P. Loadman

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Leticia Cesarino

Universidade Federal de Santa Catarina - UFSC (Federal University of Santa Catarina)

Dr Naveen Kodlady

Gujarat Ayurved University,Jamnagar

Salman Bin Hosain

University of Louisiana at Monroe

Salman Ahmed

University of Karachi

Rara Rahmatika Risanti

University of Padjadjaran (UNPAD)

keith Stewart

University of Aberdeen

Dr. Mahadeo Deshmukh

Shivaji University, Kolhapur, India

Ludwig Kappos

University of Basel, University Hospital

Michael Selch

University of California, Los Angeles

Luis M Botana

University of Santiago de Compostela

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Papers by P. Loadman

Abstract 4926: Preclinical intratumoral pharmacokinetics (PK) of capecitabine (Cap) given +/- eribulin (Eri)

Cancer Research, 2018

Background: Eri & Cap are active as single agents in metastatic breast cancer, but the combinatio... more Background: Eri & Cap are active as single agents in metastatic breast cancer, but the combination appears particularly active & well tolerated clinically. We explored the hypothesis that normalisation of tumor vasculature by Eri seen in preclinical models may enhance delivery of Cap to the tumor when given in combination. Methods: Mice bearing MDA-MD-231 xenografts were treated with Cap 540mg/kg p.o. day 1 alone or following Eri 1mg/kg i.v. on day -8 then sacrificed on day 1 at 15min, 30min, 1h, 2h, 4h, 6h or 24h after Cap (n=3/ time point). Concentrations of Cap & its metabolites (5'-deoxy-5-fluorocytidine, 5DFCR; 5-Fluoro-5'-deoxyuridine, 5DFUR; 5-Fluorouracil, 5FU; 5-Fluorouridine, 5FUrd; & 5-Fluoro-2'-deoxyuridine, 5FdUrd) in plasma, tumor, skin & muscle were analysed by LC-MS/MS. Half the tumor was reserved to study Cap distribution using matrix-assisted laser desorption/ionization mass spectrometry imaging with haem imaged as a surrogate marker for tumour vasculat...

The role of MT1-MMP in the progression and metastasis of osteosarcoma

Journal of Cancer Metastasis and Treatment, 2022

The dysregulation of Membrane - type 1 matrix metalloproteinase (MT1-MMP) has been extensively st... more The dysregulation of Membrane - type 1 matrix metalloproteinase (MT1-MMP) has been extensively studied in numerous cancer types, and plays key roles in angiogenesis, cancer progression, and metastasis. MT1-MMP is a predictor of poor prognosis in osteosarcoma (OS), yet the molecular mechanisms of disease progression are unclear. This review provides a summary of the literature relating to the gene and protein expression of MT1-MMP (MMP-14) in OS clinical samples, evaluates the expression in cell lines and experimental models, and analyses its potential role in the progression and metastasis of OS. In addition, the therapeutic potential of MT1-MMP as a drug target has been assessed. Due to the biological complexity of MMPs, inhibition has proven to be challenging. However, exploiting the expression and proteolytic capacity of MT1-MMP could open new avenues in the search for novel, safer and selective drugs for use in OS.

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Midtrimester maternal erythrocyte fatty acid composition is not associated with adverse pregnancy outcomes

Targeted microbubbles carrying lipid-oil-nanodroplets for ultrasound-triggered delivery of the hydrophobic drug, combretastatin A4

Nanomedicine: Nanotechnology, Biology and Medicine, 2021

Nanomedicine: Nanotechnology, Biology, and Medicine xxx (2021) xxxxxx Targeted microbubbles carry... more

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Examination of the distribution of the bioreductive drug AQ4N and its active metabolite AQ4 in solid tumours by imaging matrix-assisted laser desorption/ionisation mass spectrometry

Rapid Communications in Mass Spectrometry, 2007

AQ4N (banoxatrone) (1,4-bis-{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-... more AQ4N (banoxatrone) (1,4-bis-{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione) is an example of a bioreductive prodrug in clinical development. In hypoxic cells AQ4N is reduced to the topoisomerase II inhibitor AQ4 (1,4-bis- {[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione). By inhibition of topoisomerase II within these hypoxic areas, AQ4N has been shown to sensitise tumours to existing chemo- and radiotherapy treatments. In this study the distribution of AQ4N and AQ4 in treated H460 human tumour xenografts has been examined by imaging matrix-assisted laser desorption/ionisation mass spectrometry. Images of the distribution of AQ4N and AQ4 have been produced that show little overlap. The distribution of ATP in the tumour xenografts was also studied as an endogenous marker of regions of hypoxia since concentrations of ATP are known to be decreased in these regions. The distribution of ATP was similar to that of AQ4N, i.e. in regions of abundant ATP there was no evidence of conversion of AQ4N into AQ4. This indicates that the cytotoxic metabolite AQ4 is confined to hypoxic regions of the tumour as intended.

Pyrrolobenzodiazepine-polyamide libraries: synthesis and DNA binding selectivity

JOURNAL …, 2003

Immunohistochemical analysis of NAD(P)H:quinone oxidoreductase and NADPH cytochrome P450 reductase in human superficial bladder tumours: Relationship between tumour enzymology and clinical outcome following intravesical mitomycin C therapy

International Journal of Cancer, 2004

A central theme within the concept of enzyme-directed bioreductive drug development is the potent... more A central theme within the concept of enzyme-directed bioreductive drug development is the potential to predict tumour response based on the profiling of enzymes involved in the bioreductive activation process. Mitomycin C (MMC) is the prototypical bioreductive drug that is reduced to active intermediates by several reductases including NAD(P)H:quinone oxidoreductase (NQO1) and NADPH cytochrome P450 reductase (P450R). The purpose of our study was to determine whether NQO1 and P450R protein expression in a panel of low-grade, human superficial bladder tumours correlates with clinical response to MMC. A retrospective clinical study was conducted in which the response to MMC of 92 bladder cancer patients was compared to the immunohistochemical expression of NQO1 and P450R protein in archived paraffin-embedded bladder tumour specimens. A broad spectrum of NQO1 protein levels exists in bladder tumours between individual patients, ranging from intense to no immunohistochemical staining. In contrast, levels of P450R were similar with most tumours having moderate to high levels. All patients were chemotherapy naïve prior to receiving MMC and clinical response was defined as the time to first recurrence. A poor correlation exists between clinical response and NQO1, P450R or the expression patterns of various combinations of the 2 proteins. The results of our study demonstrate that the clinical response of superficial bladder cancers to MMC cannot be predicted on the basis of NQO1 and/or P450R protein expression and suggest that other factors (other reductases or post DNA damage events) have a significant bearing on tumour response.

Organometallic osmium arene anticancer complexes

Abbreviations vii Chapter 1 Introduction Courses Attended (1) Transferable skills courses in Warw... more

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Design, synthesis, biophysical and biological evaluation of a series of methyl ester-terminated pyrrolobenzodiazepine (PBD)-poly (N-methylpyrrole) conjugates

Membrane-type matrix metalloproteinases: expression, roles in metastatic prostate cancer progression and opportunities for drug targeting

Journal of Cancer Metastasis and Treatment

The membrane-type matrix metalloproteinases (MT-MMPs), an important subgroup of the wider MMP fam... more The membrane-type matrix metalloproteinases (MT-MMPs), an important subgroup of the wider MMP family, demonstrate widespread expression in multiple tumor types, and play key roles in cancer growth, migration, invasion and metastasis. Despite a large body of published research, relatively little information exists regarding evidence for MT-MMP expression and function in metastatic prostate cancer. This review provides an appraisal of the literature describing gene and protein expression in prostate cancer cells and clinical tissue, summarises the evidence for roles in prostate cancer progression, and examines the data relating to MT-MMP function in the development of bone metastases. Finally, the therapeutic potential of targeting MT-MMPs is considered. While MT-MMP inhibition presents a significant challenge, utilisation of MT-MMP expression and proteolytic capacity in prostate tumors is an attractive drug development opportunity.

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OTU-023 Randomised trial of EPA and aspirin for colorectal cancer chemoprevention: the seafood polyp prevention trial

Colon and Anorectum

Evaluation of the safety of C-1311 administered in a phase 1 dose-escalation trial as a 1-hour infusion once every 3 weeks in patients with advanced solid tumors

Journal of Clinical Oncology

12005 Background: C-1311 (Symadex) is the most active member of a new series of anti-cancer agent... more 12005 Background: C-1311 (Symadex) is the most active member of a new series of anti-cancer agents, the imidazoacridinones, specially designed compounds developed from research on the structure-activity relationships of existing cancer therapies. This clinical trial was designed to assess the safety profile of ascending doses of C-1311 and to determine the recommended dose when administered every 3 weeks (Q3W). Methods: Patients with advanced solid tumors refractory to conventional therapy were enrolled. The dose escalation scheme was divided into 2 phases with different schedules. Initially, C-1311 was given as a 1-hour daily infusion over 5 consecutive days. Following review of pre-clinical data, coupled with preliminary results of a parallel weekly study, a day 1 only schedule was explored. The maximum tolerated dose (MTD) is defined as the dose at which 2/3 or 2/6 pts experience a dose-limiting toxicity (DLT). The recommended dose (RD) is defined as the dose level below the MTD,...

$Research paper thumbnail of Phase 1 dose escalation study of AQ4N, a selective hypoxic cell cytotoxin, with fractionated radiotherapy (RT): First report$

Phase 1 dose escalation study of AQ4N, a selective hypoxic cell cytotoxin, with fractionated radiotherapy (RT): First report

Journal of Clinical Oncology

Phase I study of the DNA minor groove binding pyrrolobenzodiazepine dimer (SJG 136) administered every 21 days in patients with advanced solid tumours

Journal of Clinical Oncology

A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of the combination of an oral antimicrotubular agent, DJ-927 (D), and capecitabine (C) in patients (Pts) with advanced solid tumors

Journal of Clinical Oncology

5-Fluorouracil (5FU) intratumoural pharmacokinetics: Rapid uptake in cells and in spheroids (SPH)

Annals of Oncology, 2016

24 INVITED The evolution of CYPs from metabolising enzymes to potential targets in cancer therapy development

European Journal of Cancer Supplements, 2008

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Practical Aspects of Pharmacokinetics and Pharmacodynamics

A Practical Guide, 2015

Abstract 2505: Expression profiling of cofilin-1 in breast cancer cell lines and biopsies

Cancer Research, 2013

ABSTRACT Introduction. Despite oestrogen and human epidermal growth factor receptor (HER2) target... more ABSTRACT Introduction. Despite oestrogen and human epidermal growth factor receptor (HER2) targeted therapies improving patient survival, breast cancer continues to be a significant cause of premature death since many tumors do not respond to treatment or acquire resistance. Hence there remains the need to identify novel targets for therapy and biomarkers for prediction of response to treatment. A quantitative proteomics study of matched normal and tumor biopsies identified 63 proteins to be significantly increased or decreased in stage-specific tumors. Some have previously been associated with breast cancer, while others such as cofilin-1 represent new targets for investigation. Cofilin-1 was subject to a range of analyses to determine its association with breast cancer. Materials and Methods. Western blotting (WB) was performed on protein extracts from breast cancer cell lines and matched normal and tumor biopsies from Cypriot patients with different stages of the disease. Immunohistochemistry (IHC) was carried out on core biopsies from the Leeds Breast Tissue Bank. Multiple reaction monitoring (MRM) mass spectrometry was performed on trypsin-digested protein extracts from biopsies. Data from protein (Human Protein Atlas) and genomics (BioGPS, TiGER, UniGene) databases were assimilated with the experimental results. Results. WB indicated that cofilin-1 was ubiquitously expressed in tumor cell lines, representative of Luminal A, Luminal B, basal-like, claudin-low and HER2 phenotypes, at higher levels than normal breast cell lines. WB also indicated increased expression of cofilin-1 in invasive carcinoma tissues, compared to matched normal. Patients with ductal carcinoma in situ or fibroadenoma exhibited less clear results, either increasing slightly or remaining unchanged. MRM analysis of three cofilin-1 peptides in tissue extracts of invasive carcinoma patients indicated expression only in tumor. IHC of core biopsies exhibited strong staining for cofilin-1 in ductal invasive carcinoma tissues with no staining in normal breast cells. Genomics and proteomics databases indicate that cofilin-1 is expressed in a diverse range of normal tissues including major organs, gastro-intestinal tract, skin and tonsils. However, mRNA and protein levels are observed to be increased in skin, lung, liver, pancreatic and breast tumors. Discussion. The original quantitative proteomics data indicated only relatively small changes in expression (less than 2-fold) due to dynamic range limitations of the technique. Additional analytical approaches substantiated that cofilin-1 is significantly up-regulated in advanced breast cancer patients. Further patient sets are required to confirm the importance of cofilin-1 levels in early stages of breast cancer compared to benign tissues. Bioinformatics provided further confidence in our findings, highlighting the value of utilising databases for evidence of disease-specific proteins.

122 POSTER In silico modelling of doxorubicin penetration through multicell layers

European Journal of Cancer Supplements, 2008

Background: Locked Nucleic Acid (LNA) antisense oligonucleotides (LNA-ONs) represents a new gener... more Background: Locked Nucleic Acid (LNA) antisense oligonucleotides (LNA-ONs) represents a new generation of RNA antagonists. Unlike previous chemistry, each LNA monomer contains a methylene bridge between the 2'-oxygen and 4'-carbon of the ribose sugar. This fixes the LNA residue in a favorable RNA-like conformation and enables LNA-ONs to have much higher affinity, specificity, and resistance against degradation compared with other oligonucleotides. While unmodified LNA-ONs have activity in vivo, improved tumor targeting may further enhance efficacy. To address this goal, we have used Customized linker technology to attach polyethylene glycol (PEG) to LNA-ONs via releasable linkers. Different size PEGs were evaluated. Methods: In vitro efficacy of PEG-LNA-ONs was evaluated in tumor cell lines after transfecting cells with lipofectamine. mRNA knockdown by PEG-LNA-ONs or unpegylated LNA-ONs were evaluated by qRT-PCR. Tumor and plasma distribution of PEG-LNA-ONs were measured in the A549 xenograft model. LNA-ON concentration in organs was evaluated by an ELISA hybridization assay. In vivo, knockdown of target mRNA was evaluated in liver and tumors derived of 15PC3 (prostate) and KB (epidermoid) cells implanted subcutaneously in nude mice. Results: PEG-LNA-ONs showed good stability in buffers and could be prepared in high yield. In vitro, PEG-LNA-ON resulted in potent knockdown of target mRNA in various cells lines (IC50 < 10 nM). In mice, naked LNA-ONs had a very short circulation time. In contrast, PEG-LNA-ON had >50fold higher concentration of LNA-ON in circulation (at 2 h and 4 h) compared to naked LNA-ON. At 24 h post injection, PEG-LNA-ON conjugates had 3-fold more accumulation in tumors compared to naked LNA-ONs. The higher molecular weight PEG (40 KDa) conjugates had better tumor accumulation than lower MW PEG (10 KDa) conjugates. Treatment with PEG-LNA-ON (q3dx4) increased knockdown of target mRNA by 2-fold in 15PC3 and KB xenografts models. Additionally, PEG-LNA-ON resulted in >85% knockdown of target mRNA in mouse liver. Conclusions: Releasable PEGylation of LNA-ONs enhances the tumor targeting and efficacy of LNA-ONs. The improved effects may be due to the enhanced permeability and retention within the tumor, which has previously been observed with PEGylated molecules. Customized PEG linkers may enhance the in vivo delivery of RNA antagonists and subsequently improve efficacy.

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Abstract 4926: Preclinical intratumoral pharmacokinetics (PK) of capecitabine (Cap) given +/- eribulin (Eri)

Cancer Research, 2018

The role of MT1-MMP in the progression and metastasis of osteosarcoma

Journal of Cancer Metastasis and Treatment, 2022

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Midtrimester maternal erythrocyte fatty acid composition is not associated with adverse pregnancy outcomes

Targeted microbubbles carrying lipid-oil-nanodroplets for ultrasound-triggered delivery of the hydrophobic drug, combretastatin A4

Nanomedicine: Nanotechnology, Biology and Medicine, 2021

Nanomedicine: Nanotechnology, Biology, and Medicine xxx (2021) xxxxxx Targeted microbubbles carry... more

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Examination of the distribution of the bioreductive drug AQ4N and its active metabolite AQ4 in solid tumours by imaging matrix-assisted laser desorption/ionisation mass spectrometry

Rapid Communications in Mass Spectrometry, 2007

Pyrrolobenzodiazepine-polyamide libraries: synthesis and DNA binding selectivity

JOURNAL …, 2003

International Journal of Cancer, 2004

Organometallic osmium arene anticancer complexes

Abbreviations vii Chapter 1 Introduction Courses Attended (1) Transferable skills courses in Warw... more

Download

Design, synthesis, biophysical and biological evaluation of a series of methyl ester-terminated pyrrolobenzodiazepine (PBD)-poly (N-methylpyrrole) conjugates

Membrane-type matrix metalloproteinases: expression, roles in metastatic prostate cancer progression and opportunities for drug targeting

Journal of Cancer Metastasis and Treatment

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OTU-023 Randomised trial of EPA and aspirin for colorectal cancer chemoprevention: the seafood polyp prevention trial

Colon and Anorectum

Evaluation of the safety of C-1311 administered in a phase 1 dose-escalation trial as a 1-hour infusion once every 3 weeks in patients with advanced solid tumors

Journal of Clinical Oncology

$Research paper thumbnail of Phase 1 dose escalation study of AQ4N, a selective hypoxic cell cytotoxin, with fractionated radiotherapy (RT): First report$

Phase 1 dose escalation study of AQ4N, a selective hypoxic cell cytotoxin, with fractionated radiotherapy (RT): First report

Journal of Clinical Oncology

Phase I study of the DNA minor groove binding pyrrolobenzodiazepine dimer (SJG 136) administered every 21 days in patients with advanced solid tumours

Journal of Clinical Oncology

A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of the combination of an oral antimicrotubular agent, DJ-927 (D), and capecitabine (C) in patients (Pts) with advanced solid tumors

Journal of Clinical Oncology

5-Fluorouracil (5FU) intratumoural pharmacokinetics: Rapid uptake in cells and in spheroids (SPH)

Annals of Oncology, 2016

24 INVITED The evolution of CYPs from metabolising enzymes to potential targets in cancer therapy development

European Journal of Cancer Supplements, 2008

Download

Practical Aspects of Pharmacokinetics and Pharmacodynamics