Morphometric study of myocardial changes during doxorubicin-induced cardiomyopathy in mice

Doxorubicin (DOX) is one of the most effective anti-cancer drugs in oncology, but may cause a cumulative dose-dependent cardiomyopathy in a number of cancer patients. The effect of DOX on the heart was studied in mice treated with i.v. injections of 2 mg/kg by measuring morphometric parameters, including nuclear index (number of non-myocytes/number of myocyte nuclei), reticulin index (reticulin area/number of myocyte transsections), nuclear transsectional area, myocyte transsectional area, capillary index (number of capillaries/number of myocyte transsections) and capillary transsectional area. The highest significant difference between control mice and DOX-treated mice was observed immediately after the 12th dose of DOX except for the two capillary parameters. The highest level of significance for these two parameters was obtained 12 weeks after the end of DOX treatment. In contrast to the observations in rats, mice did not develop a nephrotic syndrome during treatment with DOX. The morphometric analysis of myocardial changes in mice, as a quantitative and objective method, seems to be a good model for comparative studies on cardiomyopathy induced by anthracycline analogues

Tetrahydrofolate and 5-methyltetrahydrofolate are folates with high antioxidant activity. Identification of the antioxidant pharmacophore.

The presumed protective effect of folic acid on the pathogenesis of cardiovascular, hematological and neurological diseases and cancer has been associated with the antioxidant activity of folic acid. Peroxynitrite (PON) scavenging activity and inhibition of lipid peroxidation (LPO) of the physiological forms of folate and of structurally related compounds were tested. It was found that the fully reduced forms of folate, i.e. tetrahydrofolate (THF) and 5-methyltetrahydrofolate (5-MTHF), had the most prominent antioxidant activity. It appeared that their protection against LPO is less pronounced than their PON scavenging activity. The antioxidant activity of these forms of folic acid resides in the pterin core, the antioxidant pharmacophore is 4-hydroxy-2,5,6-triaminopyrimidine. It is suggested that an electron donating effect of the 5-amino group is of major importance for the antioxidant activity of 4-hydroxy-2,5,6-triaminopyrimidine. A similar electron donating effect is probably important for the antioxidant activity of THF and 5-MTHF

Pharmacokinetics and preliminary clinical data of the novel chemoprotectant BNP7787 and cisplatin and their metabolites

Introduction: BNP7787 (disodium 2,2′-dithio-bis-ethane sulfonate) is currently undergoing development as a chemoprotective agent to prevent common and serious cisplatin-induced side effects. In the kidneys, intestine, and liver, BNP7787 is believed to undergo intracellular conversion into 2-mercaptoethane sulfonate (mesna), which can locally inactivate toxic platinum species. Methods and Objectives: In a phase I trial, 25 patients with advanced solid tumors received a 1-hour intravenous infusion of 75 mg/m2 cisplatin immediately preceded by a 15-minute intravenous infusion of BNP7787 every 3 weeks. For pharmacokinetic investigation of BNP7787 and mesna and a possible mutual pharmacokinetic interaction between BNP7787 and cisplatin, cisplatin and BNP7787 were also administered as single agents in 14 of 25 patients. The dose of BNP7787 was escalated from 4.1 to 41 g/m2. Patients were also monitored for tumor response and possible side effects from BNP7787. Results: The maximum plasma concentration of mesna was reached approximately 1.7 hours after the start of the BNP7787 infusion. The maximum plasma concentration and area under the curve to infinity (AUC∞) of BNP7787 and mesna increased linearly with the dose. The mean volume of distribution of BNP7787 (±SD) was approximately 0.26 ± 0.08 L/kg. The mean normalized AUC∞ of mesna was only approximately 8% of the normalized AUC∞ of BNP7787. The pharmacokinetic profile of mesna was unaffected by cisplatin and its metabolites. None of the dose levels of BNP7787 (4.1-41 g/m2) administered appeared to influence the pharmacokinetic profile of total platinum, unbound platinum, or monohydrated cisplatin. The observed effects regarding a possible mutual interaction between BNP7787 and intact cisplatin were minor, and none were statistically significant at BNP7787 dose levels of 18.4 to 41 g/m2. The confidence intervals for the pharmacokinetic parameters of BNP7787 and intact cisplatin, however, were relatively broad. Overall, BNP7787 was well tolerated at all dose levels (4.1-41.0 g/m2). The most frequently reported event related to BNP7787 was local intravenous site discomfort; the majority of events were mild (grade 1). Side effects of BNP7787 at the highest dose level of 41 g/m2 were more prominent and included nausea and vomiting, as well as a warm feeling or flushing (grade 2 or lower). Partial tumor responses and stable disease were measured in 12 of 25 patients. Conclusion: BNP7787 was relatively nontoxic at doses up to 41 g/m2. The combination of BNP7787 with cisplatin did not alter the pharmacokinetic profiles of mesna or the cisplatin metabolites. At the higher dose levels of BNP7787 (18.4 to 41 g/m2), there appeared to be no mutual interaction between BNP7787 and intact cisplatin, which needs to be confirmed in a larger number of patients. The absence of a mutual interaction between BNP7787 and intact cisplatin is consistent with the observation that several patients had objective tumor responses with BNP7787 and cisplatin administration

Relationship between the parameters cellular differentiation, doubling time and platinum accumulation and cisplatin sensitivity in a panel of head and neck cancer cell lines

Patients with head and neck squamous cell carcinoma (HNSCC) treated with cisplatin show a large inter-individual variation in tumor response. Little is known about factors that contribute to this variation. The aim of our study was to correlate the sensitivity to cisplatin with a number of cellular parameters using a panel of 10 human HNSCC cell lines. A 7-fold variation in response after 72 hr of exposure to cisplatin as determined in a colorimetric proliferation assay was observed. The IC50 values did not correlate with the DNA index, the cellular doubling time or the expression of differentiation markers. Intracellular platinum (Pt) concentrations were measured by atomic absorption spectroscopy after exposing the cells to 10 μM cisplatin for 1-72 hr. The intracellular Pt levels increased up to 24 hr. One cell line, derived from the tumor of a patient previously treated with radiotherapy, accumulated much more Pt than the other cell lines. For these other cell lines, a significant positive correlation was found between Pt accumulation and sensitivity. In conclusion, cisplatin-induced growth inhibition in HNSCC in vitro is generally positively correlated with cellular Pt levels. However, the fact that occasionally cancer cells can survive despite high intracellular Pt levels indicates that additional parameters are needed to explain a response unequivocally