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Titolo:
Combination chemotherapy of the taxanes and antimetabolites: its use and limitations
Autore:
Smorenburg, CH; Sparreboom, A; Bontenbal, M; Verweij, J;
Indirizzi:
Univ Rotterdam Hosp, Daniel den Hoed Klin, Rotterdam Canc Inst, Dept Med Oncol, Rotterdam, Netherlands Univ Rotterdam Hosp Rotterdam Netherlands Oncol, Rotterdam, Netherlands
Titolo Testata:
EUROPEAN JOURNAL OF CANCER
fascicolo: 18, volume: 37, anno: 2001,
pagine: 2310 - 2323
SICI:
0959-8049(200112)37:18<2310:CCOTTA>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
CELL LUNG-CANCER; METASTATIC BREAST-CANCER; PHASE-II TRIAL; ADVANCED SOLID TUMORS; SCHEDULE-DEPENDENT SYNERGISM; EVERY 2 WEEKS; IN-VITRO; CONTINUOUS-INFUSION; WEEKLY GEMCITABINE; PACLITAXEL TAXOL;
Keywords:
combination chemotherapy; taxanes; antimetabolites; sequence; pharmacokinetics;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
132
Recensione:
Indirizzi per estratti:
Indirizzo: Smorenburg, CH Univ Rotterdam Hosp, Daniel den Hoed Klin, Rotterdam Canc Inst, Dept Med Oncol, Rotterdam, Netherlands Univ Rotterdam Hosp RotterdamNetherlands m, Netherlands
Citazione:
C.H. Smorenburg et al., "Combination chemotherapy of the taxanes and antimetabolites: its use and limitations", EUR J CANC, 37(18), 2001, pp. 2310-2323

Abstract

In an effort to improve response rates of chemotherapy. taxanes have been combined with other cytotoxic agents such as antimetabolites. However. the use of some of these combinations in patients has been restricted by severetoxicity. The significance of the sequence of drug administration in combining methotrexate (MTX) find taxanes was recognised in in vitro Studies, showing synergistic effects for the sequence of MTX followed by paclitaxel. and antagonism for exposure in the revere order. A possible explanation might he an MTX-induced synchronisation of cells in the S phase of the cell cycle. after which cells Lire more susceptible for the cytotoxic action of taxanes. Clinical studies using this sequence were hampered by severe neutropenia and mucositis at relatively low doses of both drugs. As no pharmacokinetic interactions were observed, the excess of toxicity may have been due tosequence-dependent synergistic actions on bone (narrow find mucosa. In contrast. and confusingly, in vitro studies oil 5-fluorouracil (5-FU) and taxanes indicate that 5-FU preceeding or simultaneously given to paclitaxel impairs cytotoxicity;is compared with paclitaxel monotherapy. while the reverse sequence results in additive or synergistic cytotoxicity. While almost all clinical studies have used the sequence of a taxane followed by 5-FU, various schedules appeared feasible and effective. The combination of a 5-FU analogue, capecitabine and taxanes was supported by in vitro data. A large phase III trial confirmed the feasibility and Superior efficacy of this combination in breast cancer patients relapsing after an anthracycline. Conflicting results exist on the benefit of combining gemcitabine and taxanes in tumour cell lines. Although the accumulation of gemcitabine triphosphate (dFdCTP) in mononuclear cells was significantly higher with an increasing doseof paclitaxel, no pharmacokinetic interactions for both agents were noticed. A pharmacokinetic analysis of the gemcitabine-docetaxel combination therapy has not been published in detail. Despite numerous trials, so far no optimum schedule has been established. Regarding data on actually delivered dose intensities, a 2- or 3-weekly cycle seems favourable and feasible. However. possible severe pulmonary toxicity warrants cautious monitoring of patients treated with this combination. Different outcomes of preclinical and clinical studies reveal that combining two chemotherapeutic agents is not simply a matter of putting antitumour activities together. Drug interaction may result in synergism, not only of efficacy but also of toxic side-effects. Adding two drugs may also implicate antagonism in drug efficacy due to unwanted interference in cytotoxicity or pharmacokinetics. For agents actingat a specific phase of the cell cycle, the sequence of administration may determine the efficacy and toxicity of a combination therapy. Because of Lin observed discrepancy between in vitro data;ind clinical studies, we wouldlike to emphasise the need for adequate dose-finding clinical trials together with pharmacokinetic data analysis before examining any new combinationchemotherapy in more detail in phase II studies. (C) 2001 Published by Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/03/20 alle ore 10:10:37