The antitumour activity of the prodrug N-l-leucyl-doxorubicin and its parent compound doxorubicin in human tumour xenografts

Breistøl, Knut; Hendriks, H.R.; Berger, Dan M.; Langdon, SP; Fiebig, H.H.; Fodstad, Øystein

doi:10.1016/s0959-8049(98)00152-x

Cited by 31 publications

(19 citation statements)

References 22 publications

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“…The MTD of free DOX was previously determined to be 8-12mg/kg from several independent studies (Boven et al, 1990(Boven et al, , 1992Yokoyama et al, 1990Yokoyama et al, , 1991Breistol et al, 1998;Colbern et al, 1999;Bae et al, 2005). The MTD of DOX formulation with carriers may deviate from those of free DOX in mice, depending on the carrier effects on pharmacokinetics, biodistribution, and the drug release rate (Allen and Cullis, 2004).…”

Section: Mtd Determination Of Dphsm-f127mentioning

confidence: 99%

“…For example, the MTD of pegylated liposomal DOX (DOXIL) was lower but the potency was improved (Colbern et al, 1999;Gabizon, 2001;Gabizon et al, 2003). When the drug is inactive by polymer conjugation or given in a prodrug form, a large increase in the MTD has been reported, as in the case of N-(2-hydroxypropyl)methyacrylamide (HPMA) copolymer-DOX (4.5-fold) (Duncan et al, 1998), PEO-bpoly(L-aspartate) conjugated of DOX (NK911) (20-fold) (Yokoyama et al, 1990(Yokoyama et al, , 1991, N-L-leucyl-DOX (threefold) (Bennis et al, 1993;Breistol et al, 1998Breistol et al, , 1999, and glucuronide prodrug DOX (25-fold) (Houba et al, 2001). In addition, the changes in PK profile of the drug associated with a carrier can increase the MTD as shown by PEO-b-poly(β-benzyl-L-aspartate) (PBLA) micelle (2.3-fold) (Kwon et al, 1997;Kataoka et al, 2000) and SP1049 (1.4-fold) (Danson et al, 2004).…”

Section: Mtd Determination Of Dphsm-f127mentioning

confidence: 99%

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l-Histidine-based pH-sensitive anticancer drug carrier micelle: Reconstitution and brief evaluation of its systemic toxicity

Lee

Kim

et al. 2008

International Journal of Pharmaceutics

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Adoxorubicin (DOX)-carrier micellar system consisting of poly(histidine)(5K)-b-poly(ethylene glycol)(2K) and poly(L-lactic acid)(3K)-b-PEG(2K)-folate has been developed targeting the early endosomal pH and it have been convincingly proved that intracellular high dose strategy using such micelles is effective in overcoming multidrug resistance (MDR) of cancer cells. Due to the low DOX concentrations in the micelle solution obtained by dialysis and the lack of long-term stability of the micelles, stable and lyophilized micelle formulations were the subject of investigation reported here by using excipients of sucrose, PEG or Pluronic. The reconstituted micelle solutions were examined by particle size, pH sensitivity, and cytotoxicity for MDR cells and the results were compared with the non-lyophilized micelles. Among tested excipients, Pluronic F127 (33 wt%) added to the polymer/drug solution prior to dialysis resulted in a reconstituted product stable for a week and presented equivalent benefits as the fresh micelle formulation. The blank micelles did not present any apparent systemic toxicity in mice up to 2400 mg/kg i.v. injection (800 mg/(kg day) for 3 days). The brief toxicity of reconstituted DOX loaded micelles was examined by the maximum tolerated dose (MTD), which was approximately 7.5-fold higher than free DOX and guaranteeing further animal toxicity and efficacy study.

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Section: Mtd Determination Of Dphsm-f127mentioning

confidence: 99%

Section: Mtd Determination Of Dphsm-f127mentioning

confidence: 99%

l-Histidine-based pH-sensitive anticancer drug carrier micelle: Reconstitution and brief evaluation of its systemic toxicity

Lee

Kim

et al. 2008

International Journal of Pharmaceutics

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“…Drugs were administered five times at 3-day intervals, as shown in Figure 4. DOX dosage was modified from 8 mg/kg (q7d £ 2), the MTD of DOX previously reported (Breistøl et al 1998;Houba et al 2001), to 3 mg/kg (q3d £ 5), and GD and PGD doses were initially calculated using DOX-equivalence, although the dose of PGD was subsequently reduced to a half and then to one sixth of this value. In vitro cytotoxicity results showed that the conjugation of DOX to gelatin or PEGylated gelatin markedly reduced its cytotoxicity.…”

Section: Tumor Growth Inhibitory Effects In An Animal Modelmentioning

confidence: 99%

Anti-tumor and anti-metastatic effects of gelatin-doxorubicin and PEGylated gelatin-doxorubicin nanoparticles in SCC7 bearing mice

Lee

Park

Nam

et al. 2006

Journal of Drug Targeting

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The goal of this study was to develop a systemically non-toxic and stable circulation based passive targeting system for efficient anticancer treatment. Gelatin-doxorubicin (GD) and PEGylated gelatin-doxorubicin (PGD) nanoparticles were designed and their feasibilities as an anti-cancer drug were evaluated. The sizes of GD and PGD nanoparticles were about 135 and 250 nm, respectively, and they retained their structures for 2 days in PBS. Both GD and PGD had much lower cytotoxicity in vitro and in vivo than doxorubicin (DOX) at equivalent concentrations. However, PGD significantly inhibited tumor growth compared to the control and DOX treated group, and GD moderately suppressed tumor growth compared with the control but the suppressing effect of GD did not exceed that of DOX. And GD and PGD both remarkably suppressed pulmonary metastasis. We conclude that PGD is a potential cancer therapeutic, due to its excellent anti-tumor and anti-metastatic effects and low systemic toxicity.

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“…Leu-Dox itself was already In the early 90's it was shown that doxorubicin's efficacy against human ovarian, breast and lung carcinoma's was increased by attachment of a L-leucine residue to the amino group of the drug [124]. Recently, several reports appeared with new in vivo studies with N-L-leucyl-doxorubicin against melanoma xenografts [125] Fig. (34).…”

Section: Cathepsinsmentioning

confidence: 99%

Anticancer Prodrugs for Application in Monotherapy Targeting Hypoxia, Tumor-Associated Enzymes, and Receptors

Groot¹,

Damen²,

Scheeren

2001

CMC

115

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In order to improve current chemotherapeutic treatment and diminish severe side effects, several prodrug strategies have evolved to achieve site-specific delivery of cytotoxic anticancer agents. This review concentrates on recent developments of antitumor prodrug monotherapy with prodrugs that are designed for direct recognition of tumor-associated factors, such as hypoxia, tumor-associated enzymes and receptors. Firstly, oxygen deficiency in the core of solid tumors leads to enhanced activity of reducing enzymes, like for example nitroreductases, which can be used for site- specific conversion of prodrug to drug. Secondly, some enzymes are present in elevated levels in tumor tissue: beta-glucuronidase leaks from necrotic areas within tumors, while tumor cells for invasive and metastatic activities need several tumor-associated proteases, like plasmin. These enzymes form an attractive target for designing selective prodrugs. Finally, tumor-selective expression of receptors can be exploited for the delivery of antitumor agents. Low molecular weight binding motifs for these receptors can be coupled to cytotoxic drugs in order to obtain tumor-homing conjugates. At present, receptor-binding motifs for a number of receptors that are required for angiogenesis are used for prodrug monotherapy. There exists an increasing body of literature, which describes the complex interplay not only between tumor-associated enzymes, but also between these enzymes and tumor-associated receptors in the process of tumor invasion and metastasis, indicating the feasibility of targeting cytotoxic drugs to these key players in tumor growth. This paper reviews the development and evaluation of anticancer prodrugs, and their application in the various prodrug monotherapy approaches.

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The antitumour activity of the prodrug N-l-leucyl-doxorubicin and its parent compound doxorubicin in human tumour xenografts

Cited by 31 publications

References 22 publications

l-Histidine-based pH-sensitive anticancer drug carrier micelle: Reconstitution and brief evaluation of its systemic toxicity

l-Histidine-based pH-sensitive anticancer drug carrier micelle: Reconstitution and brief evaluation of its systemic toxicity

Anti-tumor and anti-metastatic effects of gelatin-doxorubicin and PEGylated gelatin-doxorubicin nanoparticles in SCC7 bearing mice

Anticancer Prodrugs for Application in Monotherapy Targeting Hypoxia, Tumor-Associated Enzymes, and Receptors

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