Paclitaxel Epirubicin

North American prospective trials of radiation sensitizers for cervical cancer have focused on the use of cisplatin, fluorouracil, and hydroxyurea. However, a number of other drugs also hold promise as effective radiation sensitizers for cervical cancer, including mitomycin C, epirubicin, paclitaxel, and carboplatin. 

Paclitaxel also may be given concurrently with doxorubicin or epirubicin as a combination regimen. Pharmacokinetic interactions make these regimens more difficult to give. 

AC, Adriamycin (doxorubicin), Cytoxan (cyclophosphamide) CAF, Cytoxan (cyclophosphamide), Adriamycin (doxorubicin), 5-fluorouracil CEF, cyclophosphamide, epirubicin, 5-fluorouracil CMF, cyclophosphamide, methotrexate, 5-flourouracil FAC, 5-fluorouracil, Adriamycin (doxorubicin), cyclophosphamide FEC, 5-fluorouracil, epirubicin, cyclophosphamide TAC, Taxol (paclitaxel), Adriamycin (doxorubicin), cyclophosphamide. 

A. Gadducci, S. Cosio, A. Fanucchi, V. Nardini, M. Roncella, P.F. Conte, and A.R. Genazzani. Chemotherapy with epirubicin and paclitaxel for breast cancer during pregnancy Case report and review of the literature. Anticancer Res. 23 5225-5229 (2003). 

Anticancer drugs Methotrexate Doxorubicin Daunorubicin Epirubicin Etoposide Vincristine Vinblastine Paclitaxel Iiinotecan... 

Trastuzumab (Herceptin) [Antineeplastic/Monoover express the HERlIneu. protein breast CA adjuvant, w/ doxorubicin, cyclophosphamide, and paclitaxel if pt HER2/neu(+) Action MoAb binds human EGF receptor 2 protein HER2) mediates cellular cytotox Dose Per protocol, typical 2 mg/kg/IV/wk Caution [B, ] CV dysfxn, alla-gy/inf Rxns Contra Live vaccines Disp Inj SE Anemia, cardiomyopathy, nephrotic synd, pneumonitis Interactions t Risk of cardiac dysfxn W/ anthracycline, cyclophosphamide, doxorubicin, epirubicin EMS Cardiomyopathy, ventricular dysfxn and pulm tox have been reported monitor for Sxs of reduced cardiac Fxn OD Sxs unknown... 

Herceptin with cisplatin, doxorubicin or epirubicin plus cyclophosphamide, or paclitaxel. A comparison of serum levels of trastuzumab given in combination with various chemotherapeutic agents did not suggest the possibility of any pharmacokinetic interactions except in combination with paclitaxel. Although not statistically signihcant, mean serum trough concentrations of trastuzumab were consistently elevated, about 1.5-fold, when Herceptin was administered in combination with paclitaxel. However, trastuzumab and paclitaxel were used concurrently in clinical trials with positive outcome results. The concurrent administration of anthracyclines, cyclophosphamide, and trastuzumab increased the incidence and severity of cardiac dysfunction during clinical trials. 

All patients had stage IV breast cancer receiving first-line chemotherapy, either AC (doxorubicin or epirubicin plus cyclophosphamide) or T (paclitaxel). Data from Slamon et al. (250). 

Acyclovir Erythromycin Ivermectin Itraconazole Rifampin Actinomycin D Daunorubicin Doxorubicin Docetaxel Epirubicin Etoposide Imatinib Irinotecan Paclitaxel Vinblastine Vincristine Amprenavir Indinavir Nelfinavir Ritonavir Saquinavir Cyclosporine A Tacrolimus Digoxin Quinidine Verapamil Diltiazem Aldosterone Cortisol Corticosterone Dexamethasone Hydrocortisone Cyclosporine Metkephamid Enkephalin... 

Fig. 3 Venn-diagram for selected compounds interacting with the key MDR-related ABC transporters. MDR-substrate anticancer agents. Abbreviations VCR vincristine, VP-16 etoposide, STER steroids, TAM tamoxiphen, TKI-INHIB tyrosin kinase inhibitors e.g. STI-571, DOX doxorubicine or adriamycin, DNR daunorubicin, EPIR epirubicin, MX mitoxantrone, TOPOT topotecan, iridotecan, BISANT bisanthrone, COLCH colchicin, ACT-D actinomycin D, MYTOM mytomycin, TX methotrexate, CPHAM cyclophosphamide, CHLB chlorambucil, CARM carmustine, LCV leucovorin, HUR hydroxy urea, CISPL cisplatin, TAXOL paclitaxel. (Reproduced from [4])...

EPIRUBICIN ANTICANCER AND IMMUNOMODULATING DRUGS-PACLITAXEL t plasma concentrations of epirubicin (t AUC by 37% and 1 clearance by 25%), particularly following sequential administration of paditaxel followed by epirubicin Attributed to altered distribution of epirubicin in the plasma and inhibition of P-gp by Cremophor, the vehicle of paditaxel formulation, resulting in 1 clearance Epirubicin should always be given prior to paditaxel... 

Rischin D, Smith J, Millward M, Lewis C, Boyer M, Richardson G, Toner G, Gurney H, McKendrick J. A phase 11 trial of paclitaxel and epirubicin in advanced breast cancer. Br J Cancer 2000 83(4) 438 2. 

Lalisang Rl, Voest EE, Wils JA, Nortier JW, Erdkamp FL, Hillen HF, Wals J, Schouten HC, Blijham GH. Dose-dense epirubicin and paclitaxel with G-CSF a study of decreasing intervals in metastatic breast cancer. Br J Cancer 2000 82(12) 1914-19. 

Two studies of the combination of epirubicin plus paclitaxel have shown less reduction in left ventricular ejection fraction and no clinical evidence of cardiac failure (55,56). 

Camptothecin analogs Irinotecan Topotecan Epipodophyllotoxins Etoposide Teniposide Antitumor antibiotics Bleomycin Dactinomycin Daunorubicin Doxorubicin Epirubicin Idarubicin Mitomycin Mitoxantrone Valrubicin Microtubule agents Docetaxel Paclitaxel Vinblastine Vincristine Vinorelbine Enzymes Asparaginase Pegasparaginase Metals... 

FAC may also be given with bolus doxorubicin administration, and the fluorouracil dose is then given on days 1 and 8. Paclitaxel may also be given concurrently with doxorubicin or epirubicin as a combination regimen. Pharmacokinetic interactions make these regimens more difficult to give. 

Cytotoxic drags that have been used alone and in combination as adjuvant therapy in breast cancer include doxorubicin, epirubicin, cyclophosphamide, methotrexate, fluorouracil, paclitaxel, docetaxel, melphalan, prednisone, vinorelbine, and vincristine. The most common combination chemotherapy regimens employed in the adjuvant and metastatic setting are listed in Table 125-11. 

A total of 469 patients were enrolled into a randomized, multicenter, phase III trial of chemotherapy with or without Herceptin [52]. All patients had previously untreated, IHC 2+/3+ MBC. Patients who had previously received anthracyclines in the adjuvant setting were randomized to receive paclitaxel (175 mg m 3-weekly) alone (n=96) or with Herceptin (n=92). All other patients were randomized to receive anthracycline (doxorubicin 60 mg m or epirubicin 75 mg m ) plus cyclophosphamide (600 mg m ) alone (n=138) or with Herceptin (n=143) (Fig. 5.7). The primary endpoint was TTP. Secondary endpoints were ORR, DR, TTF, OS and 1-year survival. An independent RFC determined disease progression and response. 

Tumors with HER-2 overexpression are usually highly sensitive to the anthracy-cline chemotherapy (Doxorubicin, Epirubicin) and have an enhanced response to the taxane chemotherapy (paclitaxel). 

Among all ABC transporters, P-gp, also known as MDRl protein, ABCBl or CD243, is probably the most studied and characterized member. It was first found as a 170-kDa ATP-dependent membrane glycoprotein that acts as a drug efflux pump [15], P-gp is a broad-spectrum transporter, capable of transporting several structurally and functionally unrelated substrate molecules. Its substrates are typically hydrophobic, amphipathic products, including many chemotherapeutic compounds used for cancer treatment, e.g., vinca alkaloids (vincristine, vinblastine), taxanes (paclitaxel, docetaxel), epipodophyllotoxins (etoposide, teniposide), anthracyclines (doxorubicin, daunorubicin, epirubicin), topotecan, dactinomycin, and mitomycin-C [37]. 

Toxicity associated with combinations of paclitaxel with doxorubicin or epirubicin depends on the order of administration. Some modest pharmacokinetic changes may occur when paclitaxel and epirubicin are given together. The combination of doxorubicin and pacUtaxel is more cardiotoxic than doxorubicin alone paclitaxel increases doxorubicin levels but doxorubicin does not alter pacUtaxel levels. Docetaxel may modestly affect the pharmacokinetics of epirubicin and doxorubicin. 

Studies in mice have found that the taxanes docetaxel and paclitaxel, and the vehicle used for paclitaxel Cremophor, may all modify the distribution and metabolism of doxorubicin increasing its levels in the heart, liver and kidneys. This may contribute to the cardiac toxicity seen during use with paclitaxel. Similarly, m vitro studies in human myocardium showed that paclitaxel and docetaxel increased the conversion of doxorubicin to doxorubicinol, the metabolite that is thought to be responsible for cardiotoxicity. An in vitro study on the effect of paclitaxel and Cremophor on epirubicin metabolism in human blood found that paclitaxel slightly decreased production of epirubicinol. A marked inhibition of epirubicinol production occurred in the presence of Cremophor, hut because of the low... 

Bergaglio M, Del Mastro L, Rosso R Comparative effects of paclitaxel and docetaxel cn tile metabolism and pharmacokinetics of epirubicin in breast cancer patients. J Chn Oncol (1999) 17, 1132-40. 

Danesi R, Irmocenti F, FogU S, Gennari A, Baldini E, Di Paolo A, Salvador B, Bocci G, Conte PF, Del Tacca M Pharmacokinetics and pharmacodynamics of combination chemotherapy witii paclitaxel and epirubicin in breast cancer patients. BrJ Clin Pharmacol (2002) 53,508-18. 

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