Biochemical modulation of cytotoxic drugs by cytokines: molecular mechanisms in experimental oncology.

Biochemical modulation of cytotoxic drugs by cytokines: molecular mechanisms in experimental oncology. Research Abstract Details 

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Biochemical modulation of cytotoxic drugs by cytokines: molecular mechanisms in experimental oncology. Abstract Text:

E D Kreuser,S Wadler,E Thiel,

The combination of cytokines and cytotoxic drugs offers a new approach to increase the therapeutic index in the treatment of neoplastic diseases. There is no consensus on optimal strategies for combining these agents so far. The molecular mechanisms underlying the interaction, however, should be defined in order to design clinical trials based on preclinical rationales. The broad spectrum of cytotoxic drugs whose activity can be enhanced by cytokines argues for multiple levels of drug interaction in vitro: alteration in the cellular drug uptake, modulation of drug target enzymes, and changes in metabolism or disposition of a drug. In vivo interaction between cytokines and cytotoxic agents involves an additional layer of complexity because of the effects of cytokines on the host immune system and on drug-metabolizing enzymes. A major mechanism involved in the synergistic interaction of interferon (IFN) and 5-fluorouracil (5-FU) seems to be the increase of active 5-FU metabolites by IFN. Moreover, IFN can reverse resistance against 5-FU by inhibiting the overexpression of thymidylate synthase. The absence of cytokinetic effects of IFN and FU argues against the recruitment of Gs cells into the cell cycle. Topoisomerase has emerged as a critical intracellular target of cytotoxic drugs. There is convincing evidence that the synergy between tumor necrosis factor (TNF) and topoisomerase-targeted intercalative (Adriamycin, doxorubicin hydrochloride; m-AMSA, amsacrine; mitoxantrone) and nonintercalative (VM-16, etoposide; VM-26, teniposide) drugs is related to a rapid increase in specific activity of topoisomerase I and II, resulting in enhanced DNA strand breaks and cleavage complex. Furthermore, sensitivity to topoisomerase II targeted drugs can be enhanced by granulocyte colony-stimulating factor (G-CSF) through elevated enzyme activity in tumor cell response to G-CSF. The synergistic interaction between cytokines and cytotoxic agents seems to be sequence dependent. It has recently been demonstrated that newly synthesized metal compounds and IFN are synergistic only after preincubation with cytokines. Cytokines can modulate expression of adhesion receptors on tumor cell lines, thereby influencing their metastatic potential. A considerable number of phase II trials with combination of cytokines and cytotoxic drugs based on these mechanisms have demonstrated promising response rates and tolerable toxicity. Phase III trials are currently in progress to identify enhanced activity combining cytokines and cytotoxic drugs in the treatment of malignancies.

Biochemical modulation of cytotoxic drugs by cytokines: molecular mechanisms in experimental oncology. Publishing Authors By Initials

ED Kreuser,S Wadler,E Thiel,

For similar proteins: recombinant proteins research abstracts see: proteins: recombinant proteins research

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Biochemical modulation of cytotoxic drugs by cytokines: molecular mechanisms in experimental oncology. Journal Published:

PUBLICATION TYPE: Review

Journal: Recent results in cancer research. Fortschritte de

VOLUME: 139

Page Numbers: 371-82

Journal Abbreviation: Recent Results Cancer Res.

ISSN: 0080-0015

DAY: 13

MONTH: 02

YEAR: 1995

Biochemical modulation of cytotoxic drugs by cytokines: molecular mechanisms in experimental oncology. Information

Number of References: 37

LANGUAGE: eng

NlmUniqueID: 44671

Biochemical modulation of cytotoxic drugs by cytokines: molecular mechanisms in experimental oncology. Keywords Mesh Terms:

KEYWORDS: Recombinant Proteins

MESH TERMS: therapeutic use

Chemical & Substance for Abstract: Biochemical modulation of cytotoxic drugs by cytokines: molecular mechanisms in experimental oncology. Information

Substance Name: DNA Topoisomerases, Type II

Registry Number: EC 5.99.1.3

Grant and Affiliation Information for Biochemical modulation of cytotoxic drugs by cytokines: molecular mechanisms in experimental oncology.

AFFILIATION: Department of Hematology and Oncology, Klinikum Steglitz, Free University of Berlin, Germany.

Country: GERMANY

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MEDLINETA: Recent Results Cancer Res

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