Phase I trial of 4-demethoxydaunorubicin (idarubicin) with single oral doses

Kaplan, S.; Sessa, Cristiana; Willems, Yvonne; Pacciarini, M. A.; Tamassia, V.; Cavalli, F.

doi:10.1007/bf00175378

Cited by 41 publications

(17 citation statements)

References 5 publications

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“…These results agree with the observation of a disappearance of nuclear fluorescence in colon cancer cells cultivated for 1 day or longer in the presence of DX (Chauffert et al, 1984 (Hill et al, 1985). Some anthracyclines showed a low RI like 4-demethoxy-DNR (RI=3) and 4'-deoxy-DX (RI=30) and these data too are in accordance with experimental and clinical trials (Ferrari et al, 1984;Kaplan et al, 1984;Hill et al, 1985). 4'-Deoxy-4'-iodio-DX was cytotoxic on B16VDXR to the same extent as that on B16V.…”

Section: Discussionsupporting

confidence: 89%

“…Pleiotropic drug-resistance has been reported for many different cell lines (Kaye & Merry, 1985). We tested, therefore, whether B16VDXR cells were sensitive to the cytotoxic action of other anthracyclines and of anticancer drugs having (Ferrari et al, 1984;Kaplan et al, 1984;Holdener et al, 1985), and 4'-deoxy-4'-iodio-DX, because it has been shown to be active on the DX-resistant P388 cell line (Facchinetti et al, 1984). VCR, a typical DX cross-resistant drug (Wilkoff & Dulmadge, 1978), and cis-DDP, a non DX crossresistant drug (Seeber et al, 1982), were also tested.…”

Section: Stability Of Resistancementioning

confidence: 99%

See 1 more Smart Citation

Characterization of a doxorubicin-resistant murine melanoma line: Studies on cross-resistance and its circumvention

Supino¹,

Prosperi²,

Formelli³

et al. 1986

Br J Cancer

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A B16 mouse melanoma cell line resistant to doxorubicin was obtained by continuous in vitro exposure to the drug. The ID50 for this line was 200 times higher than that for the parental cell line. The resistant cell line had some biological characteristics similar to those of the sensitive parental cell line, like saturation density and protein content. Differences were found in doubling time which was longer, cloning efficiency which was lower and DNA content which was higher in the resistant as compared to the parental line. Intracellular distribution of doxorubicin was also different having a nuclear-cytoplasmic ratio higher in sensitive than in resistant cells. Melanin content was an unstable feature in the sensitive cell line, whereas melanin was always present in resistant cells. Resistance to doxorubicin was maintained during 50 in vitro passages in the absence of the drug. Cross-resistance was found with vincristine and other anthracyclines, like daunorubicin and 4'-epi-doxorubicin but not with cis-platinum, and a new doxorubicin derivative, 4'-deoxy-4'-iodio-doxorubicin. The B16 line showed a lower resistance index to 4'-deoxy-doxorubicin and 4-demethoxy-daunorubicin (30 and 3 respectively), as compared to doxorubicin. Doxorubicin-resistance was partially circumvented by pretreatment of resistant cells with verapamil, a calcium chelating agent, and by trifluoperazine, a calmodulin-antagonist.

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Section: Discussionsupporting

confidence: 89%

Section: Stability Of Resistancementioning

confidence: 99%

Characterization of a doxorubicin-resistant murine melanoma line: Studies on cross-resistance and its circumvention

Supino¹,

Prosperi²,

Formelli³

et al. 1986

Br J Cancer

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“…Nausea and vomiting occurred even with routine antiemetic drug administration but were tolerable. These results are in agreement with other studies [4,6,[9][10][11][12][13] that showed nausea and vomiting were common and that a more aggressive use of antiemetic drugs should be considered. Mucositis was uncommon in our study, and none occurred in three previously reported studies using 4-DMDR doses between 10 and 50 mg/m 2 [7,10,12].…”

Section: Discussionsupporting

confidence: 83%

Phase II study of 4-demethoxydaunorubicin in previously untreated extensive disease non-small cell lung cancer

Umsawasdi¹,

Felder²,

Jeffries³

et al. 1990

Invest New Drugs

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Key words: non-small cell lung cancer, chemotherapy of lung cancer, 4-demethoxydaunorubicin, idarubicin, 4-DMDR, treatment of advanced lung cancer SummaryFifteen patients with previously untreated extensive non-small cell lung cancer (E-NSCLC) were treated with oral 4-demethoxydaunorubicin (4-DMDR) at the dose of 10 mg/m2/day x 5 days every 3 weeks with routine administration of antiemetic drugs. They received a median of two courses of treatment with the cumulative dose range from 50-712.5 mg/m 2. One patient achieved partial remission with a duration of 14 weeks. Two patients had minor responses with durations of 14 and 24 weeks. Stable disease occurred in three patients (21, 22, and 27 weeks). Median survival was 33 weeks (range 3-73 + weeks).Toxicities were tolerable. Neutropenia ( < 1,000 mm 3) occurred in only 16~ of all treatment courses. Three patients developed correctable arrhythmias (two with atrial fibrillation and one with accelerated junctional rhythm). The cause of arrhythmia was unclear. No clinical evidence of congestive heart failure or decreased cardiac ejection fraction was observed. Nausea and vomiting were common but tolerable. Alopecia and mucositis were uncommon.Clinical pharmacokinetic studies were done in nine patients. However, plasma 4-DMDR levels were below the limit of detection (3 ng/ml).Because 4-DMDR has shown some activity in previously untreated E-NSCLC and the toxicities at this dose schedule are mild, we suggest that further studies of this drug at a higher dose in this schedule are indicated.

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“…Preclinical toxicologic studies suggested an increased therapeutic index of DMDR compared to DNR and DX, particularly as regards cardiotoxicity (3). In phase I trials (4,5), the acute toxicity was similar to that of DNR and DX but with lower incidence of gastrointestinal side effects as well as alopecia. There was also evidence of tumor responses in patients with NHL (4).…”

Section: Introductionmentioning

confidence: 86%

Oral idarubicin in non-Hodgkin's lymphomas

Lopez¹,

Lauro²,

Papaldo³

1986

Invest New Drugs

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Idarubicin (DMDR), a new analogue of daunorubicin, was administered orally once every 3 weeks at the dose of 40 to 45 mg/m2 to 20 evaluable patients with non-Hodgkin's lymphomas (NHL). Eighty-six percent of patients with favorable histology and 54% with unfavorable histology (intermediate and high grade as IWF) achieved a response with an overall response rate of 65% (two complete and 11 partial responses). Response rates were higher (85%) in previously untreated patients than in those with prior exposure to chemotherapy (29%). Gastrointestinal and hematologic toxicity was generally mild to moderate. No signs or symptoms of cardiotoxicity were recorded. Although the quality of response, as well as the relatively low response rate in previously treated patients and in those with unfavorable histology, makes it unlikely that DMDR can replace standard anthracyclines in NHL, the drug appears attractive in selected instances, such as in elderly patients and in those with slow-growing NHL with favorable histology.

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Phase I trial of 4-demethoxydaunorubicin (idarubicin) with single oral doses

Cited by 41 publications

References 5 publications

Characterization of a doxorubicin-resistant murine melanoma line: Studies on cross-resistance and its circumvention

Characterization of a doxorubicin-resistant murine melanoma line: Studies on cross-resistance and its circumvention

Phase II study of 4-demethoxydaunorubicin in previously untreated extensive disease non-small cell lung cancer

Oral idarubicin in non-Hodgkin's lymphomas

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