 22 |
ns ns 2.01 ±0.53 |
D5 | 0 | 15 mg/kg resulted in marked BW loss at d5; | ||||
| 15 mg/kg | D3 D4 D5 |
63.8 ± 17.2 158 ± 77 225 ± 41 |
ns 2.32 ± 0.59 2.49 ± 0.59 |
D5 | HEP | 12.5 mg/kg was chosen. Histology: severe ATN: focal necrosis of the proximal tubules throughout the cortex, hyaline casts in tubular lumen, desquamation, and parenchyma degeneration of the tubular epithelium cells | ||||
|
| ||||||||||
| FVB/n | N=10 | ip | 4 x 7 mg/kg | D25 | ns | ns | D25 | 0% | Histology: evident loss of brush borders, tubular dilation, less tubular necrosis, evident inflammatory cells and interstitial fibrosis (red Sirius) Urine: ≈KIM-1, ↑NGAL |
[119] |
| Jax | per week | |||||||||
| 4 x 9 mg/kg | D25 | ns | ns | D25 | 90% | |||||
| per week | ||||||||||
|
| ||||||||||
| High lethal dose – severe systemic toxicity | ||||||||||
|
| ||||||||||
| BALB/c | 6-8wk | ip | 25 mg/kg | D1 | ns | ns | D3 | 0% | [70] | |
| South | male | D2 | ↑2x | ↑2x | D4 | 80% | ||||
| Korea | N=11 | D3 | ↑4x | ↑4x | D5 | 100% | ||||
|
| ||||||||||
| BALB/c | 6-8wk | ip | 40 mg/kg | D1 | 185 ± 22 | 2.4 ±0.48 | D1 | 20% | [70] | |
| South | male | D2 | 60% | |||||||
| Korea | N=21 | D3 | 100% | |||||||
|
| ||||||||||
| Nephrotoxicity and antitumor activity in mice with cancer | ||||||||||
|
| ||||||||||
| BALB/c | 8 wk | ip | 11.5 mg/kg | D4 | 70±42 | 1.6 ± 0.6 | D7 | 0-12% | Histology: ATN (dose dependent) nephrotoxicity and antitumor activity |
[120] |
| (Harlan) | female | 13 mg/kg | D4 | 130 ± 38 | 4.5 ± 1.0 | D7 | 0-50% | |||
| N=8 | 14.5 mg/kg | D4 | 175±52 | 5.8 ± 0.7 | D7 | 100% | ||||
| 16 mg/kg | D4 | 232 ± 40 | 6.4 ± 1.0 | D7 | nr | |||||
| 19 mg/kg | D4 | 275 ± 26 | 6.9 ± 0.2 | D7 | nr | |||||
|
| ||||||||||
| C57BL/6 | female | iv | 7x 1mg/kg every other day |
D18 | n.a. | n.a. | D18 | 0/8 | Low-dose cisplatin no changes in the BW Antitumor activity |
[121] |
| N=8 | ||||||||||
|
| ||||||||||
| C57BL/6 | female N=8 |
iv | 7x 5mg/kg every other day | D18 | n.a. | n.a. | D18 | 4/8 | High-dose cisplatin 15-30% BW loss, antitumor activity (experiment was stopped when mice started dying) |
[121] |
N: number; M: mortality; R: route of injection; TP: time point; n.a.: not analyzed; ip: intraperitoneally; iv: intravenously; sc: subcutaneously; D: day; ≈: ns; ↓: decrease; ↑: increase; BUN: blood urea nitrogen; Cr: serum creatinine; GFR: glomerular filtration rate; ATN: acute tubular necrosis; HEP: humane endpoint (animals were humanely euthanized due to severe illness). ∗Animals receiving high dose of cisplatin exhibited systemic toxicity as demonstrated by significant weight loss in excess of 25% of their starting bodyweight, requiring termination of the experiment on day 4 [103].