Copper-64-diacetyl-bis(N4-methylthiosemicarbazone): An agent for radiotherapy

Abstract

Systemic administration of hypoxia-selective (64)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) has increased significantly the survival time of hamsters bearing human GW39 colon cancer tumors. Radiotherapy experiments were performed in animals bearing either 7-day-old (0.5-1.0 g) or 15-day-old (1.5-2.0 g) tumors. Studies compared animals treated with a single dose of 0, 4, 6, 7, 8, or 10 mCi of (64)Cu-ATSM (1 Ci = 37 GBq) with or without the vasodilator hydralazine. A multiple dose regimen of 3 x 4 mCi at 72-h intervals was studied also. Single doses of >6 mCi of (64)Cu-ATSM and the dose-fractionation protocol significantly increased the survival time of the hamsters compared with controls. The highest dose, 10 mCi of (64)Cu-ATSM, increased survival to 135 days in 50% of animals bearing 7-day-old tumors, 6-fold longer than control animals' survival (20 days), with only transient leucopenia and thrombocytopenia but no overt toxicity. Human absorbed doses were calculated from hamster biodistribution; the dose-critical organs were the lower large intestine (1.43 +/- 0.19 rad/mCi) and upper large intestine (1.20 +/- 0.38 rad/mCi). High-resolution MRI and positron-emission tomography using a therapeutic administration of 10 mCi were used to monitor tumor volume and morphology and to assess tumor dosimetry accurately, giving a tumor dose of 81 +/- 7.5 rad/mCi. (64)Cu-ATSM has increased the survival time of tumor-bearing animals significantly with no acute toxicity and thus is a promising agent for radiotherapy.

Figure 1

Structure of Cu-ATSM.

Figure 2

Summary of therapy results obtained with the cardiac-puncture administration of ⁶⁴Cu-ATSM in hamsters bearing the GW39 carcinoma. Endpoint was 135 days or a tumor burden of 10 g, whichever came first. (A) Therapy of 7-day-old GW39 tumors in hamsters. Single administration of saline and hydralazine (♦, n = 10), 10 mCi of ⁶⁴Cu-ATSM without hydralazine (■, n = 10), or 10 mCi of ⁶⁴Cu-ATSM with hydralazine pretreatment (▴, n = 9). (B) Therapy of 7-day-old GW39 tumors in hamsters by using dose fractionation. Administration of saline, (♦, n = 10), 3 × 4 mCi of ⁶⁴Cu-ATSM at 72-h intervals without hydralazine (■, n = 13), or 3 × 4 mCi of ⁶⁴Cu-ATSM at 72-h intervals with hydralazine pretreatment (▴, n = 13). (C) Therapy of 7-day-old GW39 tumors in hamsters. Comparison of 10 (▴, n = 10), 8 (■, n = 11), and 6 (♦, n = 12) mCi. (D) Therapy of 15-day-old GW39 tumors in hamsters. Comparison of 4 (♦, n = 7), 6 (●, n = 9), 7 (⋄, n = 9), 8 (▵, n = 9), and 10 (▴, n = 10) mCi.

Figure 3

(A) Transaxial PET images of ⁶⁴Cu-ATSM localized in the GW39 tumor 24-h after administration. Position of the tumor mass is confirmed by T₂-weighted MRIs of the same hamster in the same plane. (B) T₂-weighted transaxial MRI of two age-matched hamsters with the GW39 tumor in the thigh. The abnormal mass was still present 4 weeks after ⁶⁴Cu-ATSM treatment (Left). However, the age-matched tumor growth without the treatment (Right) resulted in a tumor nodule that occupied the entire thigh. (C) T₂-weighted MRI of a hamster with the GW39 tumor in the thigh. The abnormal mass was still present 5 weeks after ⁶⁴Cu-ATSM treatment but with little change in overall volume. The pitted appearance is noted in the tumor mass at 36 days, suggestive of a fibrotic response.