Copper-64-diacetyl-bis(N4-methylthiosemicarbazone): An agent for radiotherapy.
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.
Lewis
J
J
Mallinckrodt Institute of Radiology and Department of Surgery, Washington University School of Medicine, 510 South Kingshighway Boulevard, St. Louis, MO 63110, USA.
Laforest
R
R
Buettner
T
T
Song
S
S
Fujibayashi
Y
Y
Connett
J
J
Welch
M
M
D000818:Animals; D001918:Brachytherapy / Q000379:methods*; D015687:Cell Hypoxia; D015179:Colorectal Neoplasms / Q000532:radiotherapy*; D056831:Coordination Complexes; D003301:Copper Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D006224:Cricetinae; D019583:Dose Fractionation, Radiation; D006801:Humans; D006830:Hydralazine / Q000627:therapeutic use; D007267:Injections; D007420:Intestine, Large / Q000187:drug effects / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D009942:Organometallic Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D011879:Radiotherapy Dosage; D013882:Thiosemicarbazones / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014183:Transplantation, Heterologous; D015431:Weight Loss
D056831:Coordination Complexes; D003301:Copper Radioisotopes; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D006830:Hydralazine