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Purpose Daunorubicin can induce left ventricular dysfunction and QT interval prolongation. This study assessed the effects of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, on cardiac repolarization. Methods Twenty-six adults with acute leukemia were treated with CPX-351 for 1–2 induction cycles and ≤ 4 consolidation cycles. The primary endpoint was mean change in QTcF from baseline. Results Mean QTcF changes were 30 h. Thirteen (50%) patients achieved remission. The most common adverse events were febrile neutropenia, fatigue, and nausea. Conclusions The cytarabine and daunorubicin in CPX-351 liposomes were metabolized and excreted similarly to conventional formulation; however, plasma pharmacokinetics were altered. CPX-351 did not prolong the QT interval, suggesting that CPX-351 may induce less cardiotoxicity than previously reported for conventional daunorubicin. Trial registration Clinicaltrials.gov identifier: NCT02238925. Electronic supplementary material The online version of this article (10.1007/s00280-019-03856-9) contains supplementary material, which is available to authorized users.

Exposure of cells of the K-562 erythroleukemia cell line to 4-hydroperoxycyclophosphamide (4-HC), an analog of activated cyclophosphamide, causes a concentration-dependent inhibition of in vitro colony formation by these cells. For investigation of the role of glutathione (GSH) in the metabolism of 4-HC, GSH levels of K-562 cells were modulated by exposing the cells to buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis, and/or to GSH ethyl esters. Both the mono- and diethyl esters of GSH were synthesized in our laboratories and their identities were determined by chromatographic methods and fast-atom-bombardment mass spectrometry. An HPLC method including electrochemical detection used for thiol determination was applied for the measurement of GSH esters. Incubation of the cells with BSO depleted GSH levels to approximately 11% of control values and potentiated the cytotoxicity of 4-HC. By contrast, exposure to GSH esters approximately doubled GSH levels and protected the cells against the toxicity of 4-HC. Moreover, when cellular GSH levels were first depleted by BSO exposure and then replenished by incubation with GSH esters, the BSO-associated potentiation of 4-HC cytotoxicity was abolished. The work described herein extends the application of an HPLC method used for thiol determination to the measurement of GSH ethyl esters. In addition, it established that GSH acts as a competitive protecting agent against the in vitro toxicity of 4-HC in the K-562 cell line.

Reduced folates in plasma after i.v. and oral leucovorin administration were estimated by a ternary complex assay based on the incorporation of CH2FH4 into a stable complex with Lactobacillus casei thymidylate synthase and [3H]FdUMP. Each of the reduced folates, CH2FH4, FH4, and 5CH3FH4, could be quantitatively recovered from plasma by this approach even in the presence of high concentrations of the parent compound leucovorin. Examination of the accumulation kinetics of these reduced folates showed that after i.v. administration of 20 mg D,L-leucovorin to a healthy volunteer, FH4 and, to a lesser extent, CH2FH4 accumulated to maximal levels very early (less than 15 min), with a subsequent depletion that had a half-life of approximately 30 min. Accumulation of FH4 reached a peak level that was 12% of the maximal level of 5CH3FH4 achieved and more than 3 times greater than the pretreatment level of this common, circulating reduced folate form. Similar accumulation patterns were observed in a female patient with metastatic colonic cancer who was undergoing methotrexate (MTX)/fluorouracil therapy followed by i.v. leucovorin (15 mg). FH4 also accumulated, but to a lesser extent and over a longer period of time, when the same dose of leucovorin given orally. When several similar doses of leucovorin were given prior to the experimental dose, greater accumulation and duration of the FH4 response was observed. We propose that accumulation of FH4 and CH2FH4 could provide a circulating source of the reduced folate thought to be the active form for both high-dose MTX with leucovorin rescue and enhancement of fluorouracil activity.

Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide (4-HC)-purged bone marrow gives long-term remission in almost half of relapsed acute nonlymphocytic leukemia and non-Hodgkin's lymphoma patients, but relapse of disease is the main cause of failure, suggesting ineffective purging in some cases. Cisplatin (CP) has activity against a variety of human tumors and is not commonly used for initial therapy of leukemia and lymphoma. Using established human leukemia cell lines, combinations of 4-HC and CP were investigated as a potential regimen for improving the ex vivo removal of leukemia cells from bone marrow. The cell lines (K-562 and Raji) were incubated for 1 (4-HC) or 4 h (CP), washed, and assayed for inhibition of colony formation in semisolid media. In both cell lines, CP (4 h) was more potent than 4-HC (1 h). Combinations of the drugs in various molar ratios were studied after the cells were sequentially incubated with 4-HC and CP. The effects of the drugs were analyzed using the multiple drug-effect analysis of Chou and Talalay [6]. Analysis of data on in vitro inhibition of colony formation suggested that all combinations studied were synergistic in both cell lines, with the greatest synergism being found in the Raji cell line. In addition, for K-562 cells we could detect at least a 4.6 log reduction in cloning with the CP:4-HC combination (1:10 molar ratio). We conclude that CP is a potential candidate in drug combinations for ex vivo bone marrow purging because of its high potency against human leukemia cell lines, its synergistic activity in combination with 4-HC, and its ability to reduce a high tumor burden when combined with 4-HC.