Effect of paclitaxel (TAXOL) alone and in combination with radiation on the gastrointestinal mucosa
- Univ. of Texas, Houston, TX (United States)
Paclitaxel is a potentially useful drug for augmenting the cytotoxic action of radiotherapy because it has independent cytotoxic activity against certain cancers and blocks cells in the radiosensitive mitotic phase of the cell cycle. However, all rapidly proliferating tissues, both normal and neoplastic, may be affected by this therapeutic strategy. The aim of this study was to define the in vivo response of rapidly dividing cells of the small bowel mucosa in mice to paclitaxel given alone and in combination with radiation. Paclitaxel blocked jejunal crypt cells in mitosis and induced apoptosis in a dose-dependent manner. Fractionating the paclitaxel dose over 1-4 days did not result in any greater accumulation of mitotically blocked cells than did a single dose. Mitosis peaked 2-4 h after paclitaxel and returned to near normal by 24 h. Apoptosis lagged several hours behind mitosis and peaked about 6 h later than mitosis. Despite these kinetic perturbations, there was little or no enhancement of radiation effect when single doses were delivered 2-4 h after paclitaxel administration. The maximum sensitizer enhancement ratio of 1.07 observed after a single paclitaxel dose of 40 mg/kg is consistent with independent crypt cell killing. Conversely, when radiation was given 24 h after paclitaxel, a significant protective effect of the drug (SER 0.89-0.92), most probably due to a regenerative overshoot induced by paclitaxel, was observed. Stem cells of the jejunal mucosa determining radiation response were not radiosensitized by paclitaxel with the drug concentrations and dose deliver schedules used, although additive cytotoxicity was observed with the highest drug dose. A radioprotective effect was observed when radiation was given 24 h after paclitaxel administration. 33 refs., 4 figs., 3 tabs.
- OSTI ID:
- 539412
- Journal Information:
- International Journal of Radiation Oncology, Biology and Physics, Vol. 32, Issue 5; Other Information: PBD: 30 Jul 1995
- Country of Publication:
- United States
- Language:
- English
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APPLIED STUDIES
55 BIOLOGY AND MEDICINE
BASIC STUDIES
GASTROINTESTINAL TRACT
NEOPLASMS
RADIATION INJURIES
COMBINED THERAPY
EVALUATION
MICE
CHEMOTHERAPY
RADIOTHERAPY
WHOLE-BODY IRRADIATION
ANTINEOPLASTIC DRUGS
BIOLOGICAL EFFECTS
RADIOSENSITIVITY EFFECTS
DOSE-RESPONSE RELATIONSHIPS
STEM CELLS
RADIOSENSITIVITY
CELL CYCLE
MITOSIS
CELL PROLIFERATION
CELL KILLING
BIOLOGICAL RADIATION EFFECTS
BIOASSAY
FRACTIONATED IRRADIATION
RADIOPROTECTIVE SUBSTANCES