Paclitaxel Analogs Research Articles

Paclitaxel uptake and transport in Taxus cell suspension cultures

The transport of paclitaxel in Taxus suspension cultures was studied with a fluorescence analog of paclitaxel (Flutax-2®) in combination with flow cytometry detection. Experiments were carried out using both isolated protoplasts and aggregated suspension cell cultures. Flutax-2® was shown to be greater than 90% stable in Taxus suspension cultures over the required incubation time (24h). Unlabeled paclitaxel was shown to inhibit the cellular uptake of Flutax-2®, although structurally similar taxanes such as cephalomannine, baccatin III, and 10-deacetylbaccatin III did not inhibit Flutax-2® uptake. Saturation kinetics of Flutax-2® uptake was demonstrated. These results indicate the presence of a specific transport system for paclitaxel. Suspension cells elicited with methyl jasmonate accumulated 60% more Flutax-2® than unelicited cells, possibly due to an increased cellular storage capacity following methyl jasmonate elicitation. The presence of a specific mechanism for paclitaxel transport is an important first result that will provide the basis of more detailed studies as well as the development of targeted strategies for increased paclitaxel secretion to the extracellular medium.

A novel C,D-spirolactone analogue of paclitaxel: autophagy instead of apoptosis as a previously unknown mechanism of cytotoxic action for taxoids

The design, synthesis and biological evaluation of a novel C,D-spirolactone analogue of paclitaxel is described. This is the first paclitaxel analogue without an oxetane D-ring that shows a significant cytotoxic effect (activity one order of magnitude lower than paclitaxel). More importantly, its cytotoxicity is a result of a different mechanism of action, involving mTOR inhibition-dependent autophagy instead of G(2)/M cell cycle arrest-dependent apoptosis.

Abstract A116: Stable and efficient delivery of docetaxel by micelle encapsulation using a tripodal cyclotriphosphazene amphiphile.

Abstract Docetaxel, a semi-synthetic analogue of paclitaxel, is currently one of the most important chemotherapeutic agents, since it is clinically very efficacious against a variety of tumors. Docetaxel is known to be more potent than paclitaxel, but its photo-instability causes more inconveniences in drug storage and patient treatment compared with paclitaxel. Docetaxel is solubilized in aqueous solution by formulation using a surfactant polysorbate 80 (Tween 80). Docetaxel in such a formulation named Taxotere is known to cause several adverse effects. Therefore, a great deal of efforts has been devoted to replace the surfactant polysorbate 80 with polymeric micelles composed of linear amphiphilic block copolymers. However, most of the linear block copolymers exposed commonly a few critical problems for practical application, and in particular, docetaxel-loaded polymeric micelles are not stable enough to hold the drug component in the micelle core and drug precipitates mostly within 24 h after drug loading. We have recently developed a novel class of cyclotriphosphazene micelles of a general formula [N=P(X)(Y)]3 prepared by stepwise substitutions of cyclic chlorophosphazene [N=PCl2]3 with equimolar hydrophilic (X) and hydrophobic (Y) nucleophiles in cis-nongeminal way. In particular, the tripodal amphiphiles with a methoxy poly(ethylene glycol) as a hydrophilic group and a linear oligopeptide as a hydrophobic group have been found to self-assemble into very stable spherical micelles with a mean diameter less than 10 nm and a CMC value of 5 mg/L in aqueous solution. Docetaxel micelle-encapsulated by a tripodal amphiphilile [NP(PEG750)(GlyPheLeu)2Et]3 (CP750) exhibited outstanding drug-loaded micelle stability in aqueous solution compared with the polymeric micelles assembled from linear block copolymers. Furthermore, docetaxel micelle-encapsulated by CP750 is obtainable in solvent free powder form, which is immediately soluble in any aqueous media including saline and PBS and very stable to photo-degradation even in the room light at room temperature. Docetaxel micelle-encapsulated by CP750 displayed significantly improved pharmacokinetic profile compared with Taxotere currently in clinical use. Furthermore, its in vivo xenograft trials exhibited outstanding antitumor efficacy by showing complete tumor regression against the breast cancer cells (MDA-MB-231) at a low dose of 5 mg/kg, which is only 1/3 of the optimum dose of Taxotere. Furthermore, according to the acute toxicity study, docetaxel micelle-encapsulated by CP750 exhibited a much higher LD50 value of 75 mg/kg compared with 28 mg/kg of docetaxel in Taxotere. Thus docetaxel micelle-encapsulated by CP750 has entered the stage of preclinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A116.

Drug-Tolerant Cancer Cells Show Reduced Tumor-Initiating Capacity: Depletion of CD44+ Cells and Evidence for Epigenetic Mechanisms

Cancer stem cells (CSCs) possess high tumor-initiating capacity and have been reported to be resistant to therapeutics. Vice versa, therapy-resistant cancer cells seem to manifest CSC phenotypes and properties. It has been generally assumed that drug-resistant cancer cells may all be CSCs although the generality of this assumption is unknown. Here, we chronically treated Du145 prostate cancer cells with etoposide, paclitaxel and some experimental drugs (i.e., staurosporine and 2 paclitaxel analogs), which led to populations of drug-tolerant cells (DTCs). Surprisingly, these DTCs, when implanted either subcutaneously or orthotopically into NOD/SCID mice, exhibited much reduced tumorigenicity or were even non-tumorigenic. Drug-tolerant DLD1 colon cancer cells selected by a similar chronic selection protocol also displayed reduced tumorigenicity whereas drug-tolerant UC14 bladder cancer cells demonstrated either increased or decreased tumor-regenerating capacity. Drug-tolerant Du145 cells demonstrated low proliferative and clonogenic potential and were virtually devoid of CD44+ cells. Prospective knockdown of CD44 in Du145 cells inhibited cell proliferation and tumor regeneration, whereas restoration of CD44 expression in drug-tolerant Du145 cells increased cell proliferation and partially increased tumorigenicity. Interestingly, drug-tolerant Du145 cells showed both increases and decreases in many “stemness” genes. Finally, evidence was provided that chronic drug exposure generated DTCs via epigenetic mechanisms involving molecules such as CD44 and KDM5A. Our results thus reveal that 1) not all DTCs are necessarily CSCs; 2) conventional chemotherapeutic drugs such as taxol and etoposide may directly target CD44+ tumor-initiating cells; and 3) DTCs generated via chronic drug selection involve epigenetic mechanisms.

Synthesis of novel D-seco-taxoids derived from 1-deoxybaccatin VI

New D-seco-taxoids were synthesized from 1-deoxybaccatin VI and their structures were confirmed by 1H NMR, 13C NMR, ESIMS and X-ray crystallography. The key step of the synthesis involved the opening of the oxetane ring under acid and basic conditions in order to obtain new multidrug resistance (MDR) reversal agents and new synthetic precursors of paclitaxel analogues.

A phase 1 study of BMS-275183, a novel oral analogue of paclitaxel given on a daily schedule to patients with advanced malignancies

BMS-275183 is an oral C-4 methyl carbonate analogue of paclitaxel that has the same mechanism of action, stabilization of tubulin polymerization. The present study was designed to: (i) assess the safety and tolerability of BMS-275183, and (ii) determine a suitable Phase II dose of BMS-275183 when given on a continuous daily schedule to patients with advanced solid tumor(s). This was a multi-institutional, open-label, Phase I, single-arm dose escalation study in which cohorts of eligible patients with advanced malignancies were treated with BMS-275183 orally on a continuous daily schedule. The starting dose level was 6 mg/m(2)/day administered once daily. Cohorts of 3 patients were treated at each dose level provided no dose-limiting toxicities (DLTs) were observed. Each cycle of treatment lasted 28 days. Twenty patients were enrolled in dose cohorts ranging from the initial dose level of 6 mg/m(2)/day to 18 mg/m(2)/day. Overall, the most frequent (>20% of patients) treatment-related adverse events (AEs) were nausea (40%), constipation (20%), diarrhea (20%), and fatigue (20%). There were 2 fatal events of neutropenic sepsis one each at the 15 mg/m(2)/day and 18 mg/m(2)/day dose level, respectively. There were no objective responses; 4 of 20 patients experienced stable disease. Pharmacokinetic data indicated no clear correlation between dose and exposure following daily oral administration of BMS-275183 doses between 6 and 18 mg/m(2). Substantial inter-patient variability was observed, and high drug exposure was associated with fatal neutropenic sepsis. BMS-275183 is a novel oral analogue of paclitaxel with high inter-patient variability in exposure. The lack of evidence of clinical benefit and the occurrence of two fatal events of neutropenic sepsis, coupled with high drug exposure, argues against further evaluation of BMS-275183 on a daily dosing schedule.

Synthesis and Characterization of a Fluorescent Water-Soluble Paclitaxel Prodrug

A fluorescence susceptible water-soluble paclitaxel was synthesized by a condensation reaction between PEGylated paclitaxel (namely, PP7) and 1-pyrene butyric acid (PBA) in order to obtain a better understanding of the mechanism of action of paclitaxel as well as of the environment of the paclitaxel-binding site. The reaction was performed successfully and the resulting paclitaxel was characterized by FT-NMR, analytical-HPLC, UV spectro photometry, and fluorescence spectrometry. The synthesized paclitaxel analogue showed a high susceptibility to fluorescence in both excitation and emission spectra. And we have investigated the time-resolved fluorescence behavior of them in different solvents and at different excitation wavelengths.

Abstract 4416: Pursuing semi-synthetic taxanes as antitumor agents effective against drug-resistant tumors

Abstract Despite the renowned success of Paclitaxel (Taxol) in cancer chemotherapy, it suffers from some disadvantages, especially ineffectiveness against drug-resistant tumors. About ten paclitaxel analogues have been evaluated in clinical trials worldwides, however, none of these drug candidates have shown promising results against drug-resistant tumors in clinical trials. Drug resistance, or multidrug resistance (MDR), is a complex phenomenon, in which various physiological or pathological factors are involved. It has been reasoned that targeting a single factor related to MDR may be disappointing. For patients resistant to taxane chemotherapy, overexpression of ABC transporters, especially P-glycoprotein (P-gp), as well as mutations in β-tubulin and/or overexpression of β-III subtype tubulin may account for the drug resistance. So we decided to pursue highly active paclitaxel analogues and simultaneously effective against drug-resistant tumors through targeting multiple factors related to drug resistance. We designed and synthesized some C-2, 7, 10, 13 modified paclitaxel analogues, based on the rationale at the very beginning to improve interactions with its receptor β-tubulin, as well as decrease interactions with P-gp. Those analogues were subjected to evaluations for the ligand-protein interactions with β-tubulin and P-gp, as well as antitumor activities in drug-sensitive and MDR tumor cells and tumor-bearing animal models. On the basis of a comprehensive analysis of the interactions of paclitaxel analogues with tubulin, it was found that ΔG (free energy change) for drug-tubulin binding at different positions is additive to that of the whole molecule, and the optimal modification for one molecule can be predicted from the free energy contributions of different positions. The more interesting observation for the SARs of these paclitaxel analogues is that we discovered the high affinity taxanes, although exhibiting similar dissociation constants to P-gp as paclitaxel, are still active in P-gp overexpressed MDR cells, in contrast to paclitaxel. On the basis of this observation, we reasoned that enhancement of the binding affinity of taxanes to microtubules may counteract the exportation of those molecules by P-gp from MDR tumor cells, thus make those molecules more effective against MDR. In addition, these high affinity taxanes are also effective against drug resistant tumor cells bearing β-tubulin mutations, as well as β-III overexpression tumor cells. One of the high affinity taxanes also showed effectiveness in nude mice exhibiting drug resistance phenotypes. All above results support that seeking for high affinity taxanes may be an promising approach to pursuing novel antitumor agents effective against drug resistance. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4416.

Anti-Cancer Effect of the Combination of Thiacremonone and Docetaxel by Inactivation of NF-κB in Human Cancer Cells

Abstract － Thiacremonone, the main component isolated from heated garlic ( Allium sativum L.), is inter-ested for using as a cancer preventive or therapeutic agent since garlic has been known to be useful plant in the treatment of cancers. Nuclear factor kappaB (NF-κB) is constitutively activated in the prostate cancer and activation of NF-κB is implicated in drug resistance in cancer cells. Docetaxel, a semisynthetic analog of pa-clitaxel, is an antineoplastic drug widely used for advanced various cancer. In previous studies, we found that thiacremonone inhibited activation of NF-κB in cancer cells and marcrophages. In the present study, we in-vestigated whether thiacremonone could increase susceptibility of prostate cancer cells (PC-3 and DU145) to docetaxel via inactivation of NF-κB. We found that the combination treatment of thiacremonone (50 μg/ml) with docetaxel (5 nM) was more effective in the inhibition of prostate cancer cell growth and induction of apoptosis accompanied with the significant inhibition of NF-κB activity than those by the treatment of thiacre-monone or docetaxel alone. It was also found that NF-κB target gene expression of Bax, caspase-3 and cas-pase-9 was much more significantly enhanced, but the expression of Bcl-2 was also much more significantly inhibited by the combination treatment. These results indicate that thiacremonone inhibits NF-κB, and enhan-ces the susceptibility of prostate cancer cells to docetaxel. Thus, thiacremonone could be useful as an ad-juvant anti-cancer agent.Keywords: Thiacremonone, Docetaxel, NF-κB, Apoptotic cell death, Prostate cancer

Design and development of high-drug-load paclitaxel (PTX)-antibody conjugates: Synthesis and preliminary evaluation of soluble paclitaxel (sPTX) and sPTX-cetuximab conjugates

e14634 Background: Tumor cell surface receptor-targeted therapy of cancer is an effective treatment strategy and monoclonal antibody (MAb)-drug conjugates hold promise as tumor-specific drug delivery systems. We have previously reported the synthesis and biological evaluation of paclitaxel (PTX)-MAb conjugates using the anti-EGFR MAb, cetuximab, as an agent for tumor-targeted drug delivery system (Safavy et al., Bioconjugate Chem 14:302–310, 2003). One limitation of these conjugates was a low drug load, i.e., PTX : MAb ratios of ≤4, and thereby, low target dose delivery. Attempts to synthesize conjugates with PTX : MAb of >4 failed due to their low water solubility. As the source of this problem was identified to be the highly lipophilic PTX moiety, we hypothesized that conjugation of water-soluble PTX analogues may lead to the preservation of the MAb solubility, and thus, to the preparation of conjugates with high PTX : MAb ratios. Methods: Newly available “discrete” poly(ethylene glycol) (dPEG) linkers were utilized for the synthesis of soluble PTX analogues. In contrast to the regular PEGs wit dispersed molecular weight ranges (MWs), the dPEGs are single-MW compounds which make possible the exact dose calculation for the resulting conjugates. Solid-phase peptide synthesis methodology was used to prepare a trifunctional dPEG-lysine (K) linker, which was first conjugated to PTX to yield the water-soluble drug analogue sPTXdPEGKdPEG, containing a free carboxylic acid group. Using the latter functionality, sPTXdPEGLysdPEG was covalently conjugated to cetuximab (C225) at increasing molar ratios. Cell binding assays were performed using MCF-7 human breast carcinoma cell line. Results: sPTXC225 conjugates with PTX : C225 ratios of up to 8 were synthesized through this method, which in contrast to the previously reported conjugates, demonstrated complete aqueous solubility. Cell binding assays indicated preservation of the immunoreactivity of the parent MAb in all conjugates. Conclusions: Water-soluble and high-drug-load PTX-MAbs such as sPTXC225, may be useful for targeted delivery of therapeutically effective doses of paclitaxel and warrant further investigation. No significant financial relationships to disclose.

Highly Enantioselective Organocatalytic Addition of Aldehydes to N‐(Phenylmethylene)benzamides: Asymmetric Synthesis of the Paclitaxel Side Chain and Its Analogues

Easily side-tracked: A simple route to the paclitaxel side chain and its analogues is based on the (R)-proline-catalyzed addition of aldehydes to N-(phenylmethylene)benzamides, followed by oxidation of the resulting protected alpha-hydroxy-beta-benzoylaminoaldehydes (92-99 % ee). Esterification of the subsequent phenylisoserine derivatives with baccatin III gives paclitaxel analogues (see scheme).A simple highly enantioselective organocatalytic addition of aldehydes to N-(phenylmethylene)benzamides is presented. The application of (R)-proline as the catalyst and subsequent oxidation of the protected alpha-hydroxy-beta-benzoylaminoaldehydes (92-99 % ee) gives access to esterification-ready phenylisoserine derivatives such as the protected paclitaxel (taxol) side chain. Esterification of these derivatives with baccatin III gives access to the cancer chemotherapeutic substance paclitaxel and its analogues that do not exist in nature.

Synthesis and bioactivity of a side chain bridged paclitaxel: A test of the T-Taxol conformation

A knowledge of the bioactive tubulin-binding conformation of paclitaxel (Taxol ™) is crucial to a full understanding of the bioactivity of this important anticancer drug, and potentially also to the design of simplified analogs. The bioactive conformation has been shown to be best approximated by the T-Taxol conformation. As a further test of this conclusion, the paclitaxel analog 4 was designed as a compound which has all the chemical functionality necessary for activity, but which cannot adopt the T-Taxol conformation. The synthesis and bioassay of 4 confirmed its lack of activity, and thus provided further support for the T-Taxol conformation as the bioactive tubulin-binding conformation.

The Tubulin-Bound Conformation of Paclitaxel: T-Taxol vs “PTX-NY”

Nearly 35 years after its discovery and 11 years after FDA approval of paclitaxel (PTX) as a breakthrough anticancer drug, the 3-D structure of the agent bound to its beta-tubulin target was proposed to be T-Taxol. The latter bioactive form has recently been challenged by the Ojima group with a structure, "PTX-NY" ("REDOR Taxol"), in which the C-13 side chain is proposed to adopt a different conformation and an alternative hydrogen-bonding pattern in the tubulin binding site. Previously, the two conformers were compared to show that only T-Taxol fits the PTX-derived electron crystallographic density. That work has been extended by molecular mechanics and quantum chemical methods to reveal that the PTX-NY conformation is relatively less stable, on average, by 10-11 kcal/mol. In agreement with NMR studies, an 11 ns molecular dynamics treatment for PTX in an explicit water pool locates T-Taxol along the trajectory, but not PTX-NY. Docking of various PTX conformers into the electron crystallographic binding site of tubulin demonstrates that PTX-NY cannot be accommodated unless the pocket is reorganized in violation of the experimental constraints. Finally, analysis of the structures of T-Taxol and PTX-NY for their capacity to predict the existence of superpotent PTX analogues discloses that only the former forecasts such analogues, as now established by the T-Taxol-inspired synthesis of bridged taxanes. In sum, all empirical criteria support T-Taxol as the bound conformation of PTX on beta-tubulin in microtubules.

Effect of Food on the Pharmacokinetic Behavior of the Potent Oral Taxane BMS-275183

BMS-275183 is a potent oral paclitaxel analogue that previously showed promising activity. The goal of the present trial was to investigate whether food affects the pharmacokinetics of BMS-275183. Additionally, we evaluated its pharmacokinetic variability using flat-fixed dosing compared with dosing individualized by body surface area (BSA). The patients were treated with 200 mg of BMS-275183 under fasting condition (A), after a standard low-fat meal (B), or after a high-fat meal (C). The patients were randomized to one of six treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA). The fourth (D) and consecutive weekly doses were normalized by BSA and consisted of 200 mg/m(2). Pharmacokinetic sampling was done up to 72 hours after the first four doses and analyzed with a validated liquid chromatography/mass spectrometry assay. A total of 31 patients were treated. Pharmacokinetic data were available for 26 patients (A and C), 24 patients (B), and 21 patients (D). Compared with administration under fasted conditions, a decrease of 39% and 63% in the maximal observed drug concentration was observed when BMS-275183 was administered after a low-fat and a high-fat meal, respectively. There was no change in systemic exposure as measured by the area under the plasma concentration versus time curve extrapolated to infinity (AUC(inf)). No apparent relationship was observed between AUC(inf) and BSA for either the 200 mg or the 200 mg/m(2) regimen. BMS-275183 was well tolerated with grade 3 and 4 toxicity in eight patients. One partial response was observed in a non-small cell lung cancer patient. Food intake does not affect the pharmacologic exposure to BMS-275183. BMS-275183 can be given orally by flat dosing instead of BSA-normalized dosing.

New taxanes in development

Background: Taxanes are presently widely employed for the medical treatment of cancer. However, despite the huge clinical success, these agents exhibit clinical problems related to poor drug solubility, toxicity and, in particular, drug resistance. Objective: To identify the critical points related to the process of development of novel taxanes. Methods: Publicly available data on the paclitaxel and docetaxel analogues, which have entered a clinical development phase in the last 2 years have been taken into consideration. The development involved novel formulations of paclitaxel and novel chemical entities. For each agent in each category the development phase is analysed and a synthetic comment for each category is included. Results/conclusions: Despite all the efforts, until now clinical success with the new development of taxanes has been limited. Moreover, the expected clinical introduction of epothilones could further restrict the space for development of novel taxanes. Despite these facts, some interesting concepts emerged during the process of development and could lead to successful drugs in the forthcoming years.

Pattern analysis of microtubule-polymerizing and -depolymerizing agent combinations as cancer chemotherapies

Subcellular distribution of mass can be analyzed by a technique that involves culturing cells on interferometers and digitizing their interference contours. Contour sampling resulted in 102 variables per cell, which were predictors of oncogenic transformation. Cell phenotypes can be deconstructed by use of latent factors, which represent the covariance of the real variables. The reversal of the cancer-type phenotype by a combination of microtubule-stabilizing and -depolymerizing agents was described previously. The implications of these results have been explored by clinicians who treated patients with the combination of docetaxel and vinorelbine (Navelbine). The current study was performed to determine the effects of different combinations on phenotype and in phases of the cell cycle other than mitosis. Combinations of paclitaxel with either colchicine, podophyllotoxin, nocodazole, or vinblastine caused phenotype reversal. Paclitaxel analogue, 7-deoxytaxol, by itself caused reversal. Factors #4, (filopodia), #5 (displacement and/or deep invaginations in the periphery), #8, and #12 took on values typical of normal cells, whereas the values of #7 (p21-activated kinase), and #13 (rounding up) shifted toward the cancer-type. All combinations altered microtubule arrangement at the cell edge. Delivery schedules and drug ratios used in clinical studies were subjected to analysis. Clinical response rates were better when the combination was not interspersed with a single agent (P=0.004). The results support the idea that efficacy depends upon simultaneous exposure to both agents, and suggest a novel mechanism for combination therapies. These therapies appear to restore in transformed cells some of the features of a contact-inhibited cell, and to impede progress through the cell cycle even when provided at nanomolar concentrations.

Imaging multidrug resistance with 4-[18F]fluoropaclitaxel

Multidrug resistance (MDR) is a cause of treatment failure in many cancer patients. MDR refers to a phenotype whereby a tumor is resistant to a large number of natural chemotherapeutic drugs. Having prior knowledge of the presence of such resistance would decrease morbidity from unsuccessful therapy and allow for the selection of individuals who may benefit from the coadministration of MDR-inhibiting drugs. The Tc-99m-labeled single-photon-emitting radiotracers sestamibi and tetrofosmin have shown some predictive value. However, positron-emitting radiotracers, which allow for dynamic quantitative imaging, hold promise for a more accurate and specific identification of MDRtumors.MDR-expressing tumors are resistant to paclitaxel, which is commonly used as a chemotherapeutic agent. 4-[18F]Fluoropaclitaxel (FPAC) is a PET-radiolabeled analogue of paclitaxel. Preclinical studies have shown the uptake of FPAC to be inversely proportional to tumor MDR expression. FPAC PET imaging in normal volunteers shows biodistribution to be similar to that in nonhuman primates. Imaging in a breast cancer patient showed FPAC localization in a primary tumor that responded to chemotherapy, while failure to localize in mediastinal disease corresponded with only partial response.FPAC PET imaging shows promise for the noninvasive pretreatment identification of MDR-expressing tumors. While much additional work is needed, this work represents a step toward image-guided personalized medicine.

A Phase I Safety and Pharmacologic Study of a Twice Weekly Dosing Regimen of the Oral Taxane BMS-275183

BMS-275183, an orally administered C-4 methyl carbonate paclitaxel analogue, showed promising activity in a phase I trial investigating a weekly treatment regimen, but was associated with a relatively high incidence of neuropathic side effects. The current dose escalation phase I trial was initiated to investigate whether twice weekly administration of BMS-275183 would improve its safety and tolerability. Additionally, the pharmacokinetics and possible antitumor activity were studied. A cycle consisted of 4 weeks (i.e., eight twice weekly oral doses). The starting dose was 60 mg/m(2) and the dose was increased by 20 mg/m(2) increments. Cohorts consisted of three patients and were expanded to at least six patients when toxicity was encountered. Plasma pharmacokinetics were done on days 1 and 15. A total of 38 patients were enrolled. The maximum tolerated dose was 100 mg/m(2) twice weekly. Seventeen patients were treated at the maximum tolerated dose; 3 of 17 patients experienced a dose-limiting toxicity, consisting of a combination of neutropenia, neuropathy, and diarrhea. BMS-275183 seemed to have a considerably lower incidence of neuropathic side effects compared with the weekly treatment regimen. Confirmed partial responses were observed in two patients with non-small cell lung cancer, one patient with prostate cancer, and one patient with melanoma. In addition, a long-lasting prostate-specific antigen response was observed in a patient with prostate carcinoma with nonmeasurable disease. BMS-275183 is preferably given in a twice weekly regimen and has considerable antitumor activity. A phase II trial in non-small cell lung cancer using the twice weekly schedule has been initiated.

Inhibition of NF-kB/Rel by Paclitaxel in Mouse Macrophages

We demonstrate that paclitaxel, an antitumor agent derived from yew tree, inhibits LPS- and <TEX>$IFN-{\gamma}$</TEX>-induced NF-kB/Rel activation in RAW 264.7 cells. Previously, paclitaxel (<TEX>$>10{\mu}M$</TEX>) has been known to induce iNOS gene expression in macrophages. However, in the previous report we described that the pretreatment of macrophages with low concentration of paclitaxel (<TEX>$0.1{\mu}M$</TEX>) for 8 h inhibited LPS-induced iNOS gene expression. Pretreatment of RAW 264.7 cells with paclitaxel significantly inhibited NF-kB/Rel transcriptional activation. Electrophoretic mobility shift assay further confirmed that pretreatment of macrophages with paclitaxel inhibited NF-kB/Rel DNA binding. Taxotere, a semisynthetic analog of paclitaxel, also inhibited LPS- and <TEX>$IFN-{\gamma}$</TEX>-induced iNOS gene expression. Collectively, these series of experiments indicate that paclitaxel inhibits iNOS gene expression by blocking NF-kB/Rel activation.

Automated synthesis of 18F analogue of paclitaxel (PAC): [ 18F]Paclitaxel (FPAC)

A positron-emitting paclitaxel (PAC) derivative could allow in vivo measurement of multidrug resistance in tumors and, therefore, predict a potential chemotherapeutic benefit to patients. [ 18F]Paclitaxel was produced using a 2-reaction vessel automated synthesizer followed by HPLC purification. Optimized reaction conditions resulted in radiochemical yields of 21.2±9.6% at end of bombardment, radiochemical purity >99%, and specific activity of 159±43 GBq/μmol. [ 18F]Paclitaxel activities of 1.33±0.729 GBq ( n = 7 ) were obtained in sterile, pyrogen-free solution for IV administration.