Table 1.
In vitro and in vivo toxicity of Prodrug 8 compared with MMAE and Prodrug 3a
| A. Estimated MTD and LD50 of prodrugs 3 and 8 (mg/kg) in BALB/c mice | ||||
| 3 | 8 | |||
| MTD | LD50 | MTD | LD50 | |
| I.p. comm. | 15 | 12 | >60 | >60 |
| I.p. 5x | 3 | 1.5 | >6 | >6 |
| B. Comparison of gross toxicity of mice; i.p. 5 x | |||||
| I.p. 5x Dose (mg/kg) | 0.1 | 0.5 | 1.5 | 3 | |
| MMAE, 1 | Wt. loss (%) | 33.4 | |||
| Death (%) | 20 | 100 | 100 | ||
| Prodrug 3 | Wt. loss (%) | 10.8 | 12.7 | 38.7 | |
| Death (%) | 0 | 0 | 40 | 100 | |
| Prodrug 8 | Wt. loss (%) | 0 | 3.4 | 8.2 | 14.9 |
| Death (%) | 0 | 0 | 0 | 10 | |
| C. Comparison of blood cell density of mice; i.p. 1 x Dose, 9 mg/kg | |||
| day 0 | day 4 | ||
| PBS | WBC (109/L) RBC (1012/L) |
8.1±1.7 9.1±1.5 |
7.8±1.5 9.3±1.4 |
| Prodrug 3 | WBC (109/L) RBC (1012/L) |
7.8±1.7 9.0±1.4 |
4.4±2.3 8.1±1.9 |
| Prodrug 8 | WBC (109/L) RBC (1012/L) |
8.2±1.8 9.4±1.4 |
7.6±1.1 9.2±2.0 |
a
Key: See Materials and methods for the experimental details.