In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells

Uçkun, Fatih M.; Stewart, Clinton F.; Reaman, Gregory H.; Chelstrom, Lisa M.; Jin, Jizhong; Chandan-Langlie, Mridula; Waddick, Kevin G.; White, James G.; Evans, William E.

doi:10.1182/blood.v85.10.2817.bloodjournal85102817

Cited by 48 publications

(8 citation statements)

References 22 publications

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“…This is similar to what is reported in the current study after the combination of andrographolide with TP on U937. 40 According to Uckun et al (1995), 41 expression of Bcl-2 was found to increase upon combination of TP with andrographolide, even though TP-induced apoptosis does necessarily require a decrease in bcl-2 expression. Pretreating the U937 cells with andrographolide prior to TP addition resulted in a significant increase in apoptosis through the upregulation of many proapoptotic proteins’ expression and was confirmed with Annexin/PI staining that showed an increase in the percentage of apoptotic cells rather than necrotic cells.…”

Section: Discussionmentioning

confidence: 99%

Andrographolide potentiates the antitumor effect of topotecan in acute myeloid leukemia cells through an intrinsic apoptotic pathway

Hodroj¹,

Jardaly²,

Raad³

et al. 2018

CMAR

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BackgroundTopotecan (TP) is an anticancer drug acting as topoisomerase I inhibitor that is used in the treatment of many types of cancers including leukemia, but it has significant side effects. Andrographolide, a compound extracted from Andrographis paniculata, was recently proven to inhibit the growth of cancer cells and can induce apoptosis. The aim of this study is to investigate the possible synergism between TP and andrographolide in acute myeloid cells in vitro.Materials and methodsU937 acute myeloid leukemic cells were cultured using Roswell Park Memorial Institute (RPMI) medium and then treated for 24 h with TP and andrographolide prepared through the dilution of dimethyl sulfoxide (DMSO) stocks with RPMI on the day of treatment. Cell proliferation was assessed using cell proliferation assay upon treatment with both compounds separately and in combination. Cell-cycle study and apoptosis detection were performed by staining the cells with propidium iodide (PI) stain and Annexin V/PI stain, respectively, followed by flow cytometry analysis. Western blotting was used to assess the expression of various proteins involved in apoptotic pathways.ResultsBoth TP and andrographolide showed an antiproliferative effect in a dose-dependent manner when applied on U937 cells separately; however, pretreating the cells with andrographolide before applying TP exhibited a synergistic effect with lower inhibitory concentrations (half-maximal inhibitory concentration). Treating the cells with TP alone led to specific cell-cycle arrest at S phase that was more prominent upon pretreatment combination with andrographolide. Using Annexin V/PI staining to assess the proapoptotic effect following the pretreatment combination showed an increase in the number of apoptotic cells, which was supported by the Western blot results that manifested an upregulation of several proapoptotic proteins expression.ConclusionThe pretreatment of U937 with andrographolide followed by low doses of TP showed an enhancement in inducing apoptosis when compared to the application of each compound separately.

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Section: Discussionmentioning

confidence: 99%

Andrographolide potentiates the antitumor effect of topotecan in acute myeloid leukemia cells through an intrinsic apoptotic pathway

Hodroj¹,

Jardaly²,

Raad³

et al. 2018

CMAR

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“…Therefore, subcutaneous administration of topotecan may cause side effects such as skin redness and hypersensitivity, which are equivalent to or higher than oral and intravenous administration. However, as mentioned above, there have been no reports of fatal toxicity following subcutaneous administration of topotecan, and there have been some non-clinical studies of subcutaneous administration of topotecan [ 14 , 21 ]. Furthermore, the results of these non-clinical studies have not identified serious side effects in experimental animals (even though topotecan was injected subcutaneously continuously for 72 h).…”

Section: Discussionmentioning

confidence: 99%

“…It is less invasive and has lower systemic side effects than intravenous administration, and bioavailability may be significantly improved compared to oral administration. Uckun et al administered topotecan hydrochloride to severe combined immuno-deficiency mice subcutaneously for 72 h using a micro-osmotic pump, and presented a plasma concentration profile in a steady state [ 14 ]. However, in the study of Uckun et al, access to pharmacokinetic information other than the mean plasma concentration and distribution volume in steady state was difficult.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Comparison of Three Different Administration Routes for Topotecan Hydrochloride in Rats

2020

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Topotecan is actively used in clinic, with its primary use being in treatment of various types of cancer. The approved administration routes are oral and intravenous. The purpose of this study was to investigate and identify pharmacokinetic profiles of different administration routes. We conducted pharmacokinetic studies on three different routes of administration in rats. Five rats in each group received a single dose of 4 mg/kg of topotecan hydrochloride intravenously, orally, or subcutaneously, and the concentrations of lactone and total forms of the drug in plasma, urine, and feces were quantified. Various pharmacokinetic parameters were compared statistically. Plasma concentrations of both the lactone and total forms at elimination phase following subcutaneous administration, were two times higher than was seen with oral administration and 10 times higher than with intravenous administration. Subcutaneous administration of topotecan showed pharmacokinetic profiles similar to sustained release. In addition, subcutaneous administration showed bioavailability from 88.05% (for lactone form) to 99.75% (for total form), and these values were four–five times greater than those of oral administration. The results of this non-clinical study will not only provide greater understanding of the in vivo pharmacokinetics of topotecan, but also be useful for development of additional formulations and/or administration routes.

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“…The studies just referred to also provided insight into the activity of the drug in two other leukemias, ALL and blastic and accelerated (AP) phases of CML. Evidence of activity of TPT in ALL was initially indicated from reports of Uckum et al 5 who observed prolongation of survival by TPT treatment of SCID mice grafted with lethal numbers of human ALL cells. In a total of 12 heavily pretreated patients with ALL, included in the aforementioned trials, antileukemic activity, measured by decrease in circulating and bone marrow blasts was noted in all patients with suggestion of dose-related response.…”

Section: Acute Leukemia and Blastic Phase Chronic Myelogenous Leukemiamentioning

confidence: 99%

Topotecan (Hycamptin) and Topotecan‐Containing Regimens in the Treatment of Hematologic Malignancies

Beran

Kantarjian

2000

Annals of the New York Academy of Sciences

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Single-agent topotecan is an active drug in chemotherapy-naive MDS and CMML and, to a lesser degree, in refractory/relapsed acute leukemias, low-/intermediate-grade lymphoma, and myeloma. Its combination with cytosine arabinoside induces complete remissions in high-risk MDS/CMML. A triplecombination regimen of cyclophosphamide, cytosine arabinoside, and topotecan (CAT) was extensively tested in refractory/relapsed as well as in untreated AML. By proving effective in inducing complete remission in newly diagnosed AML at rates comparable to those achieved by anthracycline-cytosine arabinoside regimens, for example, CAT offers a useful treatment alternative. Topotecan combined with paclitaxel is promising in low-/intermediate-grade lymphomas. The activity of topotecan justifies further evaluation of topotecan-containing combination regimens, particularly in MDS/CMML and acute leukemias.

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In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells

Cited by 48 publications

References 22 publications

Andrographolide potentiates the antitumor effect of topotecan in acute myeloid leukemia cells through an intrinsic apoptotic pathway

Andrographolide potentiates the antitumor effect of topotecan in acute myeloid leukemia cells through an intrinsic apoptotic pathway

Pharmacokinetic Comparison of Three Different Administration Routes for Topotecan Hydrochloride in Rats

Topotecan (Hycamptin) and Topotecan‐Containing Regimens in the Treatment of Hematologic Malignancies

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