Phase I and pharmacologic study of 9-aminocamptothecin given by 72-hour infusion in adult cancer patients.

Dahut, William L.; Harold, Nancy; Takimoto, Chris H.; Allegra, Carmen J.; Chen, A; Hamilton, J. Michael; Arbuck, Susan G.; Sørensen, Morten; Grollman, Frank; Nakashima, Hiroshi; Lieberman, Ronald; Liang, Michael D.; Corse, William; Grem, Jean L.

doi:10.1200/jco.1996.14.4.1236

Cited by 59 publications

(19 citation statements)

References 11 publications

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“…As an S phase-specific drug whose cytotoxicity operates during DNA synthesis, optimal therapeutic efficacy requires prolonged exposure to 9-AC concentrations exceeding a minimum threshold [14]. Due to greater sensitivity of humans (compared to animals) to its myelosuppressive effects, dose-dependent myelosuppression has precluded the use of the 9-AC levels required to achieve plasma concentrations necessary for optimal antitumor activity [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Gao

Lü

Kopečková

et al. 2007

Journal of Controlled Release

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A water soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer -9-aminocamptothecin (9-AC) conjugate was designed for oral colon-specific drug delivery for the treatment of colon cancer. Comparative studies between the polymer conjugate and free drug have been performed to assess their biodistribution and pharmacokinetics in mice. After oral administration of equal doses of the polymer conjugate or free 9-AC, the drug concentrations in major organs at fixed time points were determined using an HPLC-fluorescence assay. Only 2±1% of 9-AC released from the polymer conjugate was detected in small intestine (SI), and the mean peak concentration of free 9-AC was 45-fold higher than that from released drug. Colon-specific release of 9-AC produced high local concentrations. The mean peak concentration of released 9-AC in cecal contents, feces, cecal tissue, and colon tissue were, respectively, 3.2-fold, 3.5-fold, 2.2-fold and 1.6-fold higher than that using free 9-AC. In plasma, the high and sharp drug concentration profile from free drug was in contrast to the relatively low and flat pharmacokinetic profile obtained from drug released from the HPMA copolymer. There was no significant difference between released and free drug for the area under the concentration-time curve (AUC) and bioavailability values. As a consequence of the colonspecific release of unmodified 9-AC from the polymer conjugate, antitumor efficacy can be anticipated to be enhanced due to prolonged colon tumor exposure to higher and more localized drug concentrations.

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Section: Introductionmentioning

confidence: 99%

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Gao

Lü

Kopečková

et al. 2007

Journal of Controlled Release

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“…Leucopenia appeared to be the dose-limiting toxicity, together with modest thrombocytopenia. Nausea and vomiting, alopecia, stomatitis and diarrhoea were less frequently reported (Rubin et al, 1994;Takimoto et al, 1994;Dahut et al, 1996). Steady-state plasma concentrations increased linearly with the dose and ranged from 0.9 to 10.6 nm and correlated well with percentage decrease of granulocyte count (Takimoto et al, 1994).…”

Section: Preclinical Studiesmentioning

confidence: 99%

Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development

Gerrits

Jonge²,

Schellens³

et al. 1997

Br J Cancer

113

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Summary Topoisomerase inhibitors constitute a new class of anti-cancer agents. Recently, topotecan and irinotecan were registered for clinical use in ovarian cancer and colorectal cancer respectively. Cytotoxicity of topoisomerase inhibitors is S-phase specific, and in vitro and in vivo studies have suggested that, for efficacy, prolonged exposure might be more important than short-term exposure to high concentration. Clinical development of those topoisomerase inhibitors that have reached this stage is also focused on schedules aiming to achieve prolonged exposure. In this review, we summarize all published preclinical studies on this topic for topoisomerase inhibitors in clinical development, namely 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin, topotecan, irinotecan and G1147211. In addition, preliminary data on clinical studies concerning this topic are also reviewed. The data suggest that prolonged exposure may indeed be relevant for anti-tumour activity. However, the optimal schedule is yet to be determined. Finally, clinical data are yet too immature to draw definitive conclusions.

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“…The amino substitution at the 9 position of the A ring improves solubility of the drug, and the drug has activity against many solid tumor cell lines in athymic animals [7,8]. Phase 1 trials of 9-AC have suggested potential efficacy of the agent against brain tumors [3,9,10]. One previous trial showed a lack of efficacy of 9-AC against newly diagnosed GBM and recurrent high-grade glioma although that trial was not complete at the time this study was initiated [11].…”

Section: Introductionmentioning

confidence: 99%

Pre-irradiation 9-Amino [20s] camptothecin (9-AC) in patients with newly diagnosed glioblastoma multiforme

et al. 2005

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Phase I and pharmacologic study of 9-aminocamptothecin given by 72-hour infusion in adult cancer patients.

Abstract: The recommended phase II dose of 9-AC given by 72-hour infusion every 2 weeks is 35 microg/m2/h without G-CSF or 47 microg/m2/h with G-CSF support. Dose escalation in individual patients may be possible according to their tolerance.

Cited by 59 publications

References 11 publications

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development

Pre-irradiation 9-Amino [20s] camptothecin (9-AC) in patients with newly diagnosed glioblastoma multiforme

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