Paclitaxel receptors

Yen WC, Corpuz MR, Prudente RY, Cooke TA, Bissonnette RP, Negro-Vilar A, Lamph WW (2004) A selective retinoid X receptor agonist bexarotene (Targretin) prevents and overcomes acquired paclitaxel (Taxol) resistance in human non-small cell lung cancer. Clin Cancer Res 10(24) 8656-8664. 

Stevens PJ, Sekido M, Lee RJ. A folate receptor-targeted lipid nanoparticle formulation for a lipophilic paclitaxel prodrug. Pharm Res 2004 21 2153. 

Other anticancer agents have distinct mechanisms paclitaxel and its relatives target microtubules as do the vinca alkaloids. Antiestrogens and antiandrogens target estrogen and androgen receptors. 

Trastuzumab is licensed for the treatment of early breast cancer that overexpresses human epidermal growth factor receptor-2 (HER2). It may be administered as monotherapy or in combination with, for example, paclitaxel, docetaxel (taxanes) or anastrozole (aromatase inhibitors). Since trastuzumab can cause cardiotoxicity, concomitant use with anthracyclines such as... 

Montgomery RB, Guzman J, O Rourke DM, Stahl WL. Expression of oncogenic epidermal growth factor receptor family kinases induces paclitaxel resistance and alters beta-tubulin isotype expression. J Biol Chem 2000 275 17,358-17,363. 

Aprepitant (Emend) [Centrally Acting Antiemetic] Uses Pre-vents N/V assoc w/ emetogenic CA chemo (eg, cisplatin) (use in combo w/ other antiemetics) Action Substance P/neurokinin l(NKi) receptor antagonist Dose 125 mg PO day 1, 1 h before chemo, then 80 mg PO qAM days 2 3 Caution [B, /-] Contra Use w/ pimozide, Disp Caps SE Fatigue, asthenia, hiccups Interactions T Effects W/ clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin T effects OF alprazolam, astem-izole, cisapride, dexamethasone, methylprednisolone, midazolam, pimozide, terfe-nadine, triazolam, chemo agents, eg, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine, vinorelbine i effects W/ paroxetine,... 

Trastuzumab (Herceptin) [Antineeplastic/Monoover express the HERlIneu. protein breast CA adjuvant, w/ doxorubicin, cyclophosphamide, and paclitaxel if pt HER2/neu(+) Action MoAb binds human EGF receptor 2 protein HER2) mediates cellular cytotox Dose Per protocol, typical 2 mg/kg/IV/wk Caution [B, ] CV dysfxn, alla-gy/inf Rxns Contra Live vaccines Disp Inj SE Anemia, cardiomyopathy, nephrotic synd, pneumonitis Interactions t Risk of cardiac dysfxn W/ anthracycline, cyclophosphamide, doxorubicin, epirubicin EMS Cardiomyopathy, ventricular dysfxn and pulm tox have been reported monitor for Sxs of reduced cardiac Fxn OD Sxs unknown... 

First-line treatment of her metastatic breast cancer should therefore incorporate the monoclonal antibody trastuzumab (Herceptin). NICE (2002b) have issued a technology appraisal on the use of trastuzumab in metastatic breast cancer which states that trastuzumab be used in combination with paclitaxel for women with tumours with excessive human epidermal growth factor receptor 2 (HER2) at levels of 3+ who have not had chemotherapy for metastatic breast cancer and for whom anthracycline treatment is inappropriate. ... 

Liu et al. reported in 2003 on the synthesis and cytotoxicities of 3 -cyclopropane analogs with both Tot- and 7(3-OH and 2 R)- and 2 (5)-OH functionalities. Both 2 - R) isomers were 400 times less active than paclitaxel in A2780 cancer cell assays, and 2 -(5) isomers displayed even weaker cytotoxicities. Unsatisfactory results may have developed from small volumes of the 3 -cycloprapane, which is similar to 3 -methyl in 9(R)-dihydro paclitaxels as reported earlier. As mentioned, larger groups such as isobutyl or isobutenyl may interact with the receptor better. 

A paclitaxel analog with a C4—C6 bridge, built on the connection of a carboxyl group of 4-glutarate and the hydroxyl group of 6a-hydroxyacetate, was found almost inactive. This observation was in accordance with the hypothesis that the Southern Hemisphere of paclitaxel binds to the tubulin receptor. 

What conformation pachtaxel adopts when it binds to its receptor tubulin is an important question to be answered. There are many efforts on the constmction of common pharmacophore for several other antitubuhn natural products sharing the same binding site with paclitaxel. 

In a hypothetical common pharmacophore for a nonaromatic analog of paclitaxel and other antimicrotubule agents, it was proposed that the baccatin core structure is not essential to activity but it acts as a scaffold for the substituents. A more recent report noted the importance of the baccatin structure and the usefulness of C-13 and C-2 side chains in enhancing the binding of taxoid to its receptor. ... 

The nonpolar conformation, also termed the extended conformation, was established on the basis of NMR data of paclitaxel and docetaxel in nonpolar solvent such as chloroform, as well as crystallographic data of docetaxel. Its presence was experimentally confirmed by fluorescence and solid-state NMR spectroscopies (REDOR). Wang et al. selected 20 amino acid residues and paclitaxel conformation in CDCI3 as a starting point to construct a mini-receptor model for both paclitaxel and epothilone, a family of macrocyclic antimitotic agents that was assumed to bind to the same site on tubulin as paclitaxel. This model has been... 

Some reports focused on conformation of the C-13 phenylisoserine side chain of paclitaxel. From the point of view of setting up an active conformation model for paclitaxel, a drug-receptor complex rather than a part of the drug, for example, the C-13 side chain, will be more informative and meaningful. 

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