N. de Vries

Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)gene dosage on plasma pharmacokinetics and brain accumulation of dasatinib, sorafenib and sunitinib

Low brain accumulation of anticancer drugs due to efflux transporters may limit chemotherapeutic efficacy, necessitating a better understanding of the underlying mechanisms. P-glycoprotein (Abcb1a/1b) and breast cancer resistance protein (Abcg2) combination knockout mice often display disproportionately increased brain accumulation of shared drug substrates compared with single transporter knockout mice. Recently developed pharmacokinetic models could explain this phenomenon. To experimentally test these models and their wider relevance for tyrosine kinase inhibitors and other drugs, we selected dasatinib, sorafenib, and sunitinib because of their divergent oral availability and brain accumulation profiles: the brain accumulation of dasatinib is mainly restricted by Abcb1, that of sorafenib mainly by Abcg2, and that of sunitinib equally by Abcb1 and Abcg2. We analyzed the effect of halving the efflux activity of these transporters at the blood-brain barrier by generating heterozygous Abcb1a/1b;Abcg2 knockout mice and testing the plasma and brain levels of the drugs after oral administration at 10 mg/kg. Real-time reverse transcription-polymerase chain reaction analysis confirmed the ∼2-fold decreased expression of both transporters in brain. Interestingly, whereas complete knockout of the transporters caused 24- to 36-fold increases in brain accumulation of the drugs, the heterozygous mice only displayed 1.6- to 1.9-fold increases of brain accumulation relative to wild-type mice. These results are well in line with the predictions of the pharmacokinetic models and provide strong support for their validity for a wider range of drugs. Moreover, retrospective analysis of fetal accumulation of drugs across the placenta in Abcb1a/1b heterozygous knockout pups suggests that these models equally apply to the maternal-fetal barrier.

Chemoprevention in the management of oral cancer: EUROSCAN and other studies

patients with squamous cell cancer of the head and neck. They occur in 15-30%, mainly in the upper aerodigestive tract [l31. The majority occurs more than 6 months after the index tumour and are called “metachronous”; when they occur within 6 months “synchronous.” They occur more in males than in females and usually have a bad prognosis because they often occur at bad sites (lung/oesophagus) or in already treated areas rendering curative treatment difficult or impossible. In certain early stage diseases such as TlNO laryngeal cancer the risk of death from a later lung cancer is greater than from the primary disease. For this reason second primary tumours are regarded as the “overshadowing threat” to early stage head and neck cancer patients [4]. Second tumours are one of the main reasons that despite many advances in the treatment of head and neck cancer (e.g. in reconstructive surgery or combined treatment modalities), long time survival has only marginally increased in the past decades. Interest in the phenomenon has increased. During the past 10 years much has become known of their aetiology and pathogenesis, frequency and preferred sites. Research on the value of screening and (chemo)prevention has taken place and is still in progress, Next to many similarities, important differences are present for the four sites: oral cavity, oro- and hypopharynx and larynx, with regard to site relationships, frequency and geographic differences in it and clinical differences. For example, in laryngeal cancer, many patients present with early stage disease and have higher than 90% 5 year survival rates, making early detection or prevention measures relatively more important than in oral cancer, oro- and hypopharyngeal cancer in which many patients present with advanced disease. In addition, preferred sites have been documented; in laryngeal cancer more than half of all second tumours occur in the lung, whereas in the three other sites they occur spread over the whole of the upper aerodigestive tract. In this paper, we will focus on the problem of second tumours in oral cancer with emphasis on the role of chemoprevention.

Euroscan: the European Organization for Research and Treatment of Cancer (EORTC): Chemoprevention study in lung cancer

Cancers of the lung and head and neck arise as a focal transformation by cigarette smoke of chronically injured epithelium as one of its well recognized causes [7]. Cigarette smoke contains several (pro)carcinogens, and free radicals also [29], and it is in fact surprising that not every smoker becomes a victim of malignant disease (Table 1). It is important to realize that clinical cancer represents only the visible top of a huge iceberg. The submerged base symbolizes the interaction between lifestyle, environmental risk factors and the formidable host defense machinery, protecting the organism along all stages of disease development [2]. Two features of the host defense mechanisms are of particular interest: (a) the one governed by interindividual variability factors, which explains the individual susceptibility to carcinogenic agents, and (b) the fact that host defense mechanisms can be modulated by exogenous interventions.

Chemoprevention of Head and Neck and Lung (Pre)Cancer

Oral cancer is often preceded by precancerous lesions, the most common of which is leukoplakia. Several treatment modalities are available: elimination of the possible cause, cold knife, laser, or cryosurgery, and topical application of bleomycin and 5-fluorouracil. In research, oral leukoplakia is used as a model to study the value of chemoprevention as a strategy to prevent cancer, because its effect is directly visible and material for analysis is easily obtainable from the mouth. In several studies and chemoprevention trials the efficacy of retinoids, retinol and/or beta-carotene on oral leukoplakia has been demonstrated. Second primary tumors occur in 10-30% of head and neck cancer patients and 10% of lung cancer patients. Chemoprevention offers an attractive approach to combat this threat to such patients, which is bound to cast a shadow over their lives. In the last 10-15 years several chemoprevention studies with vitamin A, retinoids or agents working through other mechanisms (antioxidants) have been launched. The largest chemoprevention study in curatively treated early-stage oral cancer, laryngeal cancer and lung cancer (N = 2595) is EUROSCAN, an EORTC study initiated in 1988. End-points are second tumors, local/regional recurrence and distant metastases, and long-term survival rates. Preminary results will be available in 1998.

Determination of platinum surface contamination in veterinary and human oncology centres using inductively coupled plasma mass spectrometry

The objective of this study was to determine the surface contamination with platinum-containing antineoplastic drugs in veterinary and human oncology centres. Inductively coupled plasma mass spectrometry was used to measure platinum levels in surface samples. In veterinary and human oncology centres, 46.3 and 68.9% of the sampled surfaces demonstrated platinum contamination, respectively. Highest platinum levels were found in the preparation rooms (44.6 pg cm(-2)) in veterinary centres, while maximal levels in human centres were found in oncology patient-only toilets (725 pg cm(-2)). Transference of platinum by workers outside areas where antineoplastic drugs were handled was observed in veterinary and human oncology centres. In conclusion, only low levels of platinum contamination attributable to carboplatin were found in the sampled veterinary oncology centres. However, dispersion of platinum outside areas where antineoplastic drugs were handled was detected in veterinary and human oncology centres. Consequently, not only personnel, but also others may be exposed to platinum.

Development and validation of a liquid chromatography–tandem mass spectrometry analytical method for the therapeutic drug monitoring of eight novel anticancer drugs

To support therapeutic drug monitoring of patients with cancer, a fast and accurate method for simultaneous quantification of the registered anticancer drugs afatinib, axitinib, ceritinib, crizotinib, dabrafenib, enzalutamide, regorafenib and trametinib in human plasma using liquid chromatography tandem mass spectrometry was developed and validated. Human plasma samples were collected from treated patients and stored at -20°C. Analytes and internal standards (stable isotopically labeled analytes) were extracted with acetonitrile. An equal amount of 10 mm NH4 CO3 was added to the supernatant to yield the final extract. A 2 μL aliquot of this extract was injected onto a C18 -column, gradient elution was applied and triple-quadrupole mass spectrometry in positive-ion mode was used for detection. All results were within the acceptance criteria of the latest US Food and Drug Administration guidance and European Medicines Agency guidelines on method validation, except for the carry-over of ceritinib and crizotinib. These were corrected for by the injection order of samples. Additional stability tests were carried out for axitinib and dabrafenib in relation to their reported photostability. In conclusion, the described method to simultaneously quantify the eight selected anticancer drugs in human plasma was successfully validated and applied for therapeutic drug monitoring in cancer patients treated with these drugs.

Inductively coupled plasma mass-spectrometric determination of platinum in excretion products of client-owned pet dogs.

Residues of antineoplastic drugs in canine excretion products may represent exposure risks to veterinary personnel, owners of pet dogs and other animal care-takers. The aim of this study was to measure the extent and duration of platinum (Pt) excretion in pet dogs treated with carboplatin. Samples were collected before and up to 21 days after administration of carboplatin. We used validated, ultra-sensitive, inductively coupled plasma-mass spectrometry assays to measure Pt in canine urine, faeces, saliva, sebum and cerumen. Results showed that urine is the major route of elimination of Pt in dogs. In addition, excretion occurs via faeces and saliva, with the highest amounts eliminated during the first 5 days. The amount of excreted Pt decreased over time but was still quantifiable at 21 days after administration of carboplatin. In conclusion, increased Pt levels were found in all measured excretion products up to 21 days after administration of carboplatin to pet dogs, with urine as the main route of excretion. These findings may be used to further adapt current veterinary guidelines on safe handling of antineoplastic drugs and treated animals.