Effect of cyclophosphamide pretreatment on daunorubicin in rat acute leukaemia model

Nooter, Kees; Vries, Arjan de; Martens, Anton C.; Hagenbeek, Anton

doi:10.1016/0277-5379(90)90129-h

Cited by 6 publications

(4 citation statements)

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“…reduction of pH by one unit will decrease the cellular uptake by about 90% ( Dalmark, 1981). In BNML, pre‐treatment with cyclophosphamide was shown to act synergistically with anthracyclins ( Nooter et al , 1990 ) and increase the bone marrow blood flow ( Iversen et al , 1993 ). It may therefore be considered to use a pH indifferent drug rather than an anthracyclin as the first drug of choice in the treatment of acute myeloid leukaemia.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the bone marrow uptake of the anthracycline derivative daunomycin is less in leukaemic rats than in normal controls, although the uptake of daunomycin in leukaemic cells in vitro is higher than in normal leucocytes ( Nooter & Martens, 1985). Furthermore, pre‐treatment of leukaemic rats with cyclophosphamide led to an increased uptake of daunomycin in the bone marrow ( Nooter et al , 1990 ).…”

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confidence: 99%

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Changing bone marrow micro‐environment during development of acute myeloid leukaemia in rats

Mortensen¹,

Jensen

Helledie³

et al. 1998

Br J Haematol

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Summary. The Brown Norwegian rat transplanted with promyelocytic leukaemic cells (BNML) has been used as a model for human acute myeloid leukaemia. We have previously shown that both the blood supply to the bone marrow and the metabolic rate decrease in relation to the leukaemic development in these rats. Here we have investigated how the development and progression of this leukaemia affect oxygenation, pH and proliferation of normal and leukaemic cells in vivo. Bone marrow pH was measured by a needle electrode. Nitroimidazol-theophylline (NITP) was used to identify hypoxic cells, and we applied bromodeoxyuridine (BrdUrd) to identify DNA replicating cells.The leukaemia progressed slowly until day 27 after which a rapid deterioration could be observed leading to severe changes over the following 5 d. In whole blood there was evidence of progressing metabolic acidosis. In bone marrow the fraction of leukaemic cells increased to > 90% and the pH dropped to about 6·5. The fraction of NITP þ cells increased to > 80% in bone marrow and to about 40% in blood. The fraction of BrdUrd þ cells was unchanged in blood, but decreased in bone marrow both for normal cells (from about 20% to 5%), and for leukaemic cells (from about 45% to 25%), evidently as a result of the severely changed microenvironment. In this study we have demonstrated in vivo the development of an acidic and hypoxic bone marrow hampering normal haemopoiesis during leukaemic growth. Our data support the notion of BNML as a valuable tool for studying leukaemogenesis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Changing bone marrow micro‐environment during development of acute myeloid leukaemia in rats

Mortensen¹,

Jensen

Helledie³

et al. 1998

Br J Haematol

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“…On the other hand, drug uptake was significantly enhanced in leukemia-engrafted animals treated with three doses of high-dose aflibercept (25 mg/kg) administered 7 and 4 days prior to and on the same day of doxorubicin, indicating that there may be not only be a dose-dependent process, but also a time-dependent process on the increase in uptake of doxorubicin into tumor sites. In accord with this, cyclophosphamide pre-treatment in leukemic rats increased accumulation of daunomycin in bone marrow sites, presumably due to improved marrow perfusion (40). Anti-VEGF agents have previously been clinically explored in refractory and relapsed AML patients.…”

Section: Discussionmentioning

confidence: 82%

“…Leukemia expansion within the bone marrow space has been associated with decreased marrow blood flow which can markedly limit the exposure of leukemia cells to systemic chemotherapy (37). In leukemic rats, much less of the anthracycline drug, daunomycin, was found in the bone marrow as compared with other leukemia-infiltrated (but better perfused) organs or healthy non-leukemic rat marrows, even though leukemic cells took up more daunomycin in vitro than normal marrow cells (38)(39)(40). Here, we noted greater than a 100-fold lower doxorubicin concentration in leukemiainfiltrated bone marrow than subcutaneous AML xenografts Clip absorption clearance from intraperitoneal to serum, Clout elimination clearance from serum, CLD distribution clearances for liver and bone marrow (BM), CL_Lout and CL_Tout elimination clearances from liver and tumor, CL_Tup and CL_Teff uptake and efflux clearances to and from tumor, V volumes of distribution for intraperitoneum, serum, bone marrow, tumor, and liver a Coefficient of variation of the estimate; reflects inter-study variability or the liver and serum of systemically engrafted leukemic mice, consistent with the marrow as a pharmacologic sanctuary.…”

Section: Discussionmentioning

confidence: 99%

Development of a Preclinical PK/PD Model to Assess Antitumor Response of a Sequential Aflibercept and Doxorubicin-Dosing Strategy in Acute Myeloid Leukemia

Fetterly

Aras

Lal

et al. 2013

AAPS J

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Timing of the anti-angiogenic agent with respect to the chemotherapeutic agent may be crucial in determining the success of combination therapy in cancer. We investigated the effects of sequential therapy with the potent VEGF inhibitor, aflibercept, and doxorubicin (DOX) in preclinical acute myeloid leukemia (AML) models. Mice were engrafted with human HL-60 and HEL-luciferase leukemia cells via S.C. and/or I.V. injection and treated with two to three doses of aflibercept (5-25 mg/kg) up to 3-7 days prior to doxorubicin (30 mg/kg) administration. Leukemia growth was determined by local tumor measurements (days 0-16) and systemic bioluminescent imaging (days 0-28) in animals receiving DOX (3 mg/kg) with or without aflibercept. A PK/PD model was developed to characterize how prior administration of aflibercept altered intratumoral DOX uptake. DOX concentration-time profiles were described using a four-compartment PK model with linear elimination. We determined that intratumoral DOX concentrations were 6-fold higher in the aflibercept plus DOX treatment group versus DOX alone in association with increased drug uptake rates (from 0.125 to 0.471 ml/h/kg) into tumor without affecting drug efflux. PD modeling demonstrated that the observed growth retardation was mainly due to the combination of DOX plus TRAP group; 0.00794 vs. 0.0043 h(-1). This PK/PD modeling approach in leukemia enabled us to predict the effects of dosing frequency and sequence for the combination of anti-VEGF and cytotoxic agents on AML growth in both xenograft and marrow, and may be useful in the design of future rational combinatorial dosing regimens in hematological malignancies.

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Pharmacological Sanctuaries in the Treatment of Acute Leukemia in the Rat

et al. 1992

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Effect of cyclophosphamide pretreatment on daunorubicin in rat acute leukaemia model

Cited by 6 publications

References 5 publications

Changing bone marrow micro‐environment during development of acute myeloid leukaemia in rats

Changing bone marrow micro‐environment during development of acute myeloid leukaemia in rats

Development of a Preclinical PK/PD Model to Assess Antitumor Response of a Sequential Aflibercept and Doxorubicin-Dosing Strategy in Acute Myeloid Leukemia

Pharmacological Sanctuaries in the Treatment of Acute Leukemia in the Rat

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