Fluorescence assays and pharmacokinetic studies of 4′-deoxydoxorubicin and doxorubicin in organs of mice bearing solid tumors

Formelli, Franca; Pollini, C; Am, Casazza; A, Di Marco; Mariani, Antonino Pio

doi:10.1007/bf00258470

Cited by 33 publications

(10 citation statements)

References 7 publications

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“…This analogue reached the same tissue levels as Dx in all organs tested except spleen and lung where comparatively higher peaks were detected (9). In the neoplastic tissue the analogue reached higher concentrations than Dx, as shown by a comparison of the areas under the curve, up to 72 h following administration, and this finding may be correlated with its higher potency.…”

Section: Introductionsupporting

confidence: 52%

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Phase I study with 4′ -deoxydoxorubicin

et al. 1984

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4'-Deoxydoxorubicin (dxDx), a new doxorubicin analogue, was administered intravenously on a 3-week schedule to 73 patients affected by advanced malignant neoplasms. Sixty-five patients, treated with eight dose levels ranging from 10 to 45 mg/m2, were evaluable. The dose-limiting toxicity was myelosuppression, mainly leukopenia. About one third of the patients complained of vomiting which was almost always mild. Minimal hair loss was also documented in about 40% of patients. No hepatic or renal toxicity was observed. Transient and aspecific electrocardiographic changes were recorded in 6% of patients after 1 h and in 3% after 24 h from drug injection. Left ventricular ejection fraction was decreased in two patients after a cumulative dose of 90 mg/m2. One patient died with cardiorespiratory insufficiency and his initial cardiovascular disease might have been aggravated by dxDx. No changes in myocardial function parameters were documented in 18 patients who reached higher cumulative doses, i.e. greater than or equal to 100 mg/m2 and greater than or equal to 200 mg/m2. The highest total dose administered in this study was 340 mg/m2. Therapeutic activity was observed with doses ranging from 25 to 45 mg/m2. Partial response was documented in pancreatic, colon, anal and breast carcinomas as well as in non-Hodgkin's lymphoma. Minor response was observed in prostatic, thyroid, and renal carcinomas as well as in chronic lymphocytic leukemia. The maximum tolerated dose was assessed to be between 40 and 45 mg/m2. A Phase II trial is ongoing utilizing the dose of 35 mg/m2 every 3 weeks.

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Section: Introductionsupporting

confidence: 52%

“…In general, dxDx appears to be eliminated more rapidly than Dx. The faster clearance from the heart has been advocated as one of the reasons for the lower cardiotoxicity of the new analogue (9).…”

Section: Introductionmentioning

confidence: 99%

Phase I study with 4′ -deoxydoxorubicin

et al. 1984

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“…A pharmacokinetic study in the mouse indicated that equal doses of doxorubicin or esorubicin achieved equivalent drug levels in all organs, except the lung and the spleen where higher concentrations were observed with esorubicin (12). Faster elimination from normal tissues, including the heart, and larger area under the concentration versus time curve in the tumor were consistent with higher potency and the lower cardiotoxicity of the new analog (12).…”

Section: Introductionmentioning

confidence: 68%

“…Faster elimination from normal tissues, including the heart, and larger area under the concentration versus time curve in the tumor were consistent with higher potency and the lower cardiotoxicity of the new analog (12). This study was undertaken to determine the pharmacokinetic behavior of esorubicin in man.…”

Section: Introductionmentioning

confidence: 99%

Human pharmacokinetics of esorubicin (4′ -deoxydoxorubicin)

et al. 1985

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The pharmacokinetics of esorubicin, a new anthracycline antibiotic, was investigated in conjunction with a phase I clinical trial. The drug was administered to 12 patients as an intravenous bolus at a dose of 20 to 40 mg/m2. All patients had normal renal and hepatic functions and no third space fluid accumulation. Plasma and urine samples were assayed by HPLC. The peak plasma concentration of esorubicin was 0.74 +/- 0.57 microM (mean +/- SE). Esorubicin disappeared from plasma according to a tri-exponential pattern with a terminal half-life of 20.4 +/- 7.3 hr. The area under the plasma concentration versus time curve was 0.64 +/- 0.31 microM x hr. Total body plasma clearance was 45.5 +/- 26.8 liter/min/m2 and the apparent volume of the central compartment, 41.0 +/- 24.8 L. A single metabolite, 4'-deoxydoxorubicinol, was detected in plasma. This metabolite was observed in 5 patients only and its mean peak concentration was 0.029 +/- 0.017 microM. The area under the plasma versus concentration time curve for 4'-deoxydoxorubicinol was 0.02 +/- 0.014 microM xhr. The urinary excretion of total fluorescence within 5 days of therapy was 7.3 +/- 1.3% of the administered dose. Esorubicin represented more than 80% of the excreted anthracyclines. As in plasma, 4'-deoxydoxorubicinol was the only metabolite detectable in urine. No correlation between the various pharmacokinetic parameters and drug-induced toxicity was observed in this small group of patients.

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“…DXDX is active against several ex perimental tumors and human tumors transplanted into nude mice [4. 5] and DXDX showed efficacy both in vivo and in vitro also in neoplasms resistant to doxorubicin [6][7][8], Phase I trials have established gra nulocytopenia as limiting toxicity and several studies suggest a lower cardioloxicily of DXDX in com parison with doxorubicin [9][10][11]. Moreover, other nonhematologic side effects (alopecia and gastrointes tinal toxicity, in particular) appeared to be less pro nounced than those induced by the parent compound [ …”

Section: Introductionmentioning

confidence: 99%

Phase II Study of Esorubicin in the Treatment of Patients with Advanced Sarcoma

Giaccone

Donadio²,

Calciati³

1989

Oncology

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Esorubicin was administered to 12 patients with soft tissue sarcoma, 1 osteosarcoma and 1 desmoid tumor. Seven patients had never received chemotherapy before. Myelotoxicity was the main side effect, leukopenia being more pronounced than thrombocytopenia. No significant nonhematological toxicity occurred. Six patients had no change of median duration of 98 days and 7 patients progressed. The patient suffering from multiple-site lesions of a desmoid tumor obtained a long-lasting partial response. This study does not support further testing of esorubicin in sarcoma patients.

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Fluorescence assays and pharmacokinetic studies of 4′-deoxydoxorubicin and doxorubicin in organs of mice bearing solid tumors

Cited by 33 publications

References 7 publications

Phase I study with 4′ -deoxydoxorubicin

Phase I study with 4′ -deoxydoxorubicin

Human pharmacokinetics of esorubicin (4′ -deoxydoxorubicin)

Phase II Study of Esorubicin in the Treatment of Patients with Advanced Sarcoma

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