Design and regioselective synthesis of a new generation of targeted chemotherapeutics. Part 1: EC145, a folic acid conjugate of desacetylvinblastine monohydrazide

Vlahov, Iontcho R.; Santhapuram, Hari Krishna R.; Kleindl, Paul J.; Howard, Steven J.; Stanford, Katheryn M.; Leamon, Christopher P.

doi:10.1016/j.bmcl.2006.07.030

Cited by 121 publications

(99 citation statements)

References 20 publications

(4 reference statements)

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“…Under these conditions, we found that vintafolide combined extremely well (additive to synergistic effects) with doxorubicin in each of four FR-positive cell lines tested. When evaluated in vivo, a suboptimal dose of vintafolide was commonly used because chances of observing an enhanced therapeutic effect of any combination regimen would have been limited because of the potential curative activity of "optimal" single-agent vintafolide therapy (18,19,25). Our results showed that when combined with PLD, vintafolide produced superior antitumor activity compared with the individual drugs administered as single agents.…”

Section: Discussionmentioning

confidence: 73%

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

Reddy

Dorton

Bloomfield

et al. 2014

Clinical Cancer Research

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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.

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Section: Discussionmentioning

confidence: 73%

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

Reddy

Dorton

Bloomfield

et al. 2014

Clinical Cancer Research

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“…Furthermore, EC145-treated animals did not lose any significant weight throughout the dosing period; and no durable tissue damage was observed upon histologic examination of liver, spleen, kidney, lung, and heart as done on animals euthanized 80 to 120 days after EC145 administration, which is consistent with our earlier report. 2 EC145 is constructed with an all L-peptide spacer conjugated to the g-carboxylic acid of folate's glutamyl residue (24). To better understand the importance of the stereochemical configuration of the linker with regard to its overall pharmacology, the all-D enantiomer (EC0260) was synthesized.…”

Section: Resultsmentioning

confidence: 99%

“…Peptide synthesis reagents were purchased from NovaBiochem and Bachem. EC145 was synthesized as previously described (24). EC20 (FolateScan; Pte-D-gGlu-hDpr-Asp-Cys) was prepared as previously described (25).…”

Section: Methodsmentioning

confidence: 99%

Preclinical Evaluation of EC145, a Folate-Vinca Alkaloid Conjugate

et al. 2007

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We recently developed a new group of folate-conjugated Vinca alkaloids, one of which, EC145, emerged as a candidate for clinical development. Brief treatment of nude mice bearing f100 mm 3 folate receptor-positive human xenografts led to complete response (CR) in 5/5 mice and cures (i.e., remission without a relapse for >90 days post-tumor implantation) in 4/5 mice. Multiple CRs and cures were also noted when EC145 was used to treat mice initially bearing tumors as large as 750 mm 3 . Likewise, complete cures (5/5) resulted following the treatment of an aggressive folate receptor-positive J6456 lymphoma model. The activity of EC145 was not accompanied by noticeable weight loss or major organ tissue degeneration. Furthermore, no significant antitumor activity (0/5 CR) was observed in EC145-treated animals that were co-dosed with an excess of a benign folate ligand, thus demonstrating the target-specific activity of EC145. The enhanced therapeutic index due to folate conjugation was also evidenced by the fact that the unconjugated drug (desacetylvinblastine monohydrazide) was found to be completely inactive when administered at nontoxic dose levels and only marginally active when given at highly toxic dose levels. Subsequent dose regimen studies confirmed that EC145 given on a more frequent, qdx5 schedule resulted in the most effective antitumor response as compared with an equivalent total dose given on thrice-or single-injection-per-week schedule. Taken together, these studies show that EC145 has significant antiproliferative activity and tolerability, thus lending support to an ongoing phase 1 trial for the treatment of advanced malignancies. [Cancer Res 2007;67(9):4434-42]

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“…41 In brief, commercially available rapamycin was first converted into a pyridinyldisulfanyl-activated derivative while reacted with the heterobifunctional cross-linker 2-[benzotriazole-1-yl-(oxycarbonyloxy)-ethyldisulfanyl]-pyridine. The product was then reacted with the peptidic-based "folate-spacer" unit, pteroyl-gGlu-Asp-Arg-Asp-Asp-Cys.…”

Section: Ec0371 Synthesismentioning

confidence: 99%

Folate-Conjugated Rapamycin Slows Progression of Polycystic Kidney Disease

Shillingford

Leamon

Vlahov

et al. 2012

Journal of the American Society of Nephrology

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Activation of the mammalian target of rapamycin (mTOR) signaling pathway is aberrant in autosomaldominant polycystic kidney disease (ADPKD). The mTOR inhibitors, such as rapamycin, ameliorate PKD in rodent models, but clinical trials have not shown benefit, possibly as a result of low tissue concentrations of rapamycin at clinically tolerable doses. To overcome this limitation, we synthesized a folate-conjugated form of rapamycin (FC-rapa) that is taken up by folate receptor-mediated endocytosis and cleaved intracellularly to reconstitute the active drug. We found that renal cyst-lining cells highly express the folate receptor in ADPKD and mouse models. In vitro, FC-rapa inhibited mTOR activity in a dose-and folate receptor-dependent manner. Treatment of a PKD mouse model with FC-rapa inhibited mTOR in the target tissue, strongly attenuated proliferation and growth of renal cysts and preserved renal function. Furthermore, FC-rapa inhibited mTOR activity in the kidney but not in other organs. In summary, these results suggest that targeting the kidney using FC-rapa may overcome the significant side effects and lack of renal efficacy observed in clinical trials with mTOR inhibitors in ADPKD.

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Design and regioselective synthesis of a new generation of targeted chemotherapeutics. Part 1: EC145, a folic acid conjugate of desacetylvinblastine monohydrazide

Cited by 121 publications

References 20 publications

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

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

Preclinical Evaluation of EC145, a Folate-Vinca Alkaloid Conjugate

Folate-Conjugated Rapamycin Slows Progression of Polycystic Kidney Disease

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