Response to Salvage Treatment in Recurrent Ovarian Cancer Treated Initially With Paclitaxel and Platinum-Based Combination Regimens

Roland, Phillip Y.; Barnes, Mack N.; Niwas, Santosh; Robertson, Matthew; Alverez, R.; Austin, J. Max; Kilgore, Larry C.; Partridge, Edward E.

doi:10.1097/00006254-199807000-00016

Cited by 2 publications

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“…The construction of the molecule began with the synthesis of the BBN [7][8][9][10][11][12][13] segment which, upon completion, was ligated to the PEG linker through both solidand solution-phase techniques (Scheme 1). The BBN/ GRP receptor ligand peptide was made by solid-phase peptide synthesis (SPPS) through the Fmoc protocol 21 and on a Rink amide resin.…”

Section: Chemistrymentioning

confidence: 99%

“…In solution, the cleaved peptide was attached to Fmoc-PEG-NHS in dry DMF and in the presence of N,N-diisopropyl ethylamine (DIEA). The homogeneity of the PEG-BBN [7][8][9][10][11][12][13] conjugate was determined unambiguously by matrixassisted laser desorption-ionization time-of-flight mass spectrometry (MALDI MS) when a single group of peaks in the expected MW range (mean 4023 Da) was observed. Ligation of this molecule to paclitaxel pharmacophore (step vi) was carried out by activation of paclitaxel-2′-succinate (3) with 2′-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ) 23 and subsequent reaction with PEG-peptide in DMF.…”

Section: Chemistrymentioning

confidence: 99%

“…10,11 Reported side effects of the drug include neutropenia, mucositis, and cardiac and neurological toxicities in addition to hypersensitivity. [12][13][14][15][16] It would be highly desirable, therefore, to develop a mechanism through which a soluble paclitaxel derivative could be delivered specifically to the site of the disease in a targeted fashion. Possible advantages of such an approach may include (i) elimination of allergenic surfactants from the formulation due to increased solubility, (ii) efficient delivery of the drug to micrometastatic tumors, and (iii) reduction of the administered dose as a result of site-specific delivery of the drug.…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, we synthesized a ternary conjugate consisting of paclitaxel (PTX), poly(ethylene glycol) (PEG), and a bombesin (BBN)/gastrin-releasing peptide (GRP) receptor-recognizing peptide (BBN [7][8][9][10][11][12][13]) 20 as the first member of a series of soluble tumor-targeting paclitaxel derivatives (Scheme 1). These novel molecules were designed based on the premise that the soluble conjugate will be guided by the receptor-specific peptide to bind to tumor cell surface receptors, and that after internalization, the paclitaxel-PEG bond will be hydrolytically and/or enzymatically cleaved to release the cytotoxic agent.…”

Section: Introductionmentioning

confidence: 99%

“…The resulting conjugate, designated , was soluble to the upper limit of tested concentrations (250 mg/mL). The conjugate completely retained the receptor binding properties of the attached peptide as compared with those of the unconjugated BBN [7][8][9][10][11][12][13]. In experiments with NCI-H1299 human nonsmall cell lung cancer cells, the cytotoxicity of the PTXPEGBBN[7-13] conjugate at a 15 nM dose was enhanced by a factor of 17.3 for 24 h and 10 for 96 h exposure times, relative to paclitaxel.…”

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Paclitaxel Derivatives for Targeted Therapy of Cancer: Toward the Development of Smart Taxanes

et al. 1999

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The pharmacologic efficacy of the promising antitumor agent paclitaxel (Taxol) may be potentially enhanced through derivatization of the drug to a water-soluble tumor-recognizing conjugate. This work reports the design and synthesis of the first tumor-directed derivative of paclitaxel. A 7-amino acid synthetic peptide, BBN[7-13], which binds to the cell surface bombesin/gastrin-releasing peptide (BBN/GRP) receptor, was conjugated to the paclitaxel-2'-hydroxy function by a heterobifunctional poly(ethylene glycol) linker. The resulting conjugate, designated PTXPEGBBN[7-13], was soluble to the upper limit of tested concentrations (250 mg/mL). The conjugate completely retained the receptor binding properties of the attached peptide as compared with those of the unconjugated BBN[7-13]. In experiments with NCI-H1299 human nonsmall cell lung cancer cells, the cytotoxicity of the PTXPEGBBN[7-13] conjugate at a 15 nM dose was enhanced by a factor of 17.3 for 24 h and 10 for 96 h exposure times, relative to paclitaxel. The IC(50) of the conjugate, tested against the same cell line, was lower than the free drug by a factor of 2.5 for both 24 h and 96 h exposures. These results describe, for the first time, the design and synthesis of a soluble tumor-directed paclitaxel prodrug which may establish a new mode for the utilization of this drug in cancer therapy.

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Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Paclitaxel Derivatives for Targeted Therapy of Cancer: Toward the Development of Smart Taxanes

et al. 1999

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Synthesis and Biological Evaluation of Paclitaxel−C225 Conjugate as a Model for Targeted Drug Delivery¹

et al. 2003

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Tumor-targeted drug delivery is an attractive strategy in cancer treatment. We have previously reported a paclitaxel model conjugate using a bombesin receptor-recognizing peptide in which the drug cytotoxicity against H1299 human nonsmall cell lung cancer was enhanced compared to unconjugated taxol. In an effort to expand the development of tumor-recognizing taxanes, paclitaxel (PTX, taxol) was conjugated to the anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (MAb) Erbitux (C225) to serve as a model MAb-mediated drug delivery compound. Thus, paclitaxel was derivatized at its 2'-hydroxy function by introduction of a succinate linker, and the carboxyl group of the latter was covalently attached to C225 through amide bond formation. The final product conjugate (PTXC225) was analyzed mass spectrometrically for assessment of the drug-to-antibody ratios. Cytotoxicity screening of the drug-antibody conjugate against A431, UM-SCC-1, and UM-SCC-6 cells indicated an enhancement in cytocidal effect of paclitaxel as compared to those of the free drug, the intact antibody, and a physical mixture of the two (the controls). In A431 cells, the conjugate showed 25.2% +/- 2.2% of apoptosis induction as compared to little or no apoptosis caused by the controls. Biodistribution analysis of the PTXC225 in tumor-implanted nude mice and a tyrosine-kinase assay showed that conjugation of the drug did not interfere with the immunoreactivity of the antibody. The 24-h tumor uptake of C225 and PTXC225 were 11.7% +/- 6.0% and 7.1% +/- 3.6% of the injected dose per gram of tissue (%ID/g), respectively, which were not significantly different. Also, in A431-implanted nude mice, the conjugate and C225 showed tumor growth inhibition effects of 57.2% and 41.2%, respectively, against a saline-treated control, which were not significantly different from each other. This lack of difference in the in vivo antitumor activity of the MAb-delivered drug and free PTX may be due to either a relatively low dose of the antibody-delivered drug (346 microg/kg), or an untimely release of it, or both. The tumor growth inhibition pattern of the conjugate, however, was identical to that of C225, indicating that the attachment of PTX did not affect the antigen-binding and growth inhibitory features of the MAb. These preliminary results demonstrate the potential of tumor-targeted delivery of taxol as a promising strategy in cancer treatment and warrant further work to develop more suitable drug-MAb linkers as well as improved dosage and treatment protocols.

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Response to Salvage Treatment in Recurrent Ovarian Cancer Treated Initially With Paclitaxel and Platinum-Based Combination Regimens

Cited by 2 publications

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Paclitaxel Derivatives for Targeted Therapy of Cancer: Toward the Development of Smart Taxanes

Paclitaxel Derivatives for Targeted Therapy of Cancer: Toward the Development of Smart Taxanes

Synthesis and Biological Evaluation of Paclitaxel−C225 Conjugate as a Model for Targeted Drug Delivery¹

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Response to Salvage Treatment in Recurrent Ovarian Cancer Treated Initially With Paclitaxel and Platinum-Based Combination Regimens

Cited by 2 publications

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Paclitaxel Derivatives for Targeted Therapy of Cancer: Toward the Development of Smart Taxanes

Paclitaxel Derivatives for Targeted Therapy of Cancer: Toward the Development of Smart Taxanes

Synthesis and Biological Evaluation of Paclitaxel−C225 Conjugate as a Model for Targeted Drug Delivery1

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Synthesis and Biological Evaluation of Paclitaxel−C225 Conjugate as a Model for Targeted Drug Delivery¹