International Journal of Radiation Oncology*Biology*Physics

2001

DOI: 10.1016/s0360-3016(00)01419-x

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Antitumor effect of radioactive cisplatin (191Pt) on nude mice

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Johan Wennerberg

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,

Anders Johnsson

³

et al.

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Cited by 32 publications

(19 citation statements)

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“…Radiolabeled platinum drugs have been synthesized with platinum radioisotopes as radioactive drugs for imaging and therapy studies. Areberg et al (11) studied the antitumor effect of radioactive cisplatin ( 191 Pt) in tumor-bearing nude mice and demonstrated that 191 Pt-cisplatin was more effective than unlabeled cisplatin in retarding tumor growth. Patient studies by Areberg et al (22,23) demonstrated the use of cisplatin radiolabeled with 191 Pt, 193m Pt, or 195m Pt to visualize the uptake of platinum in tumor and tissues noninvasively after cisplatin treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Previous strategies for synthesizing radiolabeled platinum drugs, such as cisplatin and carboplatin, relied on the incorporation of a platinum isotope (e.g., 191 Pt, 195m Pt) as its chloride salt early in drug synthesis (11)(12)(13)(14). These studies provided valuable in vivo data, but this approach was not clinically translatable because of limited platinum radioisotope availability, long radiosynthesis, and logistic cost.…”

mentioning

confidence: 99%

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¹⁸F-Labeled Carboplatin Derivative for PET Imaging of Platinum Drug Distribution

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et al. 2017

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Increasing evidence indicates that reduced intracellular drug accumulation is the parameter most consistently associated with platinum drug resistance, emphasizing the need to directly measure the intratumor drug concentration. In the era of precision medicine and with the advent of powerful imaging and proteomics technologies, there is an opportunity to better understand drug resistance by exploiting these techniques to provide new knowledge on drug-target interactions. Here, we contribute to this endeavor by reporting on the development of an F-labeled carboplatin derivative (F-FCP) that has the potential to image drug uptake and retention, including intratumoral distribution, by PET. Fluorinated carboplatin (F-FCP) was synthesized using F-labeled 2-(5-fluoro-pentyl)-2-methyl malonic acid (F-FPMA) as the labeling agent to coordinate with the cisplatin-aqua complex. It was then used to treat cell lines and compared with cisplatin and carboplatin at different concentrations. Manual radiosynthesis and characterization of F-FCP were performed usingF-FPMA for coordination with the cisplatin-aqua complex. Automated radiosynthesis of F-FCP was optimized on the basis of manual synthesis procedures. The stability ofF-FCP was verified using high-performance liquid chromatography. F-FCP was evaluated using ex vivo biodistribution and in vivo PET imaging in non-tumor-bearing animals as well as in KB-3-1 and COLO-205 tumor xenograft-bearing nude mice. In vitro cytotoxicity studies demonstrated that F-FCP has an antitumor activity profile similar to that of the parent drug carboplatin. In vivo plasma and urine stability analysis showed intactF-FCP at 24 h after injection. PET imaging and biodistribution studies showed fast clearance from blood and major accumulation in the kidneys, indicating substantial renal clearance of F-FCP. UsingF-FCP PET, we could image and identify the intratumor drug profile. Our results demonstrated thatF-FCP, like carboplatin, retains antitumor activity in various cell lines. F-FCP could be a useful imaging tool for measuring the intratumor drug distribution. This strategy of using a new therapeutic carboplatin derivative to quantify and track platinum drugs in tumors using PET has the potential to translate into a clinically useful imaging tool for individual patients.

“…Radiolabeled platinum drugs have been synthesized with platinum radioisotopes as radioactive drugs for imaging and therapy studies. Areberg et al (11) studied the antitumor effect of radioactive cisplatin ( 191 Pt) in tumor-bearing nude mice and demonstrated that 191 Pt-cisplatin was more effective than unlabeled cisplatin in retarding tumor growth. Patient studies by Areberg et al (22,23) demonstrated the use of cisplatin radiolabeled with 191 Pt, 193m Pt, or 195m Pt to visualize the uptake of platinum in tumor and tissues noninvasively after cisplatin treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Previous strategies for synthesizing radiolabeled platinum drugs, such as cisplatin and carboplatin, relied on the incorporation of a platinum isotope (e.g., 191 Pt, 195m Pt) as its chloride salt early in drug synthesis (11)(12)(13)(14). These studies provided valuable in vivo data, but this approach was not clinically translatable because of limited platinum radioisotope availability, long radiosynthesis, and logistic cost.…”

mentioning

confidence: 99%

¹⁸F-Labeled Carboplatin Derivative for PET Imaging of Platinum Drug Distribution

¹

,

²

,

³

et al. 2017

View full text Add to dashboard Cite

Increasing evidence indicates that reduced intracellular drug accumulation is the parameter most consistently associated with platinum drug resistance, emphasizing the need to directly measure the intratumor drug concentration. In the era of precision medicine and with the advent of powerful imaging and proteomics technologies, there is an opportunity to better understand drug resistance by exploiting these techniques to provide new knowledge on drug-target interactions. Here, we contribute to this endeavor by reporting on the development of an F-labeled carboplatin derivative (F-FCP) that has the potential to image drug uptake and retention, including intratumoral distribution, by PET. Fluorinated carboplatin (F-FCP) was synthesized using F-labeled 2-(5-fluoro-pentyl)-2-methyl malonic acid (F-FPMA) as the labeling agent to coordinate with the cisplatin-aqua complex. It was then used to treat cell lines and compared with cisplatin and carboplatin at different concentrations. Manual radiosynthesis and characterization of F-FCP were performed usingF-FPMA for coordination with the cisplatin-aqua complex. Automated radiosynthesis of F-FCP was optimized on the basis of manual synthesis procedures. The stability ofF-FCP was verified using high-performance liquid chromatography. F-FCP was evaluated using ex vivo biodistribution and in vivo PET imaging in non-tumor-bearing animals as well as in KB-3-1 and COLO-205 tumor xenograft-bearing nude mice. In vitro cytotoxicity studies demonstrated that F-FCP has an antitumor activity profile similar to that of the parent drug carboplatin. In vivo plasma and urine stability analysis showed intactF-FCP at 24 h after injection. PET imaging and biodistribution studies showed fast clearance from blood and major accumulation in the kidneys, indicating substantial renal clearance of F-FCP. UsingF-FCP PET, we could image and identify the intratumor drug profile. Our results demonstrated thatF-FCP, like carboplatin, retains antitumor activity in various cell lines. F-FCP could be a useful imaging tool for measuring the intratumor drug distribution. This strategy of using a new therapeutic carboplatin derivative to quantify and track platinum drugs in tumors using PET has the potential to translate into a clinically useful imaging tool for individual patients.

“…Among various types of radiosensitizers, platinum-based (Pt) drugs belong to a class of radiosensitizers that influence the nature or repair of DNA damage 17 . Moreover, Pt-based drugs have also been investigated as radiotherapeutics by incorporation of radioactive platinum isotopes [18][19][20] . The incorporation of radioactive Pt atoms further enhances the therapeutic properties of Pt-based drugs 21,22 .…”

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confidence: 99%

Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity

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et al. 2020

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platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks. Herein, we aimed to design radioactive bisphosphonate-functionalized platinum (195m Pt-BP) complexes to confirm preferential accumulation of these pt-based drugs in metabolically active bone. In vitro nMR studies revealed that release of pt from pt Bp complexes increased with decreasing pH. Upon systemic administration to mice, Pt-BP exhibited a 4.5-fold higher affinity to bone compared to platinum complexes lacking the bone-seeking bisphosphonate moiety. these pt-Bp complexes formed less pt-DnA adducts compared to bisphosphonate-free platinum complexes, indicating that in vivo release of pt from pt-Bp complexes proceeded relatively slow. Subsequently, radioactive 195m pt-Bp complexes were synthesized using 195m pt(no 3) 2 (en) as precursor and injected intravenously into mice. Specific accumulation of 195m pt-Bp was observed at skeletal sites with high metabolic activity using micro-Spect/ct imaging. Furthermore, laser ablation-ICP-MS imaging of proximal tibia sections confirmed that 195m pt Bp colocalized with calcium in the trabeculae of mice tibia. Most types of tumors, i.e. breast, prostate, lung, kidney, and thyroid, metastasize to bone since its physiological environment facilitates the formation and growth of cancer cells 1,2. These metastases affect healthy bone, which then become the primary cause of mortality 3. Distant metastases are the leading cause of death for both breast and prostate cancer patients, with 65-75% and 90% of these patients developing bone metastases in advanced stages, respectively 4,5. Bone metastases are often associated with accelerated bone resorption leading to complications such as skeletal-related events (SREs), bone pain or hypercalcemia 6,7. Unfortunately, current treatments for bone metastases are limited. Bisphosphonates (BP) and denosumab are most commonly used for palliative treatment to prevent or limit SREs 8. Although such treatments inhibit osteoclast activity and prevent the progression of metastases, they do not kill cancer cells effectively and do not improve the quality of life of patients substantially 9. Consequently, the development of effective therapies to treat bone metastases remains a major clinical challenge.

“…3 In another in vivo study, by our group, the cytotoxic effect of 191 Pt-cisplatin was investigated in nude mice carrying human squamouscell carcinoma tumors. 4 The results indicated that 191 Pt-cisplatin was more effective than nonradioactive cisplatin in retarding tumor growth; it could be estimated that 5 mg/kg of 191 Pt-cisplatin (80 MBq/mg) would correspond to 9 mg/kg of nonradioactive cisplatin.…”

Section: Introductionmentioning

confidence: 99%

Comparative Renal, Hepatic, and Bone Marrow Toxicity of Cisplatin and Radioactive Cisplatin (¹⁹¹Pt) in Wistar Rats

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et al. 2006

Cancer Biotherapy and Radiopharmaceuticals

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The aim of the study was to investigate the possibility to increase the therapeutic gain of the cytotoxic agent, cisplatin, by incorporation of radioactive platinum. In this study, we investigated how organs at risk (i.e., kidneys, bone marrow, and liver) are affected by treatment with 191Pt-cisplatin, compared to treatment with conventional cisplatin. Rats (total, n = 69) were divided into three groups and given 5 mg/kg 191Pt-cisplatin and 5 mg/kg nonradioactive cisplatin or saline. The weight of the animals and blood samples, including analysis of creatinine, bilirubin, alanine and aspartate aminotransferases and platelet count, was followed for 6 weeks after treatment. Histopathology examinations of kidney and liver tissues were performed. An initial decrease in weight gain was seen from 3 days after treatment with cisplatin and 191Pt-cisplatin and for 1 week onward; thereafter, the weight gain continued, following the same pattern as for the control group. Concentration of plasma creatinine was increased for both cisplatin groups but with no significant difference between treatment groups. No other significant differences in effect parameters were found. There was no increase in toxicity for radioactive cisplatin on liver, kidneys, and bone marrow, compared to conventional cisplatin. Further experimental and clinical studies on preparations of this type are thus warranted.

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