Chromatographic analysis of anticancer drugs

Tjaden, U. R.; Bruijn, E. A. de

doi:10.1016/s0378-4347(00)82286-0

Cited by 67 publications

(25 citation statements)

References 353 publications

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“…It has also been used for several other diseases like choriocarcinoma, psoriasis, sarcoidosis and trophoblastic tumors. 1,2) However some limitations restrict the use of methotrexate including high toxicity due to its low specificity and short plasma half life. In recent decades some methods have been developed to overcome these limitations that polymer conjugation has been of more importance.…”

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confidence: 99%

Synthesis and Characterization of Methotrexate Polyethylene Glycol Esters as a Drug Delivery System

et al. 2010

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147Methotrexate (amethopterin, 4-amino-N 10 -methyl petroyl glutamic acid, MTX) is a drug that has been used clinically since 1953 for treatment of many tumors especially acute lymphoblastic anemia. It has also been used for several other diseases like choriocarcinoma, psoriasis, sarcoidosis and trophoblastic tumors. 1,2) However some limitations restrict the use of methotrexate including high toxicity due to its low specificity and short plasma half life. In recent decades some methods have been developed to overcome these limitations that polymer conjugation has been of more importance. Conjugation of methotrexate with natural and synthetic long chain polymers like human and rabbit serum albumins, 3,4) poly L-lysine, 5,6) dextran, 7) poly hydroxyethyl methacrylate (HEMA), 8) poly spartamide 9) and gelatin 10,11) proves the importance of methotrexate as an strategic drug and its necessities of polymer conjugation. 29) Polyethylene glycol (PEG) is the most common polymer ever used for conjugation. The researchers have mentioned many rationales for conjugation with PEG (pegylation) including increased water solubility, controlled permeability through biological barriers, longevity in blood stream, controlling of release, overcoming tumor resistance, increased antitumor effect and reduced protein immunogenicity. [12][13][14][15] Among the small molecules, anticancer and antiviral drugs have been in priority for pegylation such as paclitaxel, 16,17) podophyllotoxin 18) and 6-mercaptopurin 19) for increasing water solubility, amphotericin B for decreasing drug toxicity and side effects, 20) doxorubicin for increasing efficacy 21) and in case of campthotecin for increasing solubility, efficacy and plasma circulation half life.22,23) PROTHECAN ® , the ester of campthotecin and mPEG40000D is a typical conjugate that is under clinical phase II. 24)In despite of extensive researches on physicochemical properties of produced pegylated forms of other drugs including water solubility, in vitro and in vivo bond stability (the study of different linkages and spacers between drug and PEG) 17,[25][26][27] and in vivo fate of conjugates, 12,21,28) there is no enough information about different polymer conjugates of methotrexate.29) Furthermore, as the most of polymer conjugates contain a link between a-carboxyl group of methotrexate and amino or hydroxyl group of synthetic or natural polymers, it is expected to obtain the similar physicochemical properties including partitioning and solubility in different conjugates. In the current study, as part of our aim to improve physicochemical and biopharmaceutical properties of MTX to achieve a better drug delivery system, synthesis of esters of MTX with PEGs of different molecular weight (at low, medium and high molecular weight) and evaluation of the physicochemical properties of MTX-PEGs were described. To the best of our knowledge, no reports on the synthesis and application of the esters of MTX-PEGs as novel drug delivery for MTX has been published. Methotrexate (MTX) is one...

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confidence: 99%

Synthesis and Characterization of Methotrexate Polyethylene Glycol Esters as a Drug Delivery System

et al. 2010

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“…After elution with methanol and evaporation, the compounds were derived with trifluoroacetic anhydride and diazomethane in ether. The stable derivates were separated on a methyl phenyl siloxane GC capillary column and measured selectively by single-ion monitoring GC-MS in the positive EI mode described earlier by Tjaden and de Bruijn (24).…”

Section: Methodsmentioning

confidence: 99%

Synergistic Antitumor Response of Interleukin 2 with Melphalan in Isolated Limb Perfusion in Soft Tissue Sarcoma–Bearing Rats

et al. 2005

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The cytokine interleukin 2 (IL-2) is a mediator of immune cell activation with some antitumor activity, mainly in renal cell cancer and melanoma. We have previously shown that tumor necrosis factor (TNF)-A has strong synergistic antitumor activity in combination with chemotherapeutics in the isolated limb perfusion (ILP) setting based on a TNF-mediated enhanced tumor-selective uptake of the chemotherapeutic drug followed by a selective destruction of the tumor vasculature. IL-2 can cause vascular leakage and edema and for this reason we examined the antitumor activity of a combined treatment with IL-2 and melphalan in our wellestablished ILP in soft tissue sarcoma-bearing rats (BN175). ILP with either IL-2 or melphalan alone has no antitumor effect, but the combination of IL-2 and melphalan resulted in a strong synergistic tumor response, without any local or systemic toxicity. IL-2 enhanced significantly melphalan uptake in tumor tissue. No signs of significant vascular damage were detected to account for this observation, although the tumor sections of the IL-2-and IL-2 plus melphalan-treated animals revealed scattered extravasation of erythrocytes compared with the untreated animals. Clear differences were seen in the localization of ED-1 cells, with an even distribution in the sham, IL-2 and melphalan treatments, whereas in the IL-2 plus melphalan-treated tumors clustered ED-1 cells were found. Additionally, increased levels of TNF mRNA were found in tumors treated with IL-2 and IL-2 plus melphalan. These observations indicate a potentially important role for macrophages in the IL-2-based perfusion. The results in our study indicate that the novel combination of IL-2 and melphalan in ILP has synergistic antitumor activity and may be an alternative for ILP with TNF and melphalan. (Cancer Res 2005; 65(10): 4300-8)

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“…The stable derivatives were separated on a methylphenylsiloxane GC capillary-column and measured selectively by single-ion monitoring GC-MS in the positive EI mode. 39 Cilengitide in serum was measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS) and the cyclic peptide cyclo(Arg-Gly-Asp-D-Phe-Val) (c(RGDfV)) as an internal standard. Stock solutions of c(RGDfV) were prepared in acetonitrile/methanol/water (1:1:1, v/v/v) and further diluted with methanol/water (2:98, v/v).…”

Section: Pharmacokineticsmentioning

confidence: 99%

The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model

Hagen

Seynhaeve

Wiel-Ambagtsheer

et al. 2012

Intl Journal of Cancer

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Isolated limb perfusion (ILP) with melphalan and tumor necrosis factor (TNF)-a is used to treat bulky, locally advanced melanoma and sarcoma. However, TNF toxicity suggests a need for better-tolerated drugs. Cilengitide (EMD 121974), a novel cyclic inhibitor of alpha-V integrins, has both anti-angiogenic and direct anti-tumor effects and is a possible alternative to TNF in ILP. In this study, rats bearing a hind limb soft tissue sarcoma underwent ILP using different combinations of melphalan, TNF and cilengitide in the perfusate. Further groups had intra-peritoneal (i.p.) injections of cilengitide or saline 2 hr before and 3 hr after ILP. A 77% response rate (RR) was seen in animals treated i.p. with cilengitide and perfused with melphalan plus cilengitide. The RR was 85% in animals treated i.p. with cilengitide and ILP using melphalan plus both TNF and cilengitide. Both RRs were significantly greater than those seen with melphalan or cilengitide alone. Histopathology showed that high RRs were accompanied by disruption of tumor vascular endothelium and tumor necrosis. Compared with ILP using melphalan alone, the addition of cilengitide resulted in a three to sevenfold increase in melphalan concentration in tumor but not in muscle in the perfused limb. Supportive in vitro studies indicate that cilengitide both inhibits tumor cell attachment and increases endothelial permeability. Since cilengitide has low toxicity, these data suggest the agent is a good alternative to TNF in the ILP setting.Since the continued growth of solid tumors requires angiogenesis, an anti-angiogenic approach to cancer therapy is logical. Since angiogenesis is mediated in part by adhesion receptors of the integrin family, including the alpha-V (aV) integrins, 1,2 there is a strong rationale for assessing the effects of integrin inhibitors in cancer treatment. Cilengitide (EMD

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Chromatographic analysis of anticancer drugs

Cited by 67 publications

References 353 publications

Synthesis and Characterization of Methotrexate Polyethylene Glycol Esters as a Drug Delivery System

Synthesis and Characterization of Methotrexate Polyethylene Glycol Esters as a Drug Delivery System

Synergistic Antitumor Response of Interleukin 2 with Melphalan in Isolated Limb Perfusion in Soft Tissue Sarcoma–Bearing Rats

The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model

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