Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group Trial 01.04

Glioblastoma is associated with a poor prognosis in the elderly. Survival has been shown to increase among patients 70 years of age or younger when temozolomide chemotherapy is added to standard radiotherapy (60 Gy over a period of 6 weeks). In elderly patients, more convenient shorter courses of radiotherapy are commonly used, but the benefit of adding temozolomide to a shorter course of radiotherapy is unknown

Pyridoxine to protect from oxaliplatin-induced neurotoxicity without compromising antitumour effect

Purpose: Oxaliplatin (OHP) in combination with 5-Xuorouracil/leucovorin (FOLFOX) is clinically used as frontline therapy in patients with advanced colorectal carcinoma (CRC), with response rates ranging from 46 to 71%. This combination is now considered a standard treatment for metastatic CRC and also in the post-operative adjuvant setting. Reversible, cumulative, peripheral sensory neuropathy is the principal dose-limiting toxicity of OHP therapy. Pyridoxine (vitamin B6) has been shown to reduce cisplatin and Xuoropyrimidine-related neurotoxicity but its administration with OHP has not yet been studied. Low doses of pyridoxine are free of side effects; it can be given orally. If pyridoxine administration with oxaliplatin has no adverse effect on OHP cytotoxicity effects, it will be a simple and cost-effective way to minimise OHP-induced neurotoxicity. Methods: In vitro simultaneous combination of OHP and pyridoxine was studied in 6 CRC cell lines (HT29, Widr, SW480, HCT116, H630 and SW1116), in an ovarian cancer cell line (A2780) and its cisplatin-resistant subline (ADDP) and in an oestrogen-dependent breast cancer cell line (MCF-7). Three fixed concentrations of pyridoxine: 1, 10 and 25 μM were combined with varying concentrations of OHP, and the growth inhibitory effects were evaluated using the MTT cell growth assay. Results: Oxaliplatin induced consistent cytotoxicity in all cell lines with GI₅₀ values between 0.23 and 7.6 μM. Addition of pyridoxine at concentrations of 1–25 μM does not affect OHP cytotoxicity. Conclusions: Administration of pyridoxine, at concentrations extending across possible therapeutic plasma levels in humans, does not antagonise OHP antitumour effects in a range of relevant tumour cell lines. This study provides a foundation for clinical studies to test whether pyridoxine can minimise OHP-related neurotoxicity, and clinicians can be confident that pyridoxine is very unlikely to reverse the antitumour effects of OHP, as seems to be the case with Ca/Mg infusions. This could prove to be a cost-effective way to minimise OHP-related neurotoxicity, allowing more effective less toxic treatment and better outcomes in patients

A simple HPLC method for plasma level monitoring of mitotane and its two main metabolites in adrenocortical cancer patients

Mitotane (o,p'-DDD or (1,1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl]ethane, DDD) is the drug of choice for non-resectable and metastatic adrenocortical carcinomas (ACC). Measurement of mitotane and metabolites,o,p'-DDE (1,1-dichloro-2-[p-chlorophenyl]-2-[o-chlorophenyl]ethene, DDE) and o,p'-DDA (1,1-[o,p'-dichlorodiphenyl] acetic acid, DDA)provides a better understanding of mitotane pharmacokinetics and pharmacodynamics. We have developed a simple, robust and efficient high performance liquid chromatography (HPLC) method to measure mitotane and its two main metabolites,DDE and DDA.The method involves a single ethanol extraction of mitotane, DDE, DDA, and an internal standard (int std) p,p'-DDD (1,1-dichloro-2,2-bis(p-chlorophenyl)ethane) with an extraction efficiency of 77–88%. All compounds are measured simultaneously using a reversed-phase phenyl HPLC column with an isocratic elution of mobile phase at a flow rate of 0.6 ml/min followed by UV detection at λ226nm. Inter and intraday validation demonstrates good reproducibility and accuracy. Limits of quantitation are 0.2μg/ml for mitotane and DDE, and 0.5μg/ml for DDA. The method has been evaluated in plasma from 23 patients on mitotane therapy, revealing DDA concentrations 1–18 times higher than the parent compound

Nab-paclitaxel: a bright new SPARC in taxane therapy of cancer (editorial)

A paper in this issue exemplifies two issues that deserve consideration in the clinical research and practice of oncology: 1) adverse events that occur in response to anticancer therapy may be due to excipients rather than the active agent, and the use of a different formulation may be effective; 2) differences in pharmacology and metabolism need to be considered whenever a drug is applied in different ethnic groups

Cantharimides: a new class of modified cantharidin analogues inhibiting protein phosphatases 1 and 2A

Cantharidin and its analogues have been of considerable interest as potent inhibitors of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A). However, limited modifications to the parent compounds is tolerated. As part of an on-going study we have developed a new series of cantharidin analogues, the cantharimides. Inhibition studies indicate that cantharimides possessing a D- or L-histidine, are more potent inhibitors of PP1 and PP2A (PP1 IC₅₀=3.22±0.7 μM; PP2A IC₅₀=0.81±0.1 μM and PP1 IC₅₀=2.82±0.6 μM; PP2A IC₅₀=1.35±0.3 μM, respectively) than norcantharidin (PP1 IC₅₀=5.31±0.76 μM; PP2A IC₅₀=2.9±1.04 μM) and essentially equipotent with cantharidin (PP1 IC₅₀=3.6±0.42 μM; PP2A IC₅₀=0.36±0.08 μM). Cantharimides with non-polar or acidic amino acid residues are only poor inhibitors of PP1 and PP2A

Science and art of anticancer drug dosing: nine steps to personalised therapy

Cancer medicine is a challenging field with an increasing range of promising therapies and combinations. Increasingly, personalised medicine shows promise to improve cancer outcomes – response, symptom control, survival and cure. However, optimal dosing is an under‐appreciated aspect of personalised anticancer therapy, with few clinical trials addressing this specific issue. This position paper aims to inform various health professionals about the principles that guide anticancer drug dose selection and modifications. We discuss the available evidence base for personalised dosing, as well as the professional judgement required by experienced oncology physicians to determine the most appropriate dose for each patient. We provide nine steps to guide clinicians and trainees in this process, based on: pharmacology of each agent (absorption, distribution, metabolism, elimination and mechanism of action); scientific evidence for recommended doses; professional knowledge of patients' unique phenotype (adiposity, comorbidities, etc.); previous drug tolerance; individual dose adjustment in combination therapy; communication and documentation, with the added need for ongoing monitoring and adjustment. We strongly propose professional education and future research towards optimal dosing

Synthesis and biological evaluation of norcantharidin analogues: Towards PP1 selectivity

Simple modi. cations to the anhydride moiety of norcantharidin have lead to the development of a series of analogues displaying modest PP1 inhibition (low mu M IC(50)s) comparable to that of norcantharidin (PP1 IC50 = 10.3 +/- 1.37 mu M). However, unlike norcantharidin, which is a potent inhibitor of PP2A (IC50 = 2.69 +/- 1.37 mu M), these analogues show reduced PP2A inhibitory action resulting in the development of selective PP1 inhibitory compounds. Data indicates that the introduction of two ortho-disposed substituents on an aromatic ring, or para-substituent favours PP1 inhibition over PP2A inhibition. Introduction of a p-morphilinoaniline substituent, 35, affords an inhibitor displaying PP1 IC50 = 6.5 +/- 2.3 mu M; and PP2A IC50 = 7.9 +/- 0.82 mu M (PP1/PP2A = 0.82); and a 2,4,6-trimethylaniline, 23, displaying PP1 IC50 = 48 +/- 9; and PP2A IC5 85 +/- 3 mu M (PP1/PP2A = 0.56). The latter shows a 7-fold improvement in PP1 versus PP2A selectivity when compared with norcantharidin. Subsequent analysis of 23 and 35 as potential PP2B inhibitors revealed modest inhibition with IC(50)s of 89 +/- 6 and 42 +/- 3 mu M, respectively, and returned with PP1/PP2B selectivities of 0.54 and 0.15. Thus, these analogues are the simplest and most selective PP1 inhibitors retaining potency reported to date. Crown copyright (C) 2007 Published by Elsevier Ltd. All rights reserved

Norcantharimides, synthesis and anticancer activity: Synthesis of new norcantharidin analogues and their anticancer evaluation

A range of amines was reacted with norcantharidin (2) to provide the corresponding norcantharimides (9-43). Treatment of norcantharidin with allylamine afforded the corresponding allyl-norcantharimide (20) which was amenable to epoxidation (mCPBA, 22) and subsequent ring opening (MeOH/H+; 23) or alternatively, osmylation (OSO4/NMO; 24). These simple synthetic modifications of 2 facilitated the development of a novel series of norcantharimides displaying modest to good broad spectrum cytotoxicity against HT29 and SW480 (colorectal carcinoma); MCF-7 (breast adenocarcinoma); A2780 (ovarian carcinoma); H460 (lung carcinoma); A431 (epidermoid carcinoma); DU145 (prostate carcinoma); BE2-C (neuroblastoma); and SJ-G2 (glioblastoma). Analogues possessing a C-10, C-12 or C-14 alkyl chain or a C12 linked bis-norcantharimide displayed the highest levels of cytotoxicity. Crown copyright (c) 2007 Published by Elsevier Ltd. All rights reserved