Preclinical Antitumor Activity of a Novel Folate-Targeted Dual Drug Conjugate

Leamon, Christopher P.; Reddy, Joseph A.; Vlahov, Iontcho R.; Westrick, Elaine; Dawson, Alicia; Dorton, Ryan; Vetzel, Marilynn; Santhapuram, Hari Krishna R.; Wang, Yu

doi:10.1021/mp070049c

Cited by 103 publications

(90 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Preclinical (animal) imaging studies have been performed with normal and M109 tumor-bearing BALB/c mice (19,20). These studies showed scintigraphically detectable uptake in FR1 tumors placed intraperitoneally or subcutaneously.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Exploratory Study of ^99mTc-EC20 Imaging for Identifying Patients with Folate Receptor–Positive Solid Tumors

Fisher¹,

Siegel²,

Edell³

et al. 2008

J Nucl Med

137

123

View full text Add to dashboard Cite

99m Tc-EC20 is a folate receptor (FR)-targeted imaging agent consisting of the vitamin folate conjugated to 99m Tc. FR is expressed on a variety of epithelial cancers, with advanced cancers often expressing FR at significantly higher levels than earlier stages of the disease. The goals of this pilot study were to determine the percentages of various solid tumors that accumulate 99m Tc-EC20 in vivo and to correlate 99m Tc-EC20 uptake with immunohistochemistry (IHC) analysis of FR expression in available biopsied tumor tissue. Methods: A total of 154 patients with proven or suspected cancer and at least one lesion of $1.5 cm underwent imaging with 99m Tc-EC20. The majority of these patients (77%) had a diagnosis of renal cell carcinoma. The remaining patients had a variety of other solid tumors. Whole-body planar images were obtained 1-2 h after injection, followed by SPECT of the region containing index lesions. The uptake of 99m Tc-EC20 in tumors was scored as no uptake, mild uptake, or marked uptake. The resultant 99m Tc-EC20 data were analyzed for correlation with the expression of the a-isoform of FR, as determined by IHC analysis, in tissue available from prior or subsequent surgery or biopsy. Results: The administration of 99m Tc-EC20 was well tolerated. Tumors with increased 99m Tc-EC20 uptake were identified in 68% of patients, and IHC results were positive for the expression of the a-isoform of FR in 67% of patients. The agreement between methods was 61% overall (k 5 0.096; 95% confidence interval 5 20.085 to 0.277), with 72% agreement of positive results and 38% agreement of negative results. Conclusion: In vivo imaging with 99m Tc-EC20 identified approximately two thirds of patients as having FR-positive tumors. Agreement between imaging and in vitro IHC was poor but was potentially confounded by a lack of correlation between the time of tissue sampling and the time of 99m Tc-EC20 imaging, the heterogeneous expression of FR in metastatic lesions from the same patient, and the inability to detect the b-isoform of FR by IHC. This pilot study of 99m Tc-EC20 scintigraphy indicates that the agent is safe and well tolerated and that this noninvasive procedure may have utility in selecting patients likely to benefit from FR-targeted therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Various FR-targeted therapies intended to deliver potent cytotoxic antitumor agents to cells that selectively express FR are currently under development (17)(18)(19).…”

mentioning

confidence: 99%

Exploratory Study of ^99mTc-EC20 Imaging for Identifying Patients with Folate Receptor–Positive Solid Tumors

Fisher¹,

Siegel²,

Edell³

et al. 2008

J Nucl Med

137

123

View full text Add to dashboard Cite

show abstract

“…The relative affinity of EC0305 was determined according to a previously published procedure (29). FR quantitation.…”

Section: Methodsmentioning

confidence: 99%

Folate Targeting Enables Durable and Specific Antitumor Responses from a Therapeutically Null Tubulysin B Analogue

et al. 2008

Self Cite

View full text Add to dashboard Cite

The membrane-bound high-affinity folate receptor (FR) is highly expressed on a wide range of primary and metastatic human cancers, such as those originating in ovary, lung, breast, endometrium, kidney, and brain. Because folatelinked conjugates bind to and become internalized within FR-expressing cells (similar to that of free folic acid), we explored the possibility of using the folate ligand to target a potent, semisynthetic analogue of the microtubule inhibitor tubulysin B to FR-enriched tumors. When tested in vitro, a novel folate conjugate, herein referred to as EC0305, was found to specifically inhibit the growth of a panel of FR-positive cell lines (IC 50 range, 1-10 nmol/L) in a dosedependent manner, whereas cells lacking FR expression were unaffected. The potency of EC0305 was also confirmed against a human KB xenograft-nu/nu mouse cancer model. Here, a brief three times per week, 2-week regimen yielded remarkable antitumor activity (100% tumor-free animals) without causing significant weight loss or major organ tissue degeneration. In contrast, antitumor activity was completely abolished in EC0305-treated animals that were co-dosed with an excess of a nontoxic folate-containing analogue, thereby confirming that the antitumor effect of this agent was mediated by FRs. The advantage provided by folate conjugation was further proved by the untargeted free drug, which was found to be completely inactive at both tolerable and highly toxic dose levels. Collectively, these results show that this potent antiproliferative tubulysin compound can be specifically delivered to FR-positive tumors to provide substantial therapeutic benefit using well-tolerable dosing regimens. [Cancer Res 2008;68(23):9839-44]

show abstract

“…As a result, "folate targeting" has been successfully applied toward the delivery of a wide variety of therapeutic-and imaging-based agents to tumors that express the FR protein (9)(10)(11)(12). Compared with their nontargeted counterparts, folic acid-bearing drugs and delivery systems have repeatedly shown greater cancer cell specificity and selectivity in numerous preclinical studies (13)(14)(15)(16)(17)(18)(19)(20). Hence, this targeting strategy leads to improvements in the safety and efficacy of anticancer agents, resulting in an increased therapeutic advantage.…”

Section: Introductionmentioning

confidence: 99%

Rational Combination Therapy of Vintafolide (EC145) with Commonly Used Chemotherapeutic Drugs

Reddy

Dorton

Bloomfield

et al. 2014

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: When evaluated in patients with ovarian and other cancer, vintafolide (EC145), a potent folatetargeted vinca alkaloid conjugate, displayed a toxicity profile that seemed to be nonoverlapping with many standard-of-care cancer therapeutics. It was, therefore, hypothesized that combining vintafolide with certain approved anticancer drugs may afford greater therapeutic efficacy compared with single-agent therapy. To explore this concept, vintafolide was evaluated in combination with pegylated liposomal doxorubicin (PLD; DOXIL), cisplatin, carboplatin, paclitaxel, docetaxel, topotecan, and irinotecan against folate receptor (FR)-positive models.Experimental Design: FR-expressing KB, M109, IGROV, and L1210 cells were first exposed to graded concentrations of vintafolide, either alone or in combination with doxorubicin (active ingredient in PLD), and isobologram plots and combination index values generated. The vintafolide combinations were also studied in mice bearing various FR-expressing tumors.Results: Vintafolide displayed strong synergistic activity against KB cells when combined with doxorubicin, and no less-than-additive effects resulted when tested against M109, IGROV, and L1210 cells. In contrast, when either desacetylvinblastine hydrazide (DAVLBH; the vinca alkaloid moiety in vintafolide) or vindesine (the vinca alkaloid most structurally similar to DAVLBH) were tested in combination with doxorubicin, less-than-additive antitumor effects were observed. In vivo, all vintafolide drug combinations produced far greater antitumor effect (complete responses and cures) compared with the single agents alone, without significant increase in overall toxicity. Importantly, these benefits were not observed with combinations of PLD and DAVLBH or vindesine.Conclusions: On the basis of these encouraging preclinical results, clinical studies to evaluate vintafolide drug combination therapies are now under way.

show abstract

Preclinical Antitumor Activity of a Novel Folate-Targeted Dual Drug Conjugate

Cited by 103 publications

References 36 publications

Exploratory Study of ^99mTc-EC20 Imaging for Identifying Patients with Folate Receptor–Positive Solid Tumors

Exploratory Study of ^99mTc-EC20 Imaging for Identifying Patients with Folate Receptor–Positive Solid Tumors

Folate Targeting Enables Durable and Specific Antitumor Responses from a Therapeutically Null Tubulysin B Analogue

Rational Combination Therapy of Vintafolide (EC145) with Commonly Used Chemotherapeutic Drugs

Contact Info

Product

Resources

About

Preclinical Antitumor Activity of a Novel Folate-Targeted Dual Drug Conjugate

Cited by 103 publications

References 36 publications

Exploratory Study of 99mTc-EC20 Imaging for Identifying Patients with Folate Receptor–Positive Solid Tumors

Exploratory Study of 99mTc-EC20 Imaging for Identifying Patients with Folate Receptor–Positive Solid Tumors

Folate Targeting Enables Durable and Specific Antitumor Responses from a Therapeutically Null Tubulysin B Analogue

Rational Combination Therapy of Vintafolide (EC145) with Commonly Used Chemotherapeutic Drugs

Contact Info

Product

Resources

About

Exploratory Study of ^99mTc-EC20 Imaging for Identifying Patients with Folate Receptor–Positive Solid Tumors

Exploratory Study of ^99mTc-EC20 Imaging for Identifying Patients with Folate Receptor–Positive Solid Tumors