While cisplatin and carboplatin are active versus most common cancers, epithelial malignancies are incurable when metastatic. Even if an initial response occurs, acquired resistance due to mutations and epigenetic events limits efficacy. Resistance may be due to excess of a resistance factor, to saturation of factors required for tumor cell killing, or to mutation or alteration of a factor required for tumor cell killing. Platinum resistance could arise from decreased tumor blood flow, extracellular conditions, reduced platinum uptake, increased efflux, intracellular detoxification by glutathione, etc., decreased binding (e.g., due to high intracellular pH), DNA repair, decreased mismatch repair, defective apoptosis, antiapoptotic factors, effects of several signaling pathways, or presence of quiescent non-cycling cells. In lung cancer, flattening of dose-response curves at higher doses suggests that efficacy is limited by exhaustion of something required for cell killing, and several clinical observations suggest epigenetic events may play a major role in resistance.

Mechanisms of resistance to cisplatin and carboplatin

Between 100,000 and 170,000 patients with cancer develop central nervous system (CNS) metastases each year in the U.S., of which approximately 20% carry a primary diagnosis of breast cancer. As a consequence of improvements in systemic therapy, which have allowed patients to live longer with advanced cancer, CNS metastases are emerging as an important sanctuary site, and the incidence may be increasing in patients with particular tumor subtypes. Unless there are improvements in the treatment of CNS disease, a growing proportion of patients may be at risk of experiencing both morbidity and mortality as a result of uncontrolled CNS progression, often at a time when their extra-CNS disease is apparently under control. This article reviews changes in the epidemiology and natural history of women with brain metastases from HER2-positive breast cancer over the last decade and presents the therapeutic challenges and opportunities that have arisen in this setting. First, the apparent increase in CNS disease among women with HER2-positive breast cancer, relative to historical controls, is discussed, followed by consideration of potential causes of this observation. Next, the implications of CNS disease, in terms of prognosis and the potential development of preventive strategies are considered. Finally, new developments in systemic approaches to the treatment of CNS disease, including cytotoxic chemotherapy and targeted therapy, are explored.

https://clincancerres.aacrjournals.org/content/clincanres/13/6/1648.full.pdf

Brain Metastases: The HER2 Paradigm

Purpose This review assesses the current state of knowledge regarding preclinical and clinical pharmacology for brain tumor chemotherapy and evaluates relevant brain tumor pharmacology studies before October 2006. Results Chemotherapeutic regimens in brain tumor therapy have often emerged from empirical clinical studies with retrospective pharmacologic explanations, rather than prospective trials of rational chemotherapeutic approaches. Brain tumors are largely composed of CNS metastases of systemic cancers. Primary brain tumors, such as glioblastoma multiforme or primary CNS lymphomas, are less common. Few of these tumors have well-defined optimal treatment. Brain tumors are protected from systemic chemotherapy by the blood-brain barrier (BBB) and by intrinsic properties of the tumors. Pharmacologic studies of delivery of conventional chemotherapeutics and novel therapeutics showing actual tumor concentrations and biologic effect are lacking. Conclusion In this article, we review drug delivery across the BBB, as well as blood-tumor and ‐cerebrospinal fluid (CSF) barriers, and mechanisms to increase drug delivery to CNS and CSF tumors. Because of the difficulty in treating CNS tumors, innovative treatments and alternative delivery techniques involving brain/cord capillaries, choroid plexus, and CSF are needed. J Clin Oncol 25:2295-2305. © 2007 by American Society of Clinical Oncology

Chemotherapy delivery issues in central nervous system malignancy: a reality check.

Case Report A 62-year-old right-handed white woman presented with periodic motion-related nausea and vertigo. On physical examination, she had only mild high-frequency hearing loss on the right side. Cranial magnetic resonance imaging (MRI) revealed an unresectable contrast-enhancing lesion measuring 3.6 cm in maximal horizontal diameter within the genu of the corpus callosum, with surrounding abnormal T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity. Stereotactic biopsy of the contrast-enhancing lesion established the diagnosis of glioblastoma (GBM), WHO grade 4. Her tumor tissue was tested for genetic abnormalities using a comprehensive panel that included screening for commonly mutated loci in 15 cancer-related genes using a multiplex polymerase chain reaction platform (SNaPshot, Version 3; Applied Biosystems, Carlsbad, CA); amplification of the mesenchymal-epithelial transition (MET), epidermal growth factor receptor (EGFR), and plateletderived growth factor receptor A (PDGFRA) genes using fluorescence in situ hybridization (FISH); status of chromosomes 1p and 19q by FISH; and O-6-methylguanine-DNA methyltransferase (MGMT) promoter DNA methylation status by methylationspecific polymerase chain reaction. Her tumor was found to have MET gene amplification by a dual-color FISH assay using probes for the MET locus (Fig 1, pink dots) and centromere 7 (Fig 1, aqua dots), which served as a copy-number control. In addition, the MGMT promoter was methylated. She was enrolled onto a clinical trial for patients with newly diagnosed GBM that combined the standard regimen of concurrent radiation and temozolomide followed by monthly temozolomide with cediranib, an oral small-molecule pan–vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor. After five postradiation cycles of temozolomide and cediranib, she developed headaches, fatigue, disorientation, and short-term memory loss. A cranial MRI examination demonstrated increased size of the contrast-enhancing lesion and significantly increased surrounding T2/FLAIR hyperintensity consistent with progressive disease. Administration of dexamethasone was started at 4 mg per day, and subsequently, her headache intensity mildly decreased. Her MET amplification status enabled her to enroll onto the MET-amplification/mutation enriched molecular cohort of a phase I trial of crizotinib (PF-02341066), an oral small-molecule inhibitor of the MET and anaplastic lymphoma kinase (ALK) tyrosine kinases, in patients with advanced cancer (A8081001). This cohort includes patients with tumors harboring specific genetic alterations in MET or ALK independent of tumor type, including MET gene amplification, kinase domain activating mutation, or other chromosomal translocations leading to altered transcriptional regulation of MET as well as ALK chromosomal translocation or gene amplification. She began receiving crizotinib 250 mg twice daily, and within 2 weeks, her headaches and short-term memory had significantly improved, and she was able to decrease her dexamethasone dose to 1 mg daily. Her first scheduled cranial MRI examination performed after two 28-day cycles of crizotinib demonstrated a 40% reduction (using two-dimensional measurements) of the contrast-enhancing lesion (Fig 2A) and decreased surrounding T2/FLAIR hyperintensity (Fig 2B). After four cycles, a restaging cranial MRI examination confirmed a stable 40% reduction in size of the contrast-enhancing lesion. She was neurologically stable, and dexamethasone was discontinued. One week before her sixth cycle, she developed increased disorientation, short-term memory loss, headaches, and nausea. At that time, a scheduled restaging cranial MRI examination demonstrated interval increase in size of the contrast-enhancing lesion consistent with progressive disease. Administration of crizotinib was stopped 6 months after initiation of treatment. The only adverse effects attributed to crizotinib were asymptomatic elevated ALT (grade 2) and hypophosphatemia (grade 2). During the third crizotinib cycle, she developed left popliteal venous thrombosis (grade 2) and began receiving enoxaparin. She subsequently developed small, asymptomatic peritumoral hemorrhages (grade 1) that were noted incidentally on her cranial MRI examination at the end of cycle four. The hemorrhages were attributed to enoxaparin therapy. Enoxaparin was then discontinued, and an inferior vena cava filter was placed. Crizotinib was postponed for 1 week and then restarted after a cranial computed tomography scan showed no extension of the hemorrhages. At the time of crizotinib discontinuation, a cranial MRI confirmed stability of the peritumoral hemorrhages since their discovery. Fig 1. JOURNAL OF CLINICAL ONCOLOGY D I A G N O S I S I N O N C O L O G Y VOLUME 30 NUMBER 3 JANUARY 2

Rapid Radiographic and Clinical Improvement After Treatment of a MET-Amplified Recurrent Glioblastoma With a Mesenchymal-Epithelial Transition Inhibitor

Imaging mass cytometry was used for direct visualization of platinum localization in tissue sections from tumor and normal tissues of cisplatin-treated mice bearing pancreas cancer patient-derived xenografts. This recently-developed technology enabled simultaneous detection of multiple markers to define cell lineage, DNA damage response, cell proliferation and functional state, providing a highly detailed view of drug incorporation in tumor and normal tissues at the cellular level. A striking and unanticipated finding was the extensive binding of platinum to collagen fibers in both tumor and normal mouse tissues. Time course experiments indicated the slow release of stroma-bound platinum, although it is currently unclear if released platinum retains biological activity. Imaging mass cytometry offers a unique window into the in vivo effects of platinum compounds, and it is likely that this can be extended into the clinic in order to optimize the use of this important class of agent.

/pdf/biodistribution-of-cisplatin-revealed-by-imaging-mass-59ii7grtcu.pdf

Biodistribution of cisplatin revealed by imaging mass cytometry identifies extensive collagen binding in tumor and normal tissues.

We assessed factors which affect cisplatin concentrations in human surgical tumour specimens. Cisplatin 10 mg m-2 was given i.v. to 45 consenting patients undergoing surgical resection of neoplasms, and platinum was assayed in resected tumour and in deproteinated plasma by flameless atomic absorption spectrophotometry. By multiple stepwise regression analysis of normalised data, patient characteristics that emerged as being most closely associated (P 'others' > lung cancer > head/neck cancer > gliomas) or tumour 'type' (LMM > brain metastases > extracerebral tumours > gliomas), serum calcium and chloride (positive correlations) and bilirubin (negative). Tumour location (intracranial vs extracranial) did not correlate with platinum concentrations. If values for a single outlier were omitted, high-grade gliomas had significantly higher platinum concentrations (P < 0.003) than low-grade gliomas. For intracranial tumours, the computerised tomographic scan feature that correlated most closely with platinum concentrations in multivariate analysis was the darkness of peritumoral oedema. Tumour source or type is a much more important correlate of human tumour cisplatin concentrations than is intracranial vs extracranial location. Serum calcium, chloride and bilirubin levels may affect tumour cisplatin uptake or retention. CT scan characteristics may help predict cisplatin concentrations in intracranial tumours.

Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

A Lamothe

Author Tools

Chat about Author

Papers

Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin