Abstract
| Language | English |
|---|---|
| Pages | 4045-4053 |
| Number of pages | 9 |
| Journal | Cancer Research |
| Volume | 70 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - May 2010 |
Fingerprint
Keywords
- benzamides
- drug evaluation
- iodine radioisotopes
- macaca fascicularis
- melanins
- melanoma
- neoplasm metastasis
- radiopharmaceuticals
- radiotherapy dosage
- tomography
- xenograft model antitumor Assays
Cite this
}
Preclinical evaluation of an 131I-labeled benzamide for targeted radiotherapy of metastatic melanoma. / Joyal, John L; Barrett, John A.; Marquis, John C; Chen, Jianqing; Hillier, Shawn M; Maresca, Kevin P; Boyd, Marie; Gage, Kenneth; Nimmagadda, Sridhar; Kronauge, James F; Friebe, Matthias; Dinkelborg, Ludger; Stubbs, James B; Stabin, Michael G; Mairs, Rob; Pomper, Martin G; Babich, John W.
In: Cancer Research, Vol. 70, No. 10, 05.2010, p. 4045-4053.Research output: Contribution to journal › Article
TY - JOUR
T1 - Preclinical evaluation of an 131I-labeled benzamide for targeted radiotherapy of metastatic melanoma
AU - Joyal, John L
AU - Barrett, John A.
AU - Marquis, John C
AU - Chen, Jianqing
AU - Hillier, Shawn M
AU - Maresca, Kevin P
AU - Boyd, Marie
AU - Gage, Kenneth
AU - Nimmagadda, Sridhar
AU - Kronauge, James F
AU - Friebe, Matthias
AU - Dinkelborg, Ludger
AU - Stubbs, James B
AU - Stabin, Michael G
AU - Mairs, Rob
AU - Pomper, Martin G
AU - Babich, John W
N1 - (c)2010 AACR.
PY - 2010/5
Y1 - 2010/5
N2 - Radiolabeled benzamides are attractive candidates for targeted radiotherapy of metastatic melanoma as they bind melanin and exhibit high tumor uptake and retention. One such benzamide, N-(2-diethylamino-ethyl)-4-(4-fluoro-benzamido)-5-iodo-2-methoxy-benzamide (MIP-1145), was evaluated for its ability to distinguish melanin-expressing from amelanotic human melanoma cells, and to specifically localize to melanin-containing tumor xenografts. The binding of [(131)I]MIP-1145 to melanoma cells in vitro was melanin dependent, increased over time, and insensitive to mild acid treatment, indicating that it was retained within cells. Cold carrier MIP-1145 did not reduce the binding, consistent with the high capacity of melanin binding of benzamides. In human melanoma xenografts, [(131)I]MIP-1145 exhibited diffuse tissue distribution and washout from all tissues except melanin-expressing tumors. Tumor uptake of 8.82% injected dose per gram (ID/g) was seen at 4 hours postinjection and remained at 5.91% ID/g at 24 hours, with tumor/blood ratios of 25.2 and 197, respectively. Single photon emission computed tomography imaging was consistent with tissue distribution results. The administration of [(131)I]MIP-1145 at 25 MBq or 2.5 GBq/m(2) in single or multiple doses significantly reduced SK-MEL-3 tumor growth, with multiple doses resulting in tumor regression and a durable response for over 125 days. To estimate human dosimetry, gamma camera imaging and pharmacokinetic analysis was performed in cynomolgus monkeys. The melanin-specific binding of [(131)I]MIP-1145 combined with prolonged tumor retention, the ability to significantly inhibit tumor growth, and acceptable projected human dosimetry suggest that it may be effective as a radiotherapeutic pharmaceutical for treating patients with metastatic malignant melanoma.
AB - Radiolabeled benzamides are attractive candidates for targeted radiotherapy of metastatic melanoma as they bind melanin and exhibit high tumor uptake and retention. One such benzamide, N-(2-diethylamino-ethyl)-4-(4-fluoro-benzamido)-5-iodo-2-methoxy-benzamide (MIP-1145), was evaluated for its ability to distinguish melanin-expressing from amelanotic human melanoma cells, and to specifically localize to melanin-containing tumor xenografts. The binding of [(131)I]MIP-1145 to melanoma cells in vitro was melanin dependent, increased over time, and insensitive to mild acid treatment, indicating that it was retained within cells. Cold carrier MIP-1145 did not reduce the binding, consistent with the high capacity of melanin binding of benzamides. In human melanoma xenografts, [(131)I]MIP-1145 exhibited diffuse tissue distribution and washout from all tissues except melanin-expressing tumors. Tumor uptake of 8.82% injected dose per gram (ID/g) was seen at 4 hours postinjection and remained at 5.91% ID/g at 24 hours, with tumor/blood ratios of 25.2 and 197, respectively. Single photon emission computed tomography imaging was consistent with tissue distribution results. The administration of [(131)I]MIP-1145 at 25 MBq or 2.5 GBq/m(2) in single or multiple doses significantly reduced SK-MEL-3 tumor growth, with multiple doses resulting in tumor regression and a durable response for over 125 days. To estimate human dosimetry, gamma camera imaging and pharmacokinetic analysis was performed in cynomolgus monkeys. The melanin-specific binding of [(131)I]MIP-1145 combined with prolonged tumor retention, the ability to significantly inhibit tumor growth, and acceptable projected human dosimetry suggest that it may be effective as a radiotherapeutic pharmaceutical for treating patients with metastatic malignant melanoma.
KW - benzamides
KW - drug evaluation
KW - iodine radioisotopes
KW - macaca fascicularis
KW - melanins
KW - melanoma
KW - neoplasm metastasis
KW - radiopharmaceuticals
KW - radiotherapy dosage
KW - tomography
KW - xenograft model antitumor Assays
U2 - 10.1158/0008-5472.CAN-09-4414
DO - 10.1158/0008-5472.CAN-09-4414
M3 - Article
VL - 70
SP - 4045
EP - 4053
JO - Cancer Research
T2 - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 10
ER -