Biochemical modulation of combined radiation and 5-fluorouracil treatment of murine tumors by d,l-leucovorin.
Experiments were designed to establish whether the response of the Lewis lung tumor (LLca) to combined 5-Fluorouracil (5-FU) and radiation could be enhanced by the addition of the reduced folate leucovorin (LV) to the treatment protocol. Twenty-four hr after the tumors received a single dose of from 2.0 to 8.0 Gy of X-rays, the tumor-bearing animals were treated with a 5 day schedule of 10 mg/kg LV + 30 mg/kg 5-flourouracil (q 24 hr) in which LV preceded the 5-FU by 60 minutes. Under these time/dose configurations, no evidence of treatment-limiting gastrointestinal or hematopoietic toxicity was observed with the LV + 5-FU treatment. Following radiotherapy alone, tumor growth delays (TGDs) ranging from 1 to 6.5 days were observed with X-ray doses of from 2.0 to 8.0 Gy, respectively. When the radiotherapy was followed by the administration of 5-FU (q24 hr x 5) alone, a modest increase in the tumor response was observed; TGD increased from 1.0 to 2.0 days with 2.0 Gy and from 6.5 to 8.5 days with 8.0 Gy of X-rays. The addition of LV to the 5-FU schedule, however, resulted in a significant enhancement of the response of the tumor to the combined radiation + 5-FU treatment. TGDs increased from 1.0 to 8.0 days with a radiation dose of 2.0 Gy and from 6.5 to 34.5 days with a dose of 8.0 Gy. When administered as single agents, 5-FU and 2.0 Gy resulted in only a modest response by the LLca tumor (TGDs = 1.0 day), while LV had no effect on tumor growth. These observations, therefore, suggest that biochemical modulation of 5-FU by LV can be realized in vivo and that this biochemical modulation may be valuable in more conventional clinical schedules using combined radiation and 5-FU treatment.
Kovacs
C J
CJ
Department of Radiation Oncology, East Carolina University, School of Medicine, Greenville, North Carolina 27858.
Dainer
P M
PM
Evans
M J
MJ
Nyce
J
J
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use*; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D007583:Jejunum / Q000187:drug effects / Q000473:pathology; D002955:Leucovorin / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology* / Q000532:radiotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D011879:Radiotherapy Dosage; D013237:Stereoisomerism
D002955:Leucovorin; D005472:Fluorouracil