Balaji Venugopal

Gold Nanoparticles for the Improved Anticancer Drug Delivery of the Active Component of Oxaliplatin

The platinum-based anticancer drugs cisplatin, carboplatin, and oxaliplatin are an important component of chemotherapy but are limited by severe dose-limiting side effects and the ability of tumors to develop resistance rapidly. These drugs can be improved through the use of drug-delivery vehicles that are able to target cancers passively or actively. In this study, we have tethered the active component of the anticancer drug oxaliplatin to a gold nanoparticle for improved drug delivery. Naked gold nanoparticles were functionalized with a thiolated poly(ethylene glycol) (PEG) monolayer capped with a carboxylate group. [Pt(1R,2R-diaminocyclohexane)(H2O)2]2NO3 was added to the PEG surface to yield a supramolecular complex with 280 (±20) drug molecules per nanoparticle. The platinum-tethered nanoparticles were examined for cytotoxicity, drug uptake, and localization in the A549 lung epithelial cancer cell line and the colon cancer cell lines HCT116, HCT15, HT29, and RKO. The platinum-tethered nanoparticles demonstrated as good as, or significantly better, cytotoxicity than oxaliplatin alone in all of the cell lines and an unusual ability to penetrate the nucleus in the lung cancer cells.

Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect

The cucurbit[n]uril (CB[n]) family of macrocycles has been shown to have potential in drug delivery where they are able to provide physical and chemical stability to drugs, improve drug solubility, control drug release and mask the taste of drugs. Cisplatin is a small molecule platinum-based anticancer drug that has severe dose-limiting side-effects. Cisplatin forms a host-guest complex with cucurbit[7]uril (cisplatin@CB[7]) with the platinum atom and both chlorido ligands located inside the macrocycle, with binding stabilised by four hydrogen bonds (2.15-2.44 Å). Whilst CB[7] has no effect on the in vitro cytotoxicity of cisplatin in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant sub-lines A2780/cp70 and MCP1, there is a significant effect on in vivo cytotoxicity using human tumour xenografts. Cisplatin@CB[7] is just as effective on A2780 tumours compared with free cisplatin, and in the cisplatin-resistant A2780/cp70 tumours cisplatin@CB[7] markedly slows tumour growth. The ability of cisplatin@CB[7] to overcome resistance in vivo appears to be a pharmacokinetic effect. Whilst the peak plasma level and tissue distribution are the same for cisplatin@CB[7] and free cisplatin, the total concentration of circulating cisplatin@CB[7] over a period of 24 hours is significantly higher than for free cisplatin when administered at the equivalent dose. The results provide the first example of overcoming drug resistance via a purely pharmacokinetic effect rather than drug design or better tumour targeting, and demonstrate that in vitro assays are no longer as important in screening advanced systems of drug delivery.

An open-label study to describe pharmacokinetic parameters of erlotinib in patients with advanced solid tumors with adequate and moderately impaired hepatic function

PurposeTo compare the pharmacokinetic (PK) parameters of a single dose of erlotinib in cancer patients with moderate hepatic impairment (MHI) to those of cancer patients with adequate hepatic function (AHF).MethodsCancer patients with either AHF or MHI were treated with a single 150xa0mg dose of erlotinib on day 1 only followed by 96xa0h of plasma sampling for PK assessment. From day 5, patients were allowed to continue daily erlotinib in a maintenance phase. Non-smoking patients were stratified into an AHF cohort (total bilirubinxa0≤xa0upper limit of normal [ULN] and ALT/ASTxa0≤xa01.5xa0Xxa0ULN) or a MHI cohort (Child-Pugh score of 7–9). The frequency of adverse events and laboratory changes were assessed.ResultsThirty-six patients, 21 with AHF and 15 with MHI, received at least one dose of erlotinib. The PK of erlotinib was similar between the two cohorts with a median Cmax of 1.09 versus 0.828xa0μg/mL and corresponding median AUC0−t 29.3 versus 30.5xa0μgxa0h/mL for the AHF and MHI cohorts, respectively. Adverse events from erlotinib in cancer patients with MHI were consistent with the known safety profile.ConclusionsThe PK and safety profiles of erlotinib in patients with MHI were similar to those with AHF. As a result, a reduced starting dose of erlotinib in patients with MHI is not required and treatment should be guided by patients’ tolerability.

Efficacy of temsirolimus in metastatic chromophobe renal cell carcinoma

BackgroundRenal cell carcinoma (RCC) is a histopathologically and molecularly heterogeneous disease with the chromophobe subtype (chRCC) accounting for approximately 5% of all cases. The median overall survival of advanced RCC has improved significantly since the advent of tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors. However, high-quality evidence for the use of new generation tyrosine kinase inhibitors in patients with advanced chRCC is lacking. Few published case reports have highlighted the use of temsirolimus in chRCC.Case presentationHere, we report the case of a 36-year-old Caucasian woman with metastatic chRCC with predominantly skeletal metastases who was refractory to sunitinib who demonstrated a durable clinical response to temsirolimus lasting 20 months. We review the available evidence pertaining to the use of new generation molecularly targeted agents, in particular mTOR inhibitors in chRCC and discuss their emerging role in the management of this disease which would aid the oncologists faced with the challenge of treating this rare type of RCC.ConclusionConducting randomised clinical trials in this rarer sub-group of patients would be challenging and our case report and the evidence reviewed would guide the physicians to make informed decision regarding the management of these patients.

A first-in-human phase i and pharmacokinetic study of CP-4126 (CO-101), a nucleoside analogue, in patients with advanced solid tumours

AbstractBackgroundnCP-4126 (gemcitabine elaidate, previously CO-101) is a lipid–drug conjugate of gemcitabine designed to circumvent human equilibrative nucleoside transporter1-related resistance to gemcitabine. The purpose of this study was to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of CP-4126, and to describe its pharmacokinetic profile.MethodsEligible patients with advanced refractory solid tumours, and adequate performance status, haematological, renal and hepatic function, were treated with one of escalating doses of CP-4126 administered by a 30-min intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Blood and urine samples were collected to determine the pharmacokinetics (PKs) of CP-4126.ResultsForty-three patients, median age 59xa0years (range 18–76; malexa0=xa027, femalexa0=xa016), received one of ten dose levels (30–1600xa0mg/m2). Dose-limiting toxicities included grade 3 anaemia, grade 3 fatigue and grade 3 elevation of transaminases. The MTD and RP2D were 1250xa0mg/m2 on basis of the toxicity and PK data. CP-4126 followed dose-dependent kinetics and maximum plasma concentrations occurred at the end of CP-4126 infusion. Seven patients achieved stable disease sustained for ≥3xa0months, including two patients with pancreatic cancer who had progressed on or after gemcitabine exposure.ConclusionsCP-4126 was well tolerated with comparable toxicity profile to gemcitabine. Future studies are required to determine its anti-tumour efficacy, either alone or in combination with other cytotoxic chemotherapy regimens.

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma.

Background:The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine.Methods:A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000u2009mgu2009m-2, was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D). Secondary and tertiary objectives included tumour response, plasma and tumour MK-0752 concentration, and inhibition of the Notch pathway in hair follicles and tumour.Results:Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800u2009mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response.Conclusions:Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.

Coexistent malignant melanoma and renal cell carcinoma

Patients with malignant melanoma are at an increased risk of developing subsequent primary melanomas and also nonmelanoma cutaneous cancers. Several studies have reported an association between malignant melanoma and breast cancer, bladder cancer, colorectal cancer, neuroectodermal tumours, non-Hodgkins lymphoma, leukaemia and renal cell carcinoma. We report a case series of patients with a diagnosis of malignant melanoma who also developed a renal mass. In two of these cases, the renal mass became apparent on diagnostic imaging as part of the staging investigations at the time of initial diagnosis of the malignant melanoma. In both of these cases, biopsy of the renal mass confirmed the presence of a separate primary renal cell carcinoma which had presented concurrently with the malignant melanoma. A third case presented with bone metastases ten years after excision of a thin melanoma. Further imaging revealed pulmonary metastases and a renal mass, biopsy of which confirmed renal cell carcinoma. In contrast, a fourth patient underwent a right nephrectomy for a renal mass having presented with abdominal discomfort. The histology of this lesion was in keeping with metastatic melanoma, and the patients past history included a diagnosis of ocular melanoma eight years prior to the development of metastatic disease in the right kidney. Survival rates for patients with many types of malignant disease are improving, and there have been significant advances in clinical imaging techniques. Consequently the development and detection of a second primary cancer, either presenting concurrently or on subsequent follow-up, is likely to be increasingly observed. The series of patients reported here highlights the importance of a diagnostic biopsy in patients with malignant melanoma who develop a renal mass in order to establish a diagnosis and to plan optimal treatment.

Real world uptake, safety profile and outcomes of docetaxel in newly diagnosed metastatic prostate cancer

To investigate the uptake, safety and efficacy of docetaxel chemotherapy in hormone‐naïve metastatic prostate cancer (mPC) in the first year of use outside of a clinical trial.