Timing of cisplatin administration for chemoradiotherapy in transgenic mice bearing lens tumors

Abstract

Cisplatin-based concurrent chemoradiotherapy (CCRT) has become a standard treatment for cancer of the uterine cervix. However, there have been no investigations into the optimum timing for administration of anticancer drugs using animal models. The aim of the present study was to determine the appropriate timing for administration of the anticancer drug cisplatin in relation to delivery of radiation by assessing the antitumor activity and adverse effects of 3 different regimens in αT3 transgenic mice bearing lens epithelial tumors. CCRT showed the strongest antitumor activity. There was a significant difference between CCRT and administration of cisplatin before radiotherapy (neoadjuvant therapy) with regard to the apoptotic effect detected by TUNEL staining, but there was no significant difference between CCRT and administration of cisplatin after radiotherapy (adjuvant therapy). Assessment of adverse effects showed that there were no significant differences in the mortality rate, weight loss, anemia and leukopenia among the 3 regimens. In conclusion, these findings obtained in an animal model suggest that cisplatin should probably not be administered before irradiation, since the antitumor effect is significantly weaker than that of CCRT or administration after irradiation, while adverse effects are similar.

Figure 1

Lens tumors in αT3 mice. (A) The tumor was confined inside the eyeball at 8 weeks of age. (B) The tumor showed extraocular infiltration at 16 weeks of age. (C) The tumor destroyed the eyeball and metastasized to the cervical lymph nodes (black arrow) at 52 weeks of age.

Figure 2

Comparison of the mortality rate between each group. The mortality rate was the highest in Group 6, but there was no significant difference from any of the other groups. NS, not significant.

Figure 3

Tumor reduction rate. In Group 4, tumors showed the greatest reduction in size. There was a significant difference between Group 4 and Group 2 (P=0.019), but not between Group 4 and Groups 3, 5 or 6. NS, not significant.

Figure 4

Representative images of mice from Groups 2 and 4 before and after treatment. (A) A mouse from Group 2. The eyeball is larger after treatment than before treatment. (B) A mouse from Group 4. The eyeball showed a marked decrease in size after treatment.

Figure 5

Detection of TUNEL-positive cells in lens tissue. (A) Eyeball of a mouse from Group 4 with numerous TUNEL-positive cells in the lens tissue. (B) Eyeball of a mouse from Group 2 with few TUNEL-positive cells in the lens tissue. a, TUNEL staining, magnification, ×40; b, negative control, magnification, ×40; c, H&E staining, magnification, ×40 and d, TUNEL staining, magnification, ×400.

Figure 6

The number of TUNEL-positive cells per 10 high-power fields in lens tissue. The number of TUNEL-positive cells was the highest in Group 4, and there was a significant difference between Group 4 and Groups 2, 3 or 6 (P<0.01, P<0.01 and P=0.031, respectively). NS, not significant.

Figure 7

Changes of body weight. Comparison of the changes of body weight showed that there was no significant difference between Group 1 and any of the other groups. NS, not significant.

Figure 8

Hemoglobin and leukocyte count. (A) Comparison of the hemoglobin. There was no significant difference of hemoglobin between Group 1 and any of the other groups. (B) Comparison of the leukocyte count. Group 4 had the lowest leukocyte count and there was a significant difference compared with Group 2 (P=0.004), but there was no significant difference between Group 4 and Groups 3, 5 or 6. NS, not significant.