Effects of 9-Aminocamptothecin on Newly Synthesized DNA in Patient Bone Marrow Samples

Francois Geoffroy, William Dahut, Chris H. Takimoto, Jean L Grem

Research output: Contribution to journalArticle

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Abstract

9-Aminocamptothecin (9-AC) inhibited cell growth and DNA synthesis in HCT 116 human colon cancer cells in a concentration- and time-dependent manner. Interference with nascent DNA chain elongation was monitored using pH step alkaline elution. After a 3-day 9-AC exposure, 38% (10 nm) and 53% (50 nM) of the total [3H]DNA eluted with pH steps 11.3–11.7, compared to 9% in control cells. Effects on nascent DNA integrity were also evaluated by fixed elution with pH 12.1 buffer. After a 3-day exposure to 9-AC, 27% (10 nM) and 82.5% (50 nM) of the total [3H]DNA eluted relative to control. Paired bone marrow samples were then obtained in 10 patients before treatment and between 42 and 72 h of a continuous i.v. infusion of 9-AC (35–74 μg/m2/h for 72 h). The mononuclear cells were incubated with [3H]dThd for 2 or 4 h, and then analyzed using either pH step or fixed pH alkaline elution, respectively. In seven patients receiving ≥47 μg/m2/h 9-AC, 4% ± 1.5% (mean ± SE) of the total [3H]DNA eluted with pH steps ≤ 11.7 in the pretreatment samples compared to 13% ± 3.6% during 9-AC (P = 0.037). An altered fixed pH elution profile of nascent DNA was noted in two patients treated with 59 and 74 μg/m2/h 9-AC compared to baseline. DNA synthesis was inhibited by 89% ±5% during infusion of ≥59 μg/m2/h 9-AC (n = 7). Since hematological toxicity is dose limiting on this 9-AC schedule, these cellular pharmacodynamic studies provide evidence of a DNA-directed cytotoxic effect of 9-AC in a sensitive host target tissue.

Original languageEnglish (US)
Pages (from-to)1345-1351
Number of pages7
JournalClinical Cancer Research
Volume1
Issue number11
StatePublished - Nov 1 1995

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9-aminocamptothecin
Bone Marrow
DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Effects of 9-Aminocamptothecin on Newly Synthesized DNA in Patient Bone Marrow Samples. / Geoffroy, Francois; Dahut, William; Takimoto, Chris H.; Grem, Jean L.

In: Clinical Cancer Research, Vol. 1, No. 11, 01.11.1995, p. 1345-1351.

Research output: Contribution to journalArticle

Geoffroy, Francois ; Dahut, William ; Takimoto, Chris H. ; Grem, Jean L. / Effects of 9-Aminocamptothecin on Newly Synthesized DNA in Patient Bone Marrow Samples. In: Clinical Cancer Research. 1995 ; Vol. 1, No. 11. pp. 1345-1351.
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abstract = "9-Aminocamptothecin (9-AC) inhibited cell growth and DNA synthesis in HCT 116 human colon cancer cells in a concentration- and time-dependent manner. Interference with nascent DNA chain elongation was monitored using pH step alkaline elution. After a 3-day 9-AC exposure, 38{\%} (10 nm) and 53{\%} (50 nM) of the total [3H]DNA eluted with pH steps 11.3–11.7, compared to 9{\%} in control cells. Effects on nascent DNA integrity were also evaluated by fixed elution with pH 12.1 buffer. After a 3-day exposure to 9-AC, 27{\%} (10 nM) and 82.5{\%} (50 nM) of the total [3H]DNA eluted relative to control. Paired bone marrow samples were then obtained in 10 patients before treatment and between 42 and 72 h of a continuous i.v. infusion of 9-AC (35–74 μg/m2/h for 72 h). The mononuclear cells were incubated with [3H]dThd for 2 or 4 h, and then analyzed using either pH step or fixed pH alkaline elution, respectively. In seven patients receiving ≥47 μg/m2/h 9-AC, 4{\%} ± 1.5{\%} (mean ± SE) of the total [3H]DNA eluted with pH steps ≤ 11.7 in the pretreatment samples compared to 13{\%} ± 3.6{\%} during 9-AC (P = 0.037). An altered fixed pH elution profile of nascent DNA was noted in two patients treated with 59 and 74 μg/m2/h 9-AC compared to baseline. DNA synthesis was inhibited by 89{\%} ±5{\%} during infusion of ≥59 μg/m2/h 9-AC (n = 7). Since hematological toxicity is dose limiting on this 9-AC schedule, these cellular pharmacodynamic studies provide evidence of a DNA-directed cytotoxic effect of 9-AC in a sensitive host target tissue.",
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