Rapid uptake by cultured tumor cells and intracellular behavior of 4'-O-tetrahydropyranyladriamycin.

Kunimoto, Setsuko; Miura, Keiko; Takahashi, Yoshikazu; Takeuchi, Tomio; Umezawa, Hamao

doi:10.7164/antibiotics.36.312

Cited by 75 publications

(36 citation statements)

References 6 publications

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“…Determination of intracellular drug concentration Cellular uptake was analyzed using spectrofluorometry as described by Egorin et al and Kunimoto et al with slight modifications. 17,18) Cells were seeded at 10 6 cells/ml in growth medium containing the drugs at 10 µg/ml, and incubated at 37°C. At the indicated time, duplicate aliquots of 1 ml of cell suspension were centrifuged, and the cells were washed twice with ice-cold PBS(−).…”

Section: Methodsmentioning

confidence: 99%

Uptake and Intracellular Distribution of Amrubicin, a Novel 9‐Amino‐anthracycline, and Its Active Metabolite Amrubicinol in P388 Murine Leukemia Cells

Yamaoka¹,

Hanada²,

Ichii³

et al. 1999

Japanese Journal of Cancer Research

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Amrubicin, a 9-aminoanthracycline anti-cancer drug, and its C-13 hydroxyl metabolite amrubicinol, were examined for growth-inhibitory activity as well as cellular uptake and distribution in P388 murine leukemia cells and doxorubicin-resistant P388 cells. Also discussed are the differences in the mechanisms of action among amrubicin, amrubicinol and doxorubicin in terms of their cellular pharmacokinetic character. In P388 cells, amrubicinol was about 80 times as potent as amrubicin, and about 2 times more potent than doxorubicin in a 1-h drug exposure growth-inhibition test. A clear cross-resistance was observed to both amrubicin and amrubicinol in doxorubicin-resistant P388 cells, though the resistance index was lower for amrubicin. The intracellular concentration of amrubicinol was about 6 times and 2 times higher than those of amrubicin and doxorubicin, respectively. Compared to doxorubicin, amrubicin and amrubicinol were released rapidly after removal of the drugs from the medium. A clear correlation was found between the growth-inhibiting activity and the cellular level of amrubicin and amrubicinol in P388 cells. About 10 to 20% of amrubicin or amrubicinol taken up by the cells was detected in the cell nuclear fraction, whereas 70 to 80% of doxorubicin was localized in this fraction. These results suggest that amrubicin and amrubicinol exert cytotoxic activity via a different mechanism from that of doxorubicin.Key words: Anthracycline -Amrubicin -SM-5887 -Metabolite Amrubicin hydrochloride (SM-5887) is a completely synthetic 9-aminoanthracycline anti-cancer drug.1) It has potent antitumor activities, being more potent than doxorubicin against various mouse experimental tumors and human tumor xenografts.2) Phase II clinical trials of amrubicin for the treatment of malignant lymphoma, superficial bladder cancer, small cell lung cancer and non-small cell lung cancer are in progress.3, 4) The response rates were 25% and 79% against non-small cell lung cancer and small cell lung cancer, respectively.In our previous studies, amrubicinol, the C-13 hydroxy metabolite of amrubicin, was much more potent than the parent compound, amrubicin, and as potent as doxorubicin in inhibiting the growth of human tumor cells.5) In nude mouse-human tumor models, amrubicinol was detected in plasma, normal tissues and tumor tissues of mice treated with amrubicin. Amrubicinol was distributed more in tumor tissues than in normal tissues compared to doxorubicin, and the level of amrubicinol in the tumor correlated to the in vivo efficacy of amrubicin.6, 7) We thus suppose that amrubicinol plays an important role in the in vivo antitumor effect of amrubicin as an active metabolite.A major metabolic pathway of anthracyclines is known to be the reduction of the C-13 carbonyl group to a hydroxyl group by cytoplasmic carbonyl reductase. [8][9][10] Generally, the C-13 hydroxy metabolite of an anthracycline shows lower growth-inhibitory activity than the respective parent compound. Doxorubicinol, epirubicinol and daunorubicinol are less poten...

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Section: Methodsmentioning

confidence: 99%

Uptake and Intracellular Distribution of Amrubicin, a Novel 9‐Amino‐anthracycline, and Its Active Metabolite Amrubicinol in P388 Murine Leukemia Cells

Yamaoka¹,

Hanada²,

Ichii³

et al. 1999

Japanese Journal of Cancer Research

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“…Be-cause THP is more rapidly absorbed into the tumor cells than doxorubicin resulting in higher intracellular concentrations, even a small dosage may exert greater prophylactic effect. 8,9 Kunimoto et al reported that the uptake of THP by L5178Y cells is approximately 170 times more rapid than that of doxorubicin. 8 Akaza et al demonstrated bladder tumor tissue levels of THP is approximately 1.9 times higher than that of doxorubicin after intravesical instillation in the mouse model using MBT-2 cells implanted into the bladder.…”

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confidence: 99%

“…8,9 Kunimoto et al reported that the uptake of THP by L5178Y cells is approximately 170 times more rapid than that of doxorubicin. 8 Akaza et al demonstrated bladder tumor tissue levels of THP is approximately 1.9 times higher than that of doxorubicin after intravesical instillation in the mouse model using MBT-2 cells implanted into the bladder. 9 Moreover, immediate intravesical THP instillation does not cause detectable plasma concentration.…”

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confidence: 99%

Randomized study of single early instillation of (2″R)‐4′‐O‐tetrahydropyranyl‐doxorubicin for a single superficial bladder carcinoma

Okamura

Ono

Kinukawa

et al. 2002

Cancer

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“…1), an anthracycline drug which has been shown to have a high affinity to bladder tumor cells or tissues (14)(15)(16), is a drug used widely for intravesical instillation chemotherapy. The concentration of pirarubicin in the tumor tissue becomes markedly high in a relatively short time after administration into the bladder (15).…”

Section: Introductionmentioning

confidence: 99%

Intravesical administration of pirarubicin against superficial bladder cancer: Relationship between tumor tissue concentration and exposure time in the bladder or therapeutic effect

Arakawa

Nakamura

Yamada

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. The aim of this study was to investigate the relationship between tissue concentrations and exposure times or therapeutic effect of an anthracycline anticancer drug, pirarubicin, in bladder cancer tissue after single intravesical administration against superficial bladder cancer. The concentrations of pirarubicin in tumor tissues and serum were measured at designated collection times after a single intravesical administration of pirarubicin (30 mg) in 22 patients with superficial bladder cancer. A wide range of concentrations of pirarubicin in bladder cancer tissue was observed (2.3-125 µg/g of tissue), although serum pirarubicin concentrations were not detected in any of the patients. Recurrence of superficial bladder cancer after transurethral resection of the bladder tumor (TUR-BT) was observed in 2 patients (9%). The concentration of pirarubicin in the tumor tissue tended to be higher as the exposure time increased. There was a weak relationship between the pirarubicin tissue concentration and tumor size. However, no significant relationship between tissue pirarubicin concentrations and the prophylactic effect against intravesical recurrence of bladder cancer after TUR-BT was observed. All patients had no adverse events, such as bladder irritation and local toxicity, caused by the treatment with pirarubicin. These findings suggest that prior to single intravesical administration of pirarubicin to patients with superficial bladder cancer the exposure time and tumor size should be considered.

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Rapid uptake by cultured tumor cells and intracellular behavior of 4'-O-tetrahydropyranyladriamycin.

Cited by 75 publications

References 6 publications

Uptake and Intracellular Distribution of Amrubicin, a Novel 9‐Amino‐anthracycline, and Its Active Metabolite Amrubicinol in P388 Murine Leukemia Cells

Uptake and Intracellular Distribution of Amrubicin, a Novel 9‐Amino‐anthracycline, and Its Active Metabolite Amrubicinol in P388 Murine Leukemia Cells

Randomized study of single early instillation of (2″R)‐4′‐O‐tetrahydropyranyl‐doxorubicin for a single superficial bladder carcinoma

Intravesical administration of pirarubicin against superficial bladder cancer: Relationship between tumor tissue concentration and exposure time in the bladder or therapeutic effect

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