Preclinical evaluation of an 131I-labeled benzamide for targeted radiotherapy of metastatic melanoma

John L Joyal, John A. Barrett, John C Marquis, Jianqing Chen, Shawn M Hillier, Kevin P Maresca, Marie Boyd, Kenneth Gage, Sridhar Nimmagadda, James F Kronauge, Matthias Friebe, Ludger Dinkelborg, James B Stubbs, Michael G Stabin, Rob Mairs, Martin G Pomper, John W Babich

Research output: Contribution to journalArticle

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Abstract

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.
LanguageEnglish
Pages4045-4053
Number of pages9
JournalCancer Research
Volume70
Issue number10
DOIs
Publication statusPublished - May 2010

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Melanins
Melanoma
Radiotherapy
Neoplasms
Benzamides
Tissue Distribution
Heterografts
Amelanotic Melanoma
benzamide
Macaca fascicularis
Growth
Single-Photon Emission-Computed Tomography
Radionuclide Imaging
N-(2-diethylaminoethyl)-4-(4-fluorobenzamido)-5-iodo-2-methoxybenzamide
Pharmacokinetics
Acids
Pharmaceutical Preparations

Keywords

  • benzamides
  • drug evaluation
  • iodine radioisotopes
  • macaca fascicularis
  • melanins
  • melanoma
  • neoplasm metastasis
  • radiopharmaceuticals
  • radiotherapy dosage
  • tomography
  • xenograft model antitumor Assays

Cite this

Joyal, J. L., Barrett, J. A., Marquis, J. C., Chen, J., Hillier, S. M., Maresca, K. P., ... Babich, J. W. (2010). Preclinical evaluation of an 131I-labeled benzamide for targeted radiotherapy of metastatic melanoma. Cancer Research, 70(10), 4045-4053. https://doi.org/10.1158/0008-5472.CAN-09-4414
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. / Preclinical evaluation of an 131I-labeled benzamide for targeted radiotherapy of metastatic melanoma. In: Cancer Research. 2010 ; Vol. 70, No. 10. pp. 4045-4053.
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abstract = "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.",
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Joyal, JL, Barrett, JA, Marquis, JC, Chen, J, Hillier, SM, Maresca, KP, Boyd, M, Gage, K, Nimmagadda, S, Kronauge, JF, Friebe, M, Dinkelborg, L, Stubbs, JB, Stabin, MG, Mairs, R, Pomper, MG & Babich, JW 2010, 'Preclinical evaluation of an 131I-labeled benzamide for targeted radiotherapy of metastatic melanoma' Cancer Research, vol. 70, no. 10, pp. 4045-4053. https://doi.org/10.1158/0008-5472.CAN-09-4414

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 journalArticle

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

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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

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