A 38-year-old woman with adenocarcinoma of unknown origin was treated with cisplatin and etoposide. After the 4th course of chemotherapy she complained of blindness and had a seizure with spontaneous recovery in 4 days. The relationship between these events and the known neurotoxicity of other heavy metals indicate cisplatin as a possible etiologic factor.
Pharmacokinetic measurements to monitor and design cytotoxic treatments in cancer patients are being used more and more in order to optimize dosage and administration schedules. Ideally, information on drug concentrations over time should help reveal dose—response correlations. The cytotoxic drugs carmustine, etoposide, cyclophosphamide, iphosphamide, cis‐diammineplatinum, Adriamycin (doxorubicin), and 4′‐epi‐Adriamycin have been monitored on different treatment programs of patients with advanced lung cancers. The collected experience emphasizes the many individual variables encountered in clinical practice complicating the effort of correlating pharmacokinetic data with clinical results. The examples, presented on the basis of the authors' experiences, pertain to drug instability, gastrointestinal absorption, enzymatic induction in the liver, drug interaction, and drug tissue concentrations.
Differential pulse polarographic assay of the antineoplastic agent cis-dichlorodiamineplatinum II and its analogues was performed after acid oxidative hydrolysis (HClO4, HNO3, HCl) of biological samples (plasma, tissue homogenates, urine) and reaction with ethylenediamine. Platinum levels and kinetics were determined in blood and urine of patients with non-oat-cell lung carcinoma. Detection limit of the polarographic assay was 0.5 ng platinum; analytical error was +/- 3%. Levels of free cis-dichlorodiamineplatinum (II) in plasma fell in samples stored at -20 degrees C; the half-life of free drug was 38 h.
Background: Platinum-based doublets are the standard chemotherapy for lung cancer. The identification of markers associated with drug-toxicity may improve the success of the treatment. Single nucleotide polymorphisms (SNPs) mapping into the genes involved in platinum transport or detoxification may explain occurrence of toxicities. In this study, we evaluated the role of 3 SNPs in predicting the onset of adverse events for lung cancer patients receiving cisplatin or carboplatin in adjuvant, neo-adjuvant and metastatic settings.
Methods: Eighty-two patients affected by non-small-cell and small-cell lung cancer treated with cisplatin-or carboplatin-based chemotherapy (stage II-IV) were enrolled. Before genetic analysis, patients signed a written informed consent. DNA was extracted from peripheral blood samples and genotypes were determined by Real-Time PCR. We selected and analyzed 3 SNPs: ABCB1 c.3435C>T/rs1045642, ABCC2 -24C>T/rs717620 and GSTP1 c.313A>G/rs1695. Patient characteristics and genotypes were correlated with haematological, gastrointestinal and renal toxicity as recorded by Common Terminology Criteria for Adverse Event (CTCAE) v4.03. No neurological toxicity was observed in our patients. Results: Variant alleles were present in 53% of patients for ABCB1 c.3435C>T, 18.3% for ABCC2 -24C>T, and 34.8% for GSTP1 c.313A>G. Heterozygous CT at ABCB1 c.3435 were associated to a lower risk of haematological toxicity compared to homozygous CC (OR=0.20; 95% CI 0.05, 0.69; p=0.01). Similar results were observed by genetic dominant model (CT+TT vs CC) and haematological toxicity (OR=0.26; 95% CI 0.09, 0.79; p=0.02).No other significant associations were found between toxicity and SNPs. Multivariate analysis confirmed an independent value for the ABCB1 c.3435 C>T polymorphism.
Conclusions:The present study reveals that ABCB1 c.3435C> T polymorphism influences platinum toxicity. The T allele seems to exert a protective effect on the development of toxicities. Further studies, such as epigenetic regulation ones, are needed to validate and shed more light on this association.
The disappearance of 1,3-bis(2-chlorethyl)-1-nitrosourea (BCNU) from plasma, liver, kidney, lung, brain, spleen, tumor tissue and epididymal adipose tissue of Walker 256/B carcinoma-bearing rats and healthy animals was measured by differential pulse polarography after i.v. bolus of the drug. Only BCNU, not its decomposition products, was detected by the polarographic assay. Levels of BCNU in liver of tumor-bearing animals were significantly lower (about 10 times) than those on healthy rats. A bi-exponential fit was used to calculate the kinetics of BCNU in plasma, kidney, lung and brain, but no difference could be found between healthy and Walker tumor-bearing rats. BCNU disappeared faster from adipose tissue of tumor-bearing animals than from normals.
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