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1.  Hormone Resistance in Two MCF-7 Breast Cancer Cell Lines is Associated with Reduced mTOR Signaling, Decreased Glycolysis, and Increased Sensitivity to Cytotoxic Drugs 
Frontiers in Oncology  2014;4:221.
The mTOR pathway is a key regulator of multiple cellular signaling pathways and is a potential target for therapy. We have previously developed two hormone-resistant sub-lines of the MCF-7 human breast cancer line, designated TamC3 and TamR3, which were characterized by reduced mTOR signaling, reduced cell volume, and resistance to mTOR inhibition. Here, we show that these lines exhibit increased sensitivity to carboplatin, oxaliplatin, 5-fluorouracil, camptothecin, doxorubicin, paclitaxel, docetaxel, and hydrogen peroxide. The mechanisms underlying these changes have not yet been characterized but may include a shift from glycolysis to mitochondrial respiration. If this phenotype is found in clinical hormone-resistant breast cancers, conventional cytotoxic therapy may be a preferred option for treatment.
doi:10.3389/fonc.2014.00221
PMCID: PMC4153047  PMID: 25232533
breast cancer cells; PI3K; mTOR; estrogen receptor; cytotoxic drugs; cisplatin; tamoxifen
2.  Phase I drug-interaction study of effects of calcium and magnesium infusions on oxaliplatin pharmacokinetics and acute neurotoxicity in colorectal cancer patients 
BMC Cancer  2013;13:495.
Background
Calcium and magnesium (Ca/Mg) infusions have been suggested as an effective intervention for preventing oxaliplatin-induced neurotoxicity, but the effects of Ca/Mg infusions on oxaliplatin pharmacokinetics, motor nerve hyperexcitability and acute neurotoxicity symptoms are unclear.
Methods
In this double blind crossover study, colorectal cancer patients undergoing oxaliplatin-based chemotherapy were randomised to receive Ca/Mg (1g Ca Gluconate plus 1g MgSO4) on cycle 1 and placebo (vehicle alone) on cycle 2, or to receive the same treatments in the opposite sequence. Study endpoints included plasma pharmacokinetics of intact oxaliplatin and free platinum; electromyography (EMG) detection of abnormal spontaneous high-frequency motor unit action potential discharges; and patient-reported acute neurotoxicity symptoms and their preferred study treatment for reducing these symptoms.
Results
Nineteen of 20 enrolled patients completed the study. Plasma pharmacokinetics of intact oxaliplatin and free platinum were similar when oxaliplatin was given with Ca/Mg or placebo (ratio of geometric means of AUC0-t with Ca/Mg or placebo: intact oxaliplatin, 0.95 (90% CI, 0.90 – 1.01); free platinum, 0.99 (90% CI, 0.94 – 1.05)). EMG motor nerve hyperexcitability scores were similar with Ca/Mg and placebo (mean difference in EMG score between Ca/Mg and placebo: -0.3 (95% CI, -2.2 – 1.6)). Patient-reported acute neurotoxicity symptoms were similar in frequency with Ca/Mg and placebo. For reducing neurotoxic symptoms, fewer patients preferred Ca/Mg than placebo or neither treatment (26% versus 74%; P<0.01).
Conclusions
Ca/Mg infusions do not alter the clinical pharmacokinetics of oxaliplatin and do not seem to reduce its acute neurotoxicity.
Trial registration
Trial registration identifier ACTRN12611000738921
doi:10.1186/1471-2407-13-495
PMCID: PMC3870994  PMID: 24156389
Oxaliplatin; Calcium and magnesium; Neurotoxicity; Colorectal cancer; Hyperexcitability; Pharmacokinetics; Acute neuropathy
3.  PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours 
BMC Cancer  2012;12:496.
Background
The purpose of this phase Ib clinical trial was to determine the maximum tolerated dose (MTD) of PR-104 a bioreductive pre-prodrug given in combination with gemcitabine or docetaxel in patients with advanced solid tumours.
Methods
PR-104 was administered as a one-hour intravenous infusion combined with docetaxel 60 to 75 mg/m2 on day one given with or without granulocyte colony stimulating factor (G-CSF) on day two or administrated with gemcitabine 800 mg/m2 on days one and eight, of a 21-day treatment cycle. Patients were assigned to one of ten PR-104 dose-levels ranging from 140 to 1100 mg/m2 and to one of four combination groups. Pharmacokinetic studies were scheduled for cycle one day one and 18F fluoromisonidazole (FMISO) positron emission tomography hypoxia imaging at baseline and after two treatment cycles.
Results
Forty two patients (23 females and 19 males) were enrolled with ages ranging from 27 to 85 years and a wide range of advanced solid tumours. The MTD of PR-104 was 140 mg/m2 when combined with gemcitabine, 200 mg/m2 when combined with docetaxel 60 mg/m2, 770 mg/m2 when combined with docetaxel 60 mg/m2 plus G-CSF and ≥770 mg/m2 when combined with docetaxel 75 mg/m2 plus G-CSF. Dose-limiting toxicity (DLT) across all four combination settings included thrombocytopenia, neutropenic fever and fatigue. Other common grade three or four toxicities included neutropenia, anaemia and leukopenia. Four patients had partial tumour response. Eleven of 17 patients undergoing FMISO scans showed tumour hypoxia at baseline. Plasma pharmacokinetics of PR-104, its metabolites (alcohol PR-104A, glucuronide PR-104G, hydroxylamine PR-104H, amine PR-104M and semi-mustard PR-104S1), docetaxel and gemcitabine were similar to that of their single agents.
Conclusions
Combination of PR-104 with docetaxel or gemcitabine caused dose-limiting and severe myelotoxicity, but prophylactic G-CSF allowed PR-104 dose escalation with docetaxel. Dose-limiting thrombocytopenia prohibited further evaluation of the PR104-gemcitabine combination. A recommended dose was identified for phase II trials of PR-104 of 770 mg/m2 combined with docetaxel 60 to 75 mg/m2 both given on day one of a 21-day treatment cycle supported by prophylactic G-CSF (NCT00459836).
doi:10.1186/1471-2407-12-496
PMCID: PMC3495895  PMID: 23098625
4.  Comparative outcomes of squamous and non-squamous non-small cell lung cancer (NSCLC) patients in phase II studies of ASA404 (DMXAA) – retrospective analysis of pooled data 
Journal of Thoracic Disease  2010;2(4):199-204.
Background
ASA404 (5,6-dimethylxanthenone-4-acetic acid) is a small-molecule, flavonoid tumor-vascular disrupting agent. Pooled data from phase II studies were analyzed retrospectively to compare safety and efficacy between squamous and non-squamous non-small cell lung cancer (NSCLC) patients.
Methods
Data from previously untreated patients with stage IIIb/IV NSCLC who were randomized to receive up to six cycles of carboplatin (C; AUC 6 mg/ml•min) and paclitaxel (P; 175 mg/m2) alone or with ASA404 (1200 mg/m2), or enrolled in an extension study to receive CP and ASA404 (1800 mg/m2), were analyzed. Differences between subgroups were calculated using Fisher’s exact test.
Results
Of the 108 enrolled patients, safety data from the 104 patients included in the safety population were pooled to compare results between histological subgroups (squamous vs non-squamous) and treatment (CP alone vs CP + ASA404). Addition of ASA404 to the standard chemotherapy regimen did not appear to substantially increase toxicity, and there were no serious adverse events associated with bleeding, pulmonary hemorrhage, or hemoptysis. Activity with CP + ASA404 appeared improved over CP alone, with median survival 10.2 vs 5.5 months in squamous, and 14.9 vs 11.0 months in non-squamous populations, respectively.
Conclusion
This analysis is limited by its retrospective nature, and by the small size of the overall group, treatment and disease subgroups. However, as ASA404 appears to have a similar safety and activity profile in patients with squamous and non-squamous NSCLC, the findings support inclusion of both groups of patients in ongoing definitive phase III trials of ASA404 (NCT00832494).
doi:10.3978/j.issn.2072-1439.2010.02.04.1
PMCID: PMC3256477  PMID: 22263047
ASA404; non-small cell lung carcinoma; clinical trial; phase II; safety
5.  A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patients 
BMC Cancer  2011;11:432.
Background
The phosphate ester PR-104 is rapidly converted in vivo to the alcohol PR-104A, a nitrogen mustard prodrug that is metabolised to hydroxylamine (PR-104H) and amine (PR-104M) DNA crosslinking agents by one-electron reductases in hypoxic cells and by aldo-keto reductase 1C3 independently of oxygen. In a previous phase I study using a q 3 week schedule of PR-104, the maximum tolerated dose (MTD) was 1100 mg/m2 and fatigue, neutropenic fever and infection were dose-limiting. The primary objective of the current study was to determine the dose-limiting toxicity (DLT) and MTD of weekly PR-104.
Methods
Patients with advanced solid tumours received PR-104 as a 1-hour intravenous infusion on days 1, 8 and 15 every 28 days with assessment of pharmacokinetics on cycle 1 day 1. Twenty-six patients (pts) were enrolled (16 male/10 female; median age 58 yrs, range 30 to 70 yrs) who had received a median of two prior chemotherapy regimens (range, 0 to 3) for melanoma (8 pts), colorectal or anal cancer (3 pts), NSCLC (3 pts), sarcoma (3 pts), glioblastoma (2 pts), salivary gland tumours (2 pts) or other solid tumours (5 pts). PR-104 was administered at 135 mg/m2 (3 pts), 270 mg/m2 (6 pts), 540 mg/m2 (6 pts), 675 mg/m2 (7 pts) and 900 mg/m2 (4 pts) for a median of two treatment cycles (range, 1 to 7 cycles) and five infusions (range, 1 to 18) per patient.
Results
Dose-limiting toxicities (DLTs) during cycle one included grade four thrombocytopenia at 540 mg/m2 (1 of 6 pts) and grade four thrombocytopenia and neutropenia at 900 mg/m2 (2 of 4 pts). At an intermediate dose of 675 mg/m2, there were no DLTs among a total of seven patients given 12 treatment cycles but all experienced moderate to severe (grade 2 to 4) haematological toxicity. Thrombocytopenia was delayed in its onset and nadir, and its recovery was protracted and incomplete in many patients. There were no complete or partial tumour responses. PR-104-induced thrombocytopenia and neutropenia correlated with plasma AUC of PR-104, PR-104A and an oxidative semi-mustard metabolite (PR-104S1), but no more strongly than with PR-104 dose-level. There was no significant correlation between plasma AUC for the reduced metabolites and myelotoxicity.
Conclusions
Thrombocytopenia, and to a lesser extent neutropenia, was the DLT of weekly PR-104. The MTD was 675 mg/m2/week. PR-104 given weekly may be a suitable protocol for further clinical evaluation as a short course of treatment with fractionated radiotherapy or haematopoietic stem cell support, as its duration of dosing is restricted by delayed-onset and protracted thrombocytopenia.
doi:10.1186/1471-2407-11-432
PMCID: PMC3205073  PMID: 21982454
6.  Differential expression of ATP7A, ATP7B and CTR1 in adult rat dorsal root ganglion tissue 
Molecular Pain  2010;6:53.
Background
ATP7A, ATP7B and CTR1 are metal transporting proteins that control the cellular disposition of copper and platinum drugs, but their expression in dorsal root ganglion (DRG) tissue and their role in platinum-induced neurotoxicity are unknown. To investigate the DRG expression of ATP7A, ATP7B and CTR1, lumbar DRG and reference tissues were collected for real time quantitative PCR, RT-PCR, immunohistochemistry and Western blot analysis from healthy control adult rats or from animals treated with intraperitoneal oxaliplatin (1.85 mg/kg) or drug vehicle twice weekly for 8 weeks.
Results
In DRG tissue from healthy control animals, ATP7A mRNA was clearly detectable at levels similar to those found in the brain and spinal cord, and intense ATP7A immunoreactivity was localised to the cytoplasm of cell bodies of smaller DRG neurons without staining of satellite cells, nerve fibres or co-localisation with phosphorylated heavy neurofilament subunit (pNF-H). High levels of CTR1 mRNA were detected in all tissues from healthy control animals, and strong CTR1 immunoreactivity was associated with plasma membranes and vesicular cytoplasmic structures of the cell bodies of larger-sized DRG neurons without co-localization with ATP7A. DRG neurons with strong expression of ATP7A or CTR1 had distinct cell body size profiles with minimal overlap between them. Oxaliplatin treatment did not alter the size profile of strongly ATP7A-immunoreactive neurons but significantly reduced the size profile of strongly CTR1-immunoreactive neurons. ATP7B mRNA was barely detectable, and no specific immunoreactivity for ATP7B was found, in DRG tissue from healthy control animals.
Conclusions
In conclusion, adult rat DRG tissue exhibits a specific pattern of expression of copper transporters with distinct subsets of peripheral sensory neurons intensely expressing either ATP7A or CTR1, but not both or ATP7B. The neuron subtype-specific and largely non-overlapping distribution of ATP7A and CTR1 within rat DRG tissue may be required to support the potentially differing cuproenzyme requirements of distinct subsets of sensory neurons, and could influence the transport and neurotoxicity of oxaliplatin.
doi:10.1186/1744-8069-6-53
PMCID: PMC2949721  PMID: 20836889
7.  Detecting acute neurotoxicity during platinum chemotherapy by neurophysiological assessment of motor nerve hyperexcitability 
BMC Cancer  2010;10:451.
Background
Platinum-based drugs, such as cisplatin and oxaliplatin, are well-known for inducing chronic sensory neuropathies but their acute and motor neurotoxicities are less well characterised. Use was made of nerve conduction studies and needle electromyography (EMG) to assess motor nerve excitability in cancer patients during their first treatment cycle with platinum-based chemotherapy in this study.
Methods
Twenty-nine adult cancer patients had a neurophysiological assessment either before oxaliplatin plus capecitabine, on days 2 to 4 or 14 to 20 after oxaliplatin plus capecitabine, or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin, undertaken by a neurophysiologist who was blinded to patient and treatment details. Patients completed a symptom questionnaire at the end of the treatment cycle.
Results
Abnormal spontaneous high frequency motor fibre action potentials were detected in 100% of patients (n = 6) and 72% of muscles (n = 22) on days 2 to 4 post-oxaliplatin, and in 25% of patients (n = 8) and 13% of muscles (n = 32) on days 14 to 20 post-oxaliplatin, but in none of the patients (n = 14) or muscles (n = 56) tested prior to oxaliplatin or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin. Repetitive compound motor action potentials were less sensitive and less specific than spontaneous high frequency motor fibre action potentials for detection of acute oxaliplatin-induced motor nerve hyperexcitability but were present in 71% of patients (n = 7) and 32% of muscles (n = 32) on days 2 to 4 after oxaliplatin treatment. Acute neurotoxicity symptoms, most commonly cold-induced paraesthesiae and jaw or throat tightness, were reported by all patients treated with oxaliplatin (n = 22) and none of those treated with carboplatin plus paclitaxel or cisplatin (n = 6).
Conclusions
Abnormal spontaneous high frequency motor fibre activity is a sensitive and specific endpoint of acute oxaliplatin-induced motor nerve hyperexcitability, detectable on EMG on days 2 to 4 post-treatment. Objective EMG assessment of motor nerve excitability could compliment patient-reported symptomatic endpoints of acute oxaliplatin-induced neurotoxicity in future studies.
doi:10.1186/1471-2407-10-451
PMCID: PMC2936328  PMID: 20731872
8.  Oxaliplatin-induced loss of phosphorylated heavy neurofilament subunit neuronal immunoreactivity in rat DRG tissue 
Molecular Pain  2009;5:66.
Background
Oxaliplatin and related chemotherapeutic drugs cause painful chronic peripheral neuropathies in cancer patients. We investigated changes in neuronal size profiles and neurofilament immunoreactivity in L5 dorsal root ganglion (DRG) tissue of adult female Wistar rats after multiple-dose treatment with oxaliplatin, cisplatin, carboplatin or paclitaxel.
Results
After treatment with oxaliplatin, phosphorylated neurofilament heavy subunit (pNF-H) immunoreactivity was reduced in neuronal cell bodies, but unchanged in nerve fibres, of the L5 DRG. Morphometric analysis confirmed significant changes in the number (-75%; P < 0.0002) and size (-45%; P < 0.0001) of pNF-H-immunoreactive neurons after oxaliplatin treatment. pNF-H-immunoreactive neurons had overlapping size profiles and co-localisation with neurons displaying cell body immunoreactivity for parvalbumin, non-phospho-specific neurofilament medium subunit (NF-M) and non-phospho-specific neurofilament heavy subunit (NF-H), in control DRG. However, there were no significant changes in the numbers of neurons with immunoreactivity for parvalbumin (4.6%, P = 0.82), NF-M (-1%, P = 0.96) or NF-H (0%; P = 0.93) after oxaliplatin treatment, although the sizes of parvalbumin (-29%, P = 0.047), NF-M (-11%, P = 0.038) and NF-H (-28%; P = 0.0033) immunoreactive neurons were reduced. In an independent comparison of different chemotherapeutic agents, the number of pNF-H-immunoreactive neurons was significantly altered by oxaliplatin (-77.2%; P < 0.0001) and cisplatin (-35.2%; P = 0.03) but not by carboplatin or paclitaxel, and their mean cell body area was significantly changed by oxaliplatin (-31.1%; P = 0.008) but not by cisplatin, carboplatin or paclitaxel.
Conclusion
This study has demonstrated a specific pattern of loss of pNF-H immunoreactivity in rat DRG tissue that corresponds with the relative neurotoxicity of oxaliplatin, cisplatin and carboplatin. Loss of pNF-H may be mechanistically linked to oxaliplatin-induced neuronal atrophy, and serves as a readily measureable endpoint of its neurotoxicity in the rat model.
doi:10.1186/1744-8069-5-66
PMCID: PMC2785764  PMID: 19922644
9.  Antitumor Activity of Gold(I), Silver(I) and Copper(I) Complexes Containing Chiral Tertiary Phosphines 
Metal-Based Drugs  1998;5(4):217-223.
The in vitro cytotoxicities of a number of gold(I), silver(I) and copper(I) complexes containing chiral tertiary phosphine ligands have been examined against the mouse tumour cell lines P815 mastocytoma, B16 melanoma [gold(I) and silver(I) compounds] and P388 leukaemia [gold(I) complexes only] with many of the complexes having IC50 values comparable to that of the reference compounds cis-diamminedichloroplatinum(ll), cisplatin, and bis[1,2-bis(diphenylphosphino) ethane]gold(I) iodide. The chiral tertiary phosphine ligands used in this study include (R)-(2-aminophenyl)methylphenylphosphine; (R,R)-, (S,S)- and (R*,R*)-1,2-phenylenebis(methylphenylphosphine); and (R,R)-, (S,S)- and (R*,R*)-bis{(2-diphenylphosphinoethyl)phenylphosphino}ethane. The in vitro cytotoxicities of gold(I) and silver(I) complexes containing the optically active forms of the tetra(tertiary phosphine) have also been examined against the human ovarian carcinoma cell lines 41M and CH1, and the cisplatin resistant 41McisR, CH1cisR and SKOV-3 tumour models. IC50 values in the range 0.01 - 0.04 μM were determined for the most active compounds, silver(I) complexes of the tetra(tertiary phosphine). Furthermore, the chirality of the ligand appeared to have little effect on the overall activity of the complexes: similar IC50 data were obtained for complexes of a particular metal ion with each of the stereoisomeric forms of a specific ligand.
doi:10.1155/MBD.1998.217
PMCID: PMC2365122  PMID: 18475846

Results 1-9 (9)