Combination Chemotherapy With Cyclophosphamide, Adriamycin, and 5‐fluorouracil (Caf) in Advanced Breast Carcinoma

Dalley, D.; Levi, John A.; Aroney, R. S.

doi:10.5694/j.1326-5377.1980.tb134771.x

Cited by 2 publications

(3 citation statements)

References 14 publications

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“…Still, the results again suggest that DOX may be responsible for the toxic effects observed, since cells exposed to 50 µM 5-FU, 50 µM CYA or 50 µM 5-FU + 50 µM CYA had less cells in the field but no notorious cytotoxicity in the other assays performed. In the clinical study by Dalley et al, one of the first studies in which the combination of DOX, 5-FU and CYA was used, the authors evaluated the response and toxicity of FAC in 26 patients with metastatic breast carcinoma and found that cardiotoxicity only occurred in the one patient that received more than 450 mg/m 2 DOX [34]. Our study seems to corroborate that DOX is the major contributor to the cardiac toxicity of the FAC mixture.…”

Section: Discussionsupporting

confidence: 80%

“…Other values have been described, being the estimated cumulative percentage of patients with DOX-related heart failure 5% at a cumulative dose of 400 mg/m 2 , 26% at 550 mg/m 2 , and 48% at 700 mg/m 2 [32]. Other risk factors for cardiomyopathy development are therapy with other cardiotoxic antitumor drugs and mediastinal radiation therapy; however, clinicians usually see the DOX cumulative dose as the major culprit for the cardiotoxicity observed after FAC [34]. Nevertheless, some studies point for higher cardiotoxicity in FAC-treated patients than expected [16,17].…”

Section: Discussionmentioning

confidence: 99%

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Doxorubicin Is Key for the Cardiotoxicity of FAC (5-Fluorouracil + Adriamycin + Cyclophosphamide) Combination in Differentiated H9c2 Cells

et al. 2019

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Currently, a common therapeutic approach in cancer treatment encompasses a drug combination to attain an overall better efficacy. Unfortunately, it leads to a higher incidence of severe side effects, namely cardiotoxicity. This work aimed to assess the cytotoxicity of doxorubicin (DOX, also known as Adriamycin), 5-fluorouracil (5-FU), cyclophosphamide (CYA), and their combination (5-Fluorouracil + Adriamycin + Cyclophosphamide, FAC) in H9c2 cardiac cells, for a better understanding of the contribution of each drug to FAC-induced cardiotoxicity. Differentiated H9c2 cells were exposed to pharmacological relevant concentrations of DOX (0.13–5 μM), 5-FU (0.13–5 μM), CYA (0.13–5 μM) for 24 or 48 h. Cells were also exposed to FAC mixtures (0.2, 1 or 5 μM of each drug and 50 μM 5-FU + 1 μM DOX + 50 μM CYA). DOX was the most cytotoxic drug, followed by 5-FU and lastly CYA in both cytotoxicity assays (reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and neutral red (NR) uptake). Concerning the equimolar combination with 1 or 5 μM, FAC caused similar cytotoxicity to DOX alone. Even in the presence of higher concentrations of 5-FU and CYA (50 μM 5-FU + 1 μM DOX + 50 μM CYA), 1 μM DOX was still a determinant for the cardiotoxicity observed in the cytotoxicity assays, phase contrast morphological evaluation, and mitochondrial potential depolarization evaluation. To the best of our knowledge, this was the first in vitro work with this combination regimen, DOX being the most toxic drug and key to the toxicity of FAC.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Doxorubicin Is Key for the Cardiotoxicity of FAC (5-Fluorouracil + Adriamycin + Cyclophosphamide) Combination in Differentiated H9c2 Cells

et al. 2019

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“…In the study by Dalley et al the authors evaluated the response and toxicity of FAC combination in 26 patients with metastatic breast carcinoma. Only one patient developed cardiotoxicity and that patient received >450 mg/m 2 DOX cumulative dose [15]. Phase II and phase III clinical studies comparing DOX plus docetaxel (298 mg/m 2 DOX cumulative dose) with FAC combination (299 mg/m 2 DOX cumulative dose) as first-line chemotherapy in patients with metastatic breast cancer caused congestive heart failure in 3% patients with DOX plus docetaxel and 6% with FAC, although authors did not observe significant statistical difference between the two treatment regimens [16].…”

Section: Introductionmentioning

confidence: 99%

The Main Metabolites of Fluorouracil + Adriamycin + Cyclophosphamide (FAC) Are Not Major Contributors to FAC Toxicity in H9c2 Cardiac Differentiated Cells

et al. 2019

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In the clinical practice, the combination of 5-fluorouracil (5-FU) + Adriamycin (also known as doxorubicin, DOX) + cyclophosphamide (CYA) (known as FAC) is used to treat breast cancer. The FAC therapy, however, carries some serious risks, namely potential cardiotoxic effects, although the mechanisms are still unclear. In the present study, the role of the main metabolites regarding FAC-induced cardiotoxicity was assessed at clinical relevant concentrations. Seven-day differentiated H9c2 cells were exposed for 48 h to the main metabolites of FAC, namely the metabolite of 5-FU, α-fluoro-β-alanine (FBAL, 50 or 100 μM), of DOX, doxorubicinol (DOXOL, 0.2 or 1 μM), and of CYA, acrolein (ACRO, 1 or 10 μM), as well as to their combination. The parent drugs (5-FU 50 μM, DOX 1 μM, and CYA 50 μM) were also tested isolated or in combination with the metabolites. Putative cytotoxicity was evaluated through phase contrast microscopy, Hoechst staining, membrane mitochondrial potential, and by two cytotoxicity assays: the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and the neutral red (NR) lysosomal incorporation. The metabolite DOXOL was more toxic than FBAL and ACRO in the MTT and NR assays. When in combination, neither FBAL nor ACRO increased DOXOL-induced cytotoxicity. No nuclear condensation was observed for any of the tested combinations; however, a significant mitochondrial potential depolarization after FBAL 100 μM + DOXOL 1 μM + ACRO 10 μM or FBAL 100 μM + DOXOL 1 μM exposure was seen at 48 h. When tested alone DOX 1 μM was more cytotoxic than all the parent drugs and metabolites in both the cytotoxicity assays performed. These results demonstrated that DOXOL was the most toxic of all the metabolites tested; nonetheless, the metabolites do not seem to be the major contributors to FAC-induced cardiotoxicity in this cardiac model.

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Combination Chemotherapy With Cyclophosphamide, Adriamycin, and 5‐fluorouracil (Caf) in Advanced Breast Carcinoma

Cited by 2 publications

References 14 publications

Doxorubicin Is Key for the Cardiotoxicity of FAC (5-Fluorouracil + Adriamycin + Cyclophosphamide) Combination in Differentiated H9c2 Cells

Doxorubicin Is Key for the Cardiotoxicity of FAC (5-Fluorouracil + Adriamycin + Cyclophosphamide) Combination in Differentiated H9c2 Cells

The Main Metabolites of Fluorouracil + Adriamycin + Cyclophosphamide (FAC) Are Not Major Contributors to FAC Toxicity in H9c2 Cardiac Differentiated Cells

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