Tubulin-binding Agents Research Articles

Phase I, pharmacokinetic (PK) study of synthadotin (SYN-D; ILX651), a next generation antitubulin, administered iv weekly x 3 weeks every 4 weeks (wx3q4w)

3073 Background: SYN-D is a pentapeptide with a unique mechanism of action that potentially differs from microtubule stabilizers (taxanes and epothilones) and tubulin inhibitors (vinca alkaloids and other dolastatins) as it is postulated to inhibit microtubule nucleation. SYN-D possesses broad, potent antitumor activity, and favorable pharmacological and toxicity profiles preclinically, particularly with respect to cardiovascular effects. Methods: Based on the protracted nature of binding and retention of tubulin-binding agents in peripheral tissues and tumors, SYN-D administered IV for 30 mins wx3q4w was evaluated. The maximum tolerated dose (MTD) was the highest dose at which <2/6 new pts experienced dose-limiting toxicity (DLT) in course 1. Results: Thirty pts stratified by prior myelotoxic therapy into minimally and heavily pretreated (MP and HP, respectively) cohorts (median age 56; M/F=18/12; tumor types: colorectal [13], renal [4], melanoma [4] breast [2], NSCLC [2], larynx, ovary, mesothelioma, HCC and prostate cancers [1 each]) were treated with 66 courses (range 1–6) of SYN-D at 7.8, 15.6, 31.2, 46.8, 54.5, and 62.2 mg/m2. Unacceptably high levels of dose-limiting neutropenia (precluding day 15 SYN-D administration; 1 complicated by fever) were seen in 2/3 MP pts treated at 62.2 mg/m2 and in 3 and 2 MP and HP pts, respectively, at 54.5 mg/m2. The MTD and recommended phase II dose for both cohorts is 46.8 mg/m2. At this dose level only 1/9 pts experienced DLT. No major gastrointestinal, neurological or cardiovascular toxicities were noted. Antitumor activity included a 47% decrease in a taxane- and platinum-refractory NSCLC lasting 5 months and stable disease >4 months in 2 pts with HCC and renal cancer. The PK behavior of SYN-D (dose range of 7.8–62.2 mg/m2) was biphasic; a third non-quantifiable gamma phase was observed in a few pts; and the effective t1/2 was <1 hour. Conclusions: Weekly administration of SYN-D is safe, active, convenient and well tolerated; however, dose intensity is lower (35mg/m2/wk) than with the daily x 5 every 21 days schedule (45.5mg/m2/wk) currently in phase II evaluation. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ILEX Products, Inc., an affiliate of ILEX Oncology ILEX Products, Inc., an affiliate of ILEX Oncology ILEX Oncology, Inc. ILEX Products, Inc., an affiliate of ILEX Oncology ILEX Oncology, Inc. ILEX Products, Inc., an affiliate of ILEX Oncology ILEX Products, Inc., an affiliate of ILEX Oncology

Lack of neurotoxicity of the vascular targeting agent ZD6126 following repeated i.v. dosing in the rat

The vascular targeting agent ZD6126 is a water-soluble prodrug of N-acetylcolchinol that acts by disrupting the cytoskeleton of tumor endothelial cells. It is currently undergoing clinical evaluation in man. As peripheral neuropathy is a major dose-limiting toxicity associated with tubulin binding agents, the neurotoxic potential of ZD6126 was investigated in male and female Wistar rats. ZD6126 was administered i.v. at up to maximum tolerated doses using subacute (0 to 20 mg/kg/d for 5 days) and chronic (0 to 10 mg/kg/d for 5 days, repeated monthly for 6 months) dosing regimens. A separate study examined a combination of ZD6126 (three cycles of ZD6126 given as in the chronic dosing regimen) and paclitaxel (12 mg/kg/wk for 9 weeks) to assess whether coadministration of ZD6126 altered the time course or magnitude of a paclitaxel-induced neuropathy. Neurotoxic potential was examined using a comprehensive series of tests including a functional observation battery, measurements of muscle strength (forelimb and hind limb grip strength), nociception (tail flick test), locomotor activity, neuropathology, and whole nerve electrophysiology. There was no evidence that ZD6126 induced neurotoxicity in the rat following either subacute or chronic i.v. dosing. In a chronic electrophysiology study, ZD6126 produced a slight slowing of the maturational increase of caudal nerve amplitude, with some evidence of reversibility. However, this was not associated with any changes in caudal nerve conduction velocity, motor nerve conduction velocity or amplitude, functional observation battery behavioral and function parameters (including no effects on tail flick latency), and neuropathology. As expected, paclitaxel administration was associated with a significant decrease in caudal nerve conduction velocity (P = 0.0001). Coadministration of ZD6126 did not increase the neurotoxicity of paclitaxel. These studies suggest that ZD6126 should not induce the peripheral neuropathy associated with other antitubulin chemotherapeutic agents and that ZD6126 may not exacerbate the neurotoxicity of other agents with dose-limiting neuropathies.

Tumor selective antivascular effects of the novel antimitotic compound ABT-751: an in vivo rat regional hemodynamic study.

Selective induction of vascular damage within a growing tumor is a potentially important approach in the search for potent anticancer therapeutics. Tubulin-binding (antimitotic) agents destabilize cellular microtubules, suppress tumor growth, and exert antivascular effects with varying degrees of tumor selectivity in preclinical models. The tumor-selective, antivascular effects of ABT-751, a novel, orally active antimitotic agent, currently in phase II clinical development, were characterized in vivo in the present study. We developed an in vivo rat model designed to quantify acute changes in regional vascular resistance (VR) in both tumor and non-tumor vascular beds simultaneously. Tissue-isolated tumors (1 g) with blood flow supplied by a single epigastric artery were grown in rats. Subsequently, tumor blood flow was measured under anesthesia in solid tumors and also in mesenteric, renal, and normal epigastric arteries. Phenylephrine-induced (1 micromol/kg) increases in VR were not different between tumor and non-tumor epigastric arteries, suggesting that tumor vessels possess relatively normal vasoconstrictive function. ABT-751 (3, 10, and 30 mg/kg; i.v.) produced modest transient increases in mean arterial pressure with no effect on heart rate. Tumor VR increased to 75+/-36, 732+/-172, and 727+/-125% above baseline, respectively (P<0.05 for the 10 and 30 mg/kg doses), whereas VR in normal epigastric arteries was not significantly affected. Administration of ABT-751 produced transient modest ( P<0.05) increases in mesenteric VR and no effect on renal VR. These results demonstrate that ABT-751 produces marked reductions in tumor blood flow in the intact rat at doses that exert negligible effects on normal vascular function.

Genistein inversely affects tubulin-binding agent-induced apoptosis in human breast cancer cells

Genistein, a natural isoflavone phytoestrogen present in soybeans, has been extensively studied as a chemopreventive or therapeutic agent in several types of cancer. The traditional Asian diet is rich in soy products may explain in part why the incidence of breast cancer in Asian women is relatively low. To improve therapeutic benefits, we investigated the combination of genistein with chemotherapeutic agents in phenotypically dissimilar human breast cancer cells, MCF-7 and MDA-MB-231, in which estrogen receptor expression is positive and negative, respectively. In the present study, genistein significantly decreased cell apoptosis induced by tubulin-binding agents, paclitaxel and vincristine. FACScan analysis revealed that genistein also diminished the accumulation of the G2/M phase in the cell cycle caused by tubulin-binding agents. In situ staining of microtubules revealed that genistein could decrease paclitaxel-induced tubulin polymerization. However, in vivo tubulin polymerization assay revealed that simultaneous treatment of genistein did not change the tubulin/microtubule dynamic. Genistein reduced Bcl-2 phosphorylation triggered by paclitaxel and vincristine without changing Bax protein expression. p53 and p21 expression, monitored by Western blotting, was not altered by genistein. However, the expression of cyclin B1 and CDC2 kinase was markedly decreased in combination with genistein. In conclusion, genistein inversely affected tubulin-binding agent-induced apoptosis via down-regulation of cyclin B1/CDC2 kinase expression resulting in reduced Bcl-2 phosphorylation.

A novel bioassay for screening and quantification of taxanes.

We report a novel method for screening and quantifying tubulin-binding antimitotic agents that promote microtubule formation. The method is based on the shift in the peak of the fluorescence emission difference spectrum of tubulin complexed to metal free tetrakis(4-carboxyphenyl)porphyrin (TCPP) in the presence of antimitotic agents. Taxol (paclitaxel), an anti-tumor drug approved for the treatment of a variety of cancers, caused the appearance of a new fluorescence peak at 645 nm at concentrations as low as 125 nM, the intensity of which was a function of the paclitaxel concentration. Cephalomannine caused the induction of a new fluorescence peak at 651 nm only above 1 muM. Baccatin did not induce the appearance of any new peak within detectable operating measurement conditions. These observations are in accordance with the biological activities/cytotoxicities of these compounds. Accordingly, it is proposed that the new method can be used for high throughput screening of antimitotic compounds.

P1713 The tubulin-binding agent paclitaxel improves the recovery of post-ischaemic cardiomyocytes

P1713 The tubulin-binding agent paclitaxel improves the recovery of post-ischaemic cardiomyocytes

Combretastatin A4 phosphate has primary antineoplastic activity against human anaplastic thyroid carcinoma cell lines and xenograft tumors.

Anaplastic thyroid carcinoma (ATC) is a fatal malignancy the clinical outcome of which is unaltered by current therapeutic modalities. A recent phase 1 clinical trial of combretastatin A4 phosphate (CA4P) produced a long-lasting total remission in a patient with ATC. CA4P is a tubulin-binding agent derived from the African bush willow, Combretum caffrum, which possesses tumor vascular-targeting activity. In order to discriminate primary antineoplastic effects from tumor antivascular activity, we evaluated CA4P cytotoxicity in eight human ATC cell lines and compared it to paclitaxel, another tubulin-binding agent with significant clinical activity. CA4P displayed significant cytotoxicity against the ATC cell lines, comparable to that of paclitaxel, and these effects were longer lasting in two cell lines compared to the duration of paclitaxel. We further investigated the effects of CA4P on xenograft tumors from four ATC cell lines injected in athymic nude mice. Significantly lower tumor weights were observed in animals treated with CA4P compared to those treated with vehicle alone. Continuous monitoring of xenograft tumor volumes from one of the ATC cell lines also revealed a significantly lower rate of tumor growth in the CA4P-treated mice compared to those receiving vehicle alone. These results suggest that antitumoral effects of CA4P can be consequent to a combination of primary antineoplastic effects as well as the potential destruction of tumor vasculature.

Effect of auristatin PHE on microtubule integrity and nuclear localization in Cryptococcus neoformans.

The mechanism of action of the fungicidal peptide auristatin PHE was investigated in Cryptococcus neoformans. Since auristatin PHE causes budding arrest in C. neoformans (T. Woyke, G. R. Pettit, G. Winkelmann, and R. K. Pettit, Antimicrob. Agents Chemother. 45:3580-3584, 2001), microtubule integrity and nuclear localization in auristatin PHE-treated cells were examined. Iterative deconvolution in conjunction with an optimized C. neoformans microtubule immunolabeling procedure enabled detailed visualization of the microtubule cytoskeleton in auristatin PHE-treated C. neoformans. The effect of auristatin PHE on C. neoformans microtubule organization was compared with that of the tubulin-binding agent nocodazole. Both drugs produced complete disruption first of cytoplasmic and then of spindle microtubules in a time- and concentration-dependent manner. Sub-MICs of auristatin PHE caused complete microtubule disruption within 4.5 h, while 1.5 times the nocodazole MIC was required for the same effect. For both drugs, disruption of microtubules was accompanied by blockage of nuclear migration and of nuclear and cellular division, resulting in cells arrested in a uninucleate, large-budded stage. Nocodazole and the linear peptide auristatin PHE are remarkably different in structure and spectrum of activity, yet on the cellular level, they have similar effects.

Enhancement of vascular targeting by inhibitors of nitric oxide synthase

Purpose: This study investigates the enhancement of the vascular targeting activity of the tubulin-binding agent combretastatin A4 phosphate (CA4P) by various inhibitors of nitric oxide synthases.Methods and Materials: The syngeneic tumors CaNT and SaS growing in CBA mice were used for this study. Reduction in perfused vascular volume was measured by injection of Hoechst 33342 24 h after drug administration. Necrosis (hematoxylin and eosin stain) was assessed also at 24 h after treatment. Combretastatin A4 phosphate was synthesized by a modification of the published procedure and the nitric oxide synthase inhibitors L-NNA, L-NMMA, L-NIO, L-NIL, S-MTC, S-EIT, AMP, AMT, and L-TC, obtained from commercial sources.Results: A statistically significant augmentation of the reduction in perfused vascular volume by CA4P in the CaNT tumor was observed with L-NNA, AMP, and AMT. An increase in CA4P-induced necrosis in the same tumor achieved significance with L-NNA, L-NMMA, L-NIL, and AMT. CA4P induced little necrosis in the SaS tumor, but combination with the inhibitors L-NNA, L-NMMA, L-NIO, S-EIT, and L-TC was effective.Conclusions: Augmentation of CA4P activity by nitric oxide synthase inhibitors of different structural classes supports a nitric oxide-related mechanism for this effect. L-NNA was the most effective inhibitor studied.

Cardiac Glycosides Induce Resistance to Tubulin-Dependent Anticancer Drugs in Androgen-Independent Human Prostate Cancer

Due to high prevalence and mortality and the lack of effective therapies, prostate cancer is one of the most crucial health problems in men. Drug resistance aggravates the situation, not only in human prostate cancer but also in other cancers. In this study, we report for the first time that cardiac glycosides (e.g. ouabain and digitoxin) induced resistance of human prostate cancer cells (PC-3) in vitro to tubulin-binding anticancer drugs, such as paclitaxel, colchicine, vincristine and vinblastine. Cardiac glycosides exhibited amazing ability to reverse the G2/M arrest of the cell cycle and cell apoptosis induced by tubulin-binding agents. However, neither ionomycin (a Ca²⁺ ionophore) nor veratridine (a Na⁺ ionophore) mimicked the preventive action of cardiac glycosides, indicating that elevation of the intracellular Ca²⁺ concentration and Na⁺ accumulation were not involved in the cardiac glycoside action. Furthermore, cardiac glycosides showed little influence on the effects induced by actinomycin D, anisomycin and doxorubicin, suggesting selectivity for microtubule-targeted anticancer drugs. Using in situ immunofluorescent detection of mitotic spindles, our data showed that cardiac glycosides diminished paclitaxel-induced accumulation of microtubule spindles; however, in a non-cell assay system, cardiac glycosides had little influence on colchicine- and paclitaxel-induced microtubule dynamics. Using an isotope-labeled assay method, we found that ouabain modestly but significantly inhibited the transport of [¹⁴C]paclitaxel from the cytosol into the nucleus. It is suggested that cardiac glycosides inhibit the G2/M arrest induced by tubulin-binding anticancer drugs via an indirect blockade on microtubule function. The decline in transport of these drugs into the nucleus may partly explain the action of cardiac glycosides.

Cardiac glycosides induce resistance to tubulin-dependent anticancer drugs in androgen-independent human prostate cancer.

Due to high prevalence and mortality and the lack of effective therapies, prostate cancer is one of the most crucial health problems in men. Drug resistance aggravates the situation, not only in human prostate cancer but also in other cancers. In this study, we report for the first time that cardiac glycosides (e.g. ouabain and digitoxin) induced resistance of human prostate cancer cells (PC-3) in vitro to tubulin-binding anticancer drugs, such as paclitaxel, colchicine, vincristine and vinblastine. Cardiac glycosides exhibited amazing ability to reverse the G2/M arrest of the cell cycle and cell apoptosis induced by tubulin-binding agents. However, neither ionomycin (a Ca(2+) ionophore) nor veratridine (a Na(+) ionophore) mimicked the preventive action of cardiac glycosides, indicating that elevation of the intracellular Ca(2+) concentration and Na(+) accumulation were not involved in the cardiac glycoside action. Furthermore, cardiac glycosides showed little influence on the effects induced by actinomycin D, anisomycin and doxorubicin, suggesting selectivity for microtubule-targeted anticancer drugs. Using in situ immunofluorescent detection of mitotic spindles, our data showed that cardiac glycosides diminished paclitaxel-induced accumulation of microtubule spindles; however, in a non-cell assay system, cardiac glycosides had little influence on colchicine- and paclitaxel-induced microtubule dynamics. Using an isotope-labeled assay method, we found that ouabain modestly but significantly inhibited the transport of [(14)C]paclitaxel from the cytosol into the nucleus. It is suggested that cardiac glycosides inhibit the G2/M arrest induced by tubulin-binding anticancer drugs via an indirect blockade on microtubule function. The decline in transport of these drugs into the nucleus may partly explain the action of cardiac glycosides.

Microtubule alterations and resistance to tubulin-binding agents (Review)

Antimitotic agents that bind to tubulin and disrupt microtubule dynamics, such as vinca alkaloids and taxanes, are an integral part of the treatment of many human cancers. Unfortunately the clinical success of these agents can be severely hindered by the emergence of drug resistant tumour cells. In recent years interest has focused on alterations in the cellular target of antimicrotubule compounds, the tubulin/ microtubule system, and their role in drug resistance. This review will discuss tubulin/microtubule alterations associated with resistance to tubulin-binding agents. Novel antimicrotubule compounds that hold promise in the treatment of drug-resistant disease and are currently undergoing clinical evaluation will also be reviewed.

A new paradigm of chemotherapy for gastric cancer: speeding up, and more clinical trials to catch up

tarium of useful agents and to accelerate the process of evaluating new treatment modalities. But what type of novel treatment modalities should we examine? And how can we make up for the delay in establishing gastric cancer treatment modalities, compared with those for other major solid tumors, without going by a roundabout way that was not successful a decade ago [7]? Paclitaxel, which has been heralded as a unique cytotoxic agent, could be one of the most promising novel chemotherapeutic agents for gastric cancer. To understand the effect of paclitaxel, a review of its basic and clinical pharmacology is necessary. Paclitaxel is a novel diterpenoid that contains a complex ring system, called a taxane ring, coupled with a complex ester chain. This taxane derivative is a member of the tubulin-binding agent class. But, unlike other agents in the tubulinbinding family that promote microtubule disassembly, paclitaxel shifts the equilibrium toward microtubule assembly, and stabilizes microtubules by preventing depolymerization [8,9]. Experimental studies have shown that paclitaxel has multiple biological activities, and different mechanisms of action are speculated depending on the concentration of paclitaxel. At a higher dose, paclitaxel blocks dividing cells in the G2/M phase, inhibits microtubular depolymerization, and directly kills tumor cells. At a lower concentration, paclitaxel induces apoptosis [10,11] anti-angiogenesis, and immunomodulation. Paclitaxel has already been used extensively in clinical practice, as one of the key drugs for the treatment of ovarian cancer, breast cancer, and lung cancer. As paclitaxel possesses a totally different mechanism of action compared with that of the fluoropyrimidines, the drug may bring about considerable improvements in the treatment of gastric cancer. The safety profile of paclitaxel has been well established. The incidence of severe hypersensitivity reactions observed in the initial clinical trials has been significantly reduced by the prophylactic administration of antiallergy medication, including a corticosteroid  2002 by International and Japanese Gastric Cancer Associations

Tubulin-binding agent taxol improves the recovery of postischemic cardiac myocytes

Tubulin-binding agent taxol improves the recovery of postischemic cardiac myocytes

Inhibition of Proliferative Retinopathy by the Anti-Vascular Agent Combretastatin-A4

Retinal neovascularization occurs in a variety of diseases including diabetic retinopathy, the most common cause of blindness in the developed world. There is accordingly considerable incentive to develop drugs that target the aberrant angiogenesis associated with these conditions. Previous studies have shown that a number of anti-angiogenic agents can inhibit retinal neovascularization in a well-characterized murine model of ischemia-induced proliferative retinopathy. Combretastatin-A4 (CA-4) is an anti-vascular tubulin-binding agent currently undergoing clinical evaluation for the treatment of solid tumors. We have recently shown that CA-4 is not tumor-specific but elicits anti-vascular effects in nonneoplastic angiogenic vessels. In this study we have examined the capacity of CA-4 to inhibit retinal neovascularization in vivo. CA-4 caused a dose-dependent inhibition of neovascularization with no apparent side effects. The absence of vascular abnormalities or remnants of disrupted neovessels in retinas of CA-4-treated mice suggests an anti-angiogenic mechanism in this model, in contrast to the anti-vascular effects observed against established tumor vessels. Importantly, histological and immunohistochemical analyses indicated that CA-4 permitted the development of normal retinal vasculature while inhibiting aberrant neovascularization. These data are consistent with CA-4 eliciting tissue-dependent anti-angiogenic effects and suggest that CA-4 has potential in the treatment of nonneoplastic diseases with an angiogenic component.

Evaluation of the anti-vascular effects of combretastatin in rodent tumours by dynamic contrast enhanced MRI.

The anti-vascular effects of the tubulin binding agent, disodium combretastatin A-4 3-O-phosphate (CA-4-P), have been investigated in the rat P22 carcinosarcoma by measurements of radiolabelled iodoantipyrine uptake and dynamic contrast-enhanced MRI. The iodoantipyrine estimates of absolute tumour blood flow showed a reduction from 0.35 to 0.04 ml g(-1) min(-1) 6 h after 10 mg kg(-1) CA-4-P and to <0.01 ml g(-1) min(-1) after 100 mg kg(-1). Tumour blood flow recovered to control values 24 h after 10 mg kg(-1) CA-4-P, but there was no recovery by 24 h after the higher dose. Dynamic contrast-enhanced MR images were obtained at 4.7 T, following injection of 0.1 mmol kg(-1) Gd-DTPA and analysed assuming a model arterial input function. A parameter, K(trans), which is related to blood flow rate and permeability of the tumour vasculature to Gd-DTPA, was calculated from the uptake data. K(trans) showed a reduction from 0.34 to 0.11 min(-1) 6 h after 10 mg kg(-1) CA-4-P and to 0.07 min(-1) after 100 mg kg(-1). Although the magnitude of changes in K(trans) was smaller than that in tumour blood flow, the time course and dose-dependency patterns were very similar. The apparent extravascular extracellular volume fraction, nu(e), showed a four-fold reduction 6 h after 100 mg kg(-1) CA-4-P, possibly associated with vascular shutdown within large regions of the tumour. These results suggest that K(trans) values for Gd-DTPA uptake into tumours could be a useful non-invasive indicator of blood flow changes induced by anti-vascular agents such as combretastatin.

Potent anti-metastatic activity of combretastatin-A4

The requirement for tumour vascularisation to permit the expansion of solid tumours beyond a threshold size of approximately 1 mm diameter has focussed attention on anti-vascular and anti-angiogenic agents for cancer therapy. Combretastatin-A4 (cis CA-4P) is a tubulin-binding agent that is cytotoxic for proliferating endothelial cells in vitro and causes anti-vascular effects in the established tumour vessels of some primary tumours. Preliminary data from Phase I clinical trials indicate that cis CA-4 may also be effective in targeting the vasculature of human tumours. As metastatic disease is the principal cause of mortality in cancer, we have investigated the effects of cis CA-4 on metastatic development using an in vivo model. We show that bolus or continuous administration of cis CA-4P results in potent inhibition of metastases derived from ectopic primary Lewis lung carcinomas in mice whereas the trans CA-4 isomer is without effect. These data further characterise the activity of CA-4 in vivo and suggest that the drug should be evaluated clinically as an anti-metastatic agent.

Inactivation of wild-type p53 by a dominant negative mutant renders MCF-7 cells resistant to tubulin-binding agent cytotoxicity.

The present study was performed to gain insight into the role of p53 on the cytotoxicity of tubulin-binding agents (TBA) on cancer cells. Drug sensitivity, cell cycle distribution and drug-induced apoptosis were compared in 2 lines derived from the mammary adenocarcinoma MCF-7: the MN-1 cell line containing wild-type p53 (wt-p53) and the MDD2 line, containing a dominant negative variant of the p53 protein (mut-p53). The MDD2 cell line was significantly more resistant to the cytotoxic effects of vinblastine and paclitaxel than the MN1 cell line. MN1 cells, but not MDD2 cells, displayed wt-p53 protein accumulation as well as p21/WAF1 and cyclin G1 induction after exposure to TBA. Both cell lines arrested at G2/M after drug treatment. However exposure of MN1 cells to TBA resulted in a stronger variation in mitochondrial membrane potential, associated with cleavage of PARP, and more apoptosis, as measured by annexin V expression. After exposure to vinblastine, Raf 1 kinase activity was reduced in MDD2 cells but not in MN1 cells. Addition of flavopiridol to vinblastine- and paclitaxel-treated cells reversed the MDD2-resistant phenotype by inducing G1 cell cycle arrest and inhibiting endoreduplication. We conclude that the p53 status of cancer cells influences their sensitivity to TBA cytotoxicity. This effect is likely to involve differences in the apoptotic cascade. © 2001 Cancer Research Campaignhttp://www.bjcancer.com

ChemInform Abstract: A Novel Palladium‐Mediated Coupling Approach to 2,3‐Disubstituted Benzo[b]thiophenes and Its Application to the Synthesis of Tubulin Binding Agents.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The effects of tubulin-binding agents on stretch-induced ventricular arrhythmias

Stretch-activated ion channels have been identified as transducers of mechanoelectric coupling in the heart, where they may play a role in arrhythmogenesis. The role of the cytoskeleton in ion channel control has been a topic of recent study and the transmission of mechanical stresses to stretch-activated channels by cytoskeletal attachment has been hypothesized. We studied the arrhythmogenic effects of stretch in 16 Langendorff-perfused rabbit hearts in which we pharmacologically manipulated the microtubular network of the cardiac myocytes. Group 1 ( n=5) was treated with colchicine, which depolymerizes microtubules, and Group 2 ( n=6) was treated with taxol, which polymerizes microtubules. Stretch-induced arrhythmias were produced by transiently increasing the volume of a fluid-filled left ventricular balloon with a volume pump driven by a computer-controlled stepper motor. Electrical events were recorded by a contact electrode which provided high-fidelity recordings of monophasic action potentials and stretch-induced depolarizations. The probability of eliciting a stretch-induced arrhythmia increased (0.22±0.11 to 0.62±0.19, p=0.001) in hearts treated with taxol (5 μM), whereas hearts treated with colchicine (100 μM) showed no statistically significant change. We conclude that proliferation of microtubules increased the arrhythmogenic effect of transient left ventricle diastolic stretch. This result indicates a possible mode of arrhythmogenesis in chemotherapeutic patients and patients exhibiting uncompensated ventricular hypertrophy. The data would indicate that the cytoskeleton represents a possible target for antiarrhythmic therapies.