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-fluorouracil (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 (q 24 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.