Effects of 9-aminocamptothecin on newly synthesized DNA in patient bone marrow samples.
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 microgram/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 microgram/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 microgram/m2/h 9-AC compared to baseline. DNA synthesis was inhibited by 89% +/- 5% during infusion of >/=59 microgram/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.
Geoffroy
F
F
National Cancer Institute-Navy Medical Oncology Branch, Clinical Oncology Program, Division of Cancer Treatment, National Cancer Institute, National Naval Medical Center, Bethesda, Maryland 20889-5105, USA.
Dahut
W
W
Takimoto
C H
CH
Grem
J L
JL
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects*; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008875:Middle Aged
D000970:Antineoplastic Agents; C080125:9-aminocamptothecin; D004247:DNA; D002166:Camptothecin