Effects of paclitaxel, cyclophosphamide, ifosfamide, tamoxifen and cyclosporine on the metabolism of methoxymorpholinodoxorubicin in human liver microsomes

Beulz-Riché, Dominique; Robert, Jacques; Riche, C.; Ratanasavanh, Damrong

doi:10.1007/s00280-001-0415-1

Cited by 11 publications

(5 citation statements)

References 16 publications

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“…These findings were extended by the present study, which revealed a strong correlation between CYP3A-catalyzed testosterone 6␤-hydroxylase activity and the potentiation of MMDX cytotoxicity in a panel of human liver microsomes and demonstrated that the human enzyme CYP3A4 and its rodent counterparts CYP3A1 and CYP3A2 are active catalysts of the prodrug activation reaction. These findings are consistent with the observation that the metabolism of MMDX by human liver microsomes can be competitively inhibited by the CYP3A4 substrates paclitaxel, tamoxifen, and cyclosporin (Beulz-Riche et al, 2002).…”

Section: Discussionsupporting

confidence: 80%

Antitumor Activity of Methoxymorpholinyl Doxorubicin: Potentiation by Cytochrome P450 3A Metabolism

Lü¹,

Waxman²

2004

Mol Pharmacol

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Methoxymorpholinyl doxorubicin (MMDX) is a novel liver cytochrome P450 (P450)-activated anticancer prodrug whose toxicity toward cultured tumor cells can be potentiated up to 100-fold by incubation with liver microsomes and NADPH. In the present study, a panel of human liver microsomes activated MMDX with potentiation ratios directly correlated to the CYP3A-dependent testosterone 6␤-hydroxylase activity of each liver sample. Microsome-activated MMDX exhibited nanomolar IC 50 values in growth-inhibition assays of human tumor cell lines representing multiple tissues of origin: lung (A549 cells), brain (U251 cells), colon (LS180 cells), and breast (MCF-7 cells). Analysis of individual cDNA-expressed CYP3A enzymes revealed that rat CYP3A1 and human CYP3A4 activated MMDX more efficiently than rat CYP3A2 and that human P450s 3A5 and 3A7 displayed little or no activity. MMDX cytotoxicity was substantially increased in Chinese hamster ovary cells after stable expression of CYP3A4 in combination with P450 reductase. CYP3A activation of MMDX abolished the parent drug's residual cross-resistance in a doxorubicin-resistant MCF-7 cell line that overexpresses P-glycoprotein. CYP3A-activated MMDX displayed a comparatively high intrinsic stability, with a t 1/2 of ϳ5.5 h at 37°C. MMDX was rapidly activated by CYP3A at low (ϳ1-5 nM) prodrug concentrations, with 100% tumor cell kill obtained after as short as a 2-h exposure to the activated metabolite. These findings demonstrate that MMDX can be activated by CYP3A metabolism to a potent, long-lived, and cell-permeable cytotoxic metabolite and suggest that this anthracycline prodrug may be used in combination with CYP3A4 in a P450 prodrug activation-based gene therapy for cancer treatment.

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Section: Discussionsupporting

confidence: 80%

Antitumor Activity of Methoxymorpholinyl Doxorubicin: Potentiation by Cytochrome P450 3A Metabolism

Lü¹,

Waxman²

2004

Mol Pharmacol

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“…PTX exhibited not only strong cytotoxic activities against the growth of human cervical cancer cell line HeLa cells at nanomolar concentrations but also cell-cycle arrest in the mitotic (M) phase without disturbing the synthesis (S) phase [ 19 , 20 ]. PTX has been demonstrated as an effective anticancer agent against lung, breast, ovarian, leukopenia, and liver cancer in various studies [ 21 , 22 , 23 , 24 , 25 , 26 ]. Thus, PTX was approved by the FDA in 1992 [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Paclitaxel-Based Chemotherapy Targeting Cancer Stem Cells from Mono- to Combination Therapy

et al. 2021

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Paclitaxel (PTX) is a chemotherapeutical agent commonly used to treat several kinds of cancer. PTX is known as a microtubule-targeting agent with a primary molecular mechanism that disrupts the dynamics of microtubules and induces mitotic arrest and cell death. Simultaneously, other mechanisms have been evaluated in many studies. Since the anticancer activity of PTX was discovered, it has been used to treat many cancer patients and has become one of the most extensively used anticancer drugs. Regrettably, the resistance of cancer to PTX is considered an extensive obstacle in clinical applications and is one of the major causes of death correlated with treatment failure. Therefore, the combination of PTX with other drugs could lead to efficient therapeutic strategies. Here, we summarize the mechanisms of PTX, and the current studies focusing on PTX and review promising combinations.

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“…The AUC of paclitaxel was increased by 1.2 (1.1-1.4) by the combination. Paclitaxel had been reported as a CYP3A4 substrate (Beulz-Riche et al 2002). These pharmacokinetic data suggest that paclitaxel may act as an inhibitor of CYP3A4.…”

Section: Potential Drug Interactionsmentioning

confidence: 83%

Targeted treatment of advanced and metastatic breast cancer with lapatinib

Corkery

O’Donovan²,

Crown³

2008

OTT

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Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER-2 and EGFR. Lapatinib is a potent dual inhibitor of HER-2 and EGFR. Preclinical and phase I studies have shown activity with lapatinib in a number of cancers, including breast cancer, and the drug is well tolerated. The main known drug interactions are with paclitaxel and irinotecan. The most signifi cant side-effects of lapatinib are diarrhea and adverse skin events. Rates of cardiotoxicity compare favorably with trastuzumab, a monoclonal antibody against HER-2. This paper focuses on lapatinib in advanced and metastatic breast cancer, which remains an important therapeutic challenge. Phase II and III studies show activity as monotherapy, and in combination with chemotherapy or hormonal agents. Results from these studies suggest that the main benefi t from lapatinib is in the HER-2 positive breast cancer population. Combinations of lapatinib and trastuzumab are also being studied and show encouraging results, particularly in trastuzumab-refractory metastatic breast cancer. Lapatinib may have a specifi c role in treating HER-2 positive CNS metastases. The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated.

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Effects of paclitaxel, cyclophosphamide, ifosfamide, tamoxifen and cyclosporine on the metabolism of methoxymorpholinodoxorubicin in human liver microsomes

Cited by 11 publications

References 16 publications

Antitumor Activity of Methoxymorpholinyl Doxorubicin: Potentiation by Cytochrome P450 3A Metabolism

Antitumor Activity of Methoxymorpholinyl Doxorubicin: Potentiation by Cytochrome P450 3A Metabolism

Paclitaxel-Based Chemotherapy Targeting Cancer Stem Cells from Mono- to Combination Therapy

Targeted treatment of advanced and metastatic breast cancer with lapatinib

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