Pentoxifylline enhances tumor oxygenation and radiosensitivity in rat rhabdomyosarcomas during continuous hyperfractionated irradiation.
OBJECTIVE
To examine the influence of the hemorrheologic agent pentoxifylline (PTX) on tumor oxygenation and radiosensitivity.


METHODS
Tumor oxygenation in rat rhabdomyosarcomas R1H after PTX administration (50 mg/kg body weight) was measured using interstitial pO(2) probes (Licox CMP system and Eppendorf pO(2)-Histograph). Tumors were irradiated with (60)Co gamma-irradiation using single doses (15 and 30 Gy), conventional fractionation (60 Gy/30 fractions/6 weeks), and continuous hyperfractionation (54 Gy/36 fractions/18 days) in combination with PTX or an equivalent volume of physiological saline. Radiation effects were determined by tumor growth delay (2V(o)), and by partial and complete tumor remission.


RESULTS
PTX increased tumor oxygenation for up to 45 min after administration of the drug. Single doses of 15 and 30 Gy of irradiation, when combined with PTX, produced little radiosensitization of the R1H tumors as indicated by dose-modifying factors (DMFs) of 1.11 and 1.04, respectively. In conventional fractionated irradiation with PTX, a DMF of 1.10 was obtained only. However, in continuous hyperfractionated irradiation with 18 x 50 mg/kg of PTX, the DMF with respect to tumor growth delay was found to be 1.37. Local tumor control was not influenced by PTX. In vitro studies identified R1H cells as p53 wildtype and showed a G1 arrest in response to irradiation. When 2 mM PTX was given prior to irradiation, it did not improve radiosensitivity of R1H cells as measured by clonogenic survival assays.


CONCLUSIONS
PTX effectively enhances tumor oxygenation and radiosensitivity of R1H rhabdomyosarcomas, especially during continuous hyperfractionated irradiation. Given to rats as an adjuvant to fractionated irradiation, PTX does not enhance acute or late skin reactions or tumor metastasis. No radiosensitization was observed in vitro, when oxygen was not limiting. The observed radiosensitization by PTX is caused mainly by improved tumor oxygenation.
Zywietz
Friedrich
F
Institute for Biophysics and Radiobiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany. f.zywietz@uke.uni-hamburg.de
Böhm
Lothar
L
Sagowski
Christoph
C
Kehrl
Wolfgang
W
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy / Q000379:methods; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D008297:Male; D010100:Oxygen / Q000378:metabolism*; D010431:Pentoxifylline / Q000008:administration & dosage*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D011836:Radiation Tolerance / Q000187:drug effects*; D011879:Radiotherapy Dosage; D051381:Rats; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy / Q000628:therapy*; D016896:Treatment Outcome
D010975:Platelet Aggregation Inhibitors; D010100:Oxygen; D010431:Pentoxifylline