Pharmacokinetics of adriamycin in patients with breast cancer: Correlation between pharmacokinetic parameters and clinical short-term response

Robert, Jacques; Illiadis, Athanassions; Hoerni, B; Cano, J. P.; Durand, M.; Lagarde, C

doi:10.1016/0277-5379(82)90072-4

Cited by 88 publications

(44 citation statements)

References 10 publications

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“…These differences may be due to the widely different lipophilicities of the different compounds. A comparison of the cellular pharmacokinetics of ADM (partition coefficient, PC= 0.5) and aclacinomycin A (PC = 21.8) (Zenebergh et al, 1982) (Robert et al, 1982). The relative contributions of these various phases to overall tumour response is not established, although there appeared to be a correlation between tumour response and a parameter related to the early phase of plasma clearance (Robert et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

“…A comparison of the cellular pharmacokinetics of ADM (partition coefficient, PC= 0.5) and aclacinomycin A (PC = 21.8) (Zenebergh et al, 1982) (Robert et al, 1982). The relative contributions of these various phases to overall tumour response is not established, although there appeared to be a correlation between tumour response and a parameter related to the early phase of plasma clearance (Robert et al, 1982). Recent in vitro concentration x time studies using NCI-H69 cells (Twentyman & Fox, in preparation) (Giavazzi et al, 1983) and similar conclusions were reached by Schabel et al (1983) using an ADM-resistant subline of P388 leukaemia.…”

Section: Discussionmentioning

confidence: 99%

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The in vitro effects and cross-resistance patterns of some novel anthracyclines

Twentyman¹,

Fox²,

Wright³

et al. 1986

Br J Cancer

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Summary A range of new anthracyclines, structurally related to adriamycin (ADM), has been synthesised and studied in vitro. Three compounds described in this paper (Ro 31-1215; Ro 31-1741; Ro 31-2035) are all 4-demethoxyanthracyclines. In the mouse mammary tumour cell line, EMT6/Ca/VJAC, using a 1 h drug exposure followed by colony formation as the response endpoint, we found Ro 31-1215 and Ro 31-1741 to be 2-3 x and 4-7 x more potent then ADM, whilst Ro 31-2035 was 3-4 x less potent. For continuous drug exposure and suppression of population growth as the endpoint, the potency of Ro 31-1741 was similar to that of ADM, whereas that of Ro 31-1215 was 1.5-2 x higher and that of Ro al., 1978;Kaye & Merry, 1985). The mechanism of such resistance is currently the subject of much ongoing laboratory work and a variety of strategies for overcoming resistance are being investigated (Tsuruo et al., 1983;Skovsgaard et al., 1984).Over the last 10 years a large number of analogues of ADM have been produced with the major objective of finding a drug which is less cardiotoxic for a given amount of anti-tumour effect (Naff et al., 1982

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The in vitro effects and cross-resistance patterns of some novel anthracyclines

Twentyman¹,

Fox²,

Wright³

et al. 1986

Br J Cancer

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“…Doxorubicin concentrations are known to decay in a tri-exponential manner following intravenous (IV) bolus or infusion and typical parameters are available in the literature (e.g. [29], in which doxorubicin is administered as an IV bolus, not infusion).…”

Section: Pharmacokinetic Profilesmentioning

confidence: 99%

“…The first PK profile considered here is based on the data provided by Robert et al [29], in which C v (t) is assumed to decay as a tri-exponential (see also [8]), i.e.…”

Section: Pharmacokinetic Profilesmentioning

confidence: 99%

Mathematical and computational models of drug transport in tumours

Groh

Hubbard

Jones

et al. 2014

J. R. Soc. Interface.

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The ability to predict how far a drug will penetrate into the tumour microenvironment within its pharmacokinetic (PK) lifespan would provide valuable information about therapeutic response. As the PK profile is directly related to the route and schedule of drug administration, an in silico tool that can predict the drug administration schedule that results in optimal drug delivery to tumours would streamline clinical trial design. This paper investigates the application of mathematical and computational modelling techniques to help improve our understanding of the fundamental mechanisms underlying drug delivery, and compares the performance of a simple model with more complex approaches. Three models of drug transport are developed, all based on the same drug binding model and parametrized by bespoke in vitro experiments. Their predictions, compared for a 'tumour cord' geometry, are qualitatively and quantitatively similar. We assess the effect of varying the PK profile of the supplied drug, and the binding affinity of the drug to tumour cells, on the concentration of drug reaching cells and the accumulated exposure of cells to drug at arbitrary distances from a supplying blood vessel. This is a contribution towards developing a useful drug transport modelling tool for informing strategies for the treatment of tumour cells which are 'pharmacokinetically resistant' to chemotherapeutic strategies.

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“…In order to determine the effects of this drug on our cells, we treated MCF7 cells with increasing concentrations of doxorubicin for 24 hr, followed by a drug-free incubation period of 48 hr. Following an intravenous bolus administration of doxorubicin, plasma levels of 1 M are achieved within the first few hours, 35,40 while plasma concentrations of doxorubicin of up to 50 nM are maintained for up to 24 hr. 41,42 Though doxorubicin has a variety of antitumor effects, it did not induce significant amount of apoptosis in MCF7 cells (p ϭ 0.057; Fig.…”

Section: Effect Of Clinically Relevant Concentrations Of Doxorubicin mentioning

confidence: 99%

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

Neville-Webbe

Rostami‐Hodjegan

Evans

et al. 2004

Intl Journal of Cancer

146

104

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We investigated whether the combination of zoledronic acid and doxorubicin induced apoptosis of breast and prostate cancer cell lines, and if synergistic interaction was present. We investigated whether the levels of cell death altered depending on the sequence in which the drugs were administered and the possible mechanism of action responsible for the increased cell death following combined treatments. Breast and prostate cancer cells were treated with zoledronic acid alone, doxorubicin alone, or drugs in sequence (doxorubicin before, after, or with zoledronic acid), and the levels of apoptotic death were determined by evaluation of nuclear morphology. We found that clinically relevant concentrations of doxorubicin and zoledronic acid induced sequence-and schedule-dependent apoptosis of breast and prostate cancer cells. For maximal apoptosis, cells had to be pretreated for 24 hr with doxorubicin before immediate treatment with zoledronic acid for 1 hr. This observation is a characteristic feature of cell cycle phase-specific synergistic effect. Replacing zoledronic acid with the nonnitrogen-containing bisphosphonate clodronate did not induce increased apoptosis. Induction of apoptosis was mainly via inhibition of the mevalonate (MVA) pathway, as addition of the MVA pathway intermediary geranylgeraniol inhibited the induction of apoptosis by doxorubicin followed by zoledronic acid. In conclusion, combined treatment of breast and prostate cancer cell lines with clinically relevant doses of doxorubicin and zoledronic acid induces apoptosis in a synergistic fashion. These findings may have relevance for the clinical setting, particularly breast cancer patients receiving these drugs in the adjuvant setting.Key words: breast cancer; apoptosis; zoledronic acid; doxorubicin; synergistic interaction Zoledronic acid is a potent third-generation nitrogen-containing bisphosphonate and is the only bisphosphonate licensed to treat bone metastases from a variety of solid tumors and in multiple myeloma. In clinical practice, an increasing number of breast and prostate cancer patients are receiving zoledronic acid at earlier stages of their treatment in order to manage their metastatic bone disease.Zoledronic acid inhibits osteoclastic bone resorption, which occurs at an accelerated pace due to the presence of tumor cells in the bone microenvironment. 1 Nitrogen-containing bisphosphonates affect osteoclast action by inhibition of enzymes of the mevalonate pathway. 2 Target enzymes include farnesyl pyrophosphate synthase 3,4 and/or geranylgeranylpyrophosphate synthase, 5 leading to a lack of formation of farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These isoprenoids are requisite for posttranslation lipid modification (i.e., farnesylation and geranylgeranylation) of signaling GTPases, such as Ras, Rho and Rac. 6 As these control a variety of important osteoclast cell functions, their loss ultimately leads to osteoclast apoptosis through caspase-3 enzyme activation. 7 In addition to their inhibitory effect on osteocl...

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Pharmacokinetics of adriamycin in patients with breast cancer: Correlation between pharmacokinetic parameters and clinical short-term response

Cited by 88 publications

References 10 publications

The in vitro effects and cross-resistance patterns of some novel anthracyclines

The in vitro effects and cross-resistance patterns of some novel anthracyclines

Mathematical and computational models of drug transport in tumours

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

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