Folinic Acid is an Active Chemosensitizer of 5-Fluorouracil in vivo against Human Transitional Cell Carcinoma

Choi, Han Yong

Abstract

While augmentation of 5-fluorouracil (5FU) cytotoxicity by folinic acid (FA) has clearly been demonstrated in vitro, its value in human is controversial. Unfortunately, essentially all tumors studied in vivo have been murine and none were transitional cell carcinoma (TCC); no in vivo studies of FA+5FU against TCC xenografts have been performed. The present study was initiated to test the effects of FA on 5FU induced cytotoxicity in two human bladder cancer xenografts, DU4184 and DU4284, and to further test the sequence dependence of FA+5FU synergism. To perform the in vivo chemosensitivity assay, we used modified nude mouse subrenal capsule assay. Before treatment, the mice were randomly allocated into four groups. Group A was given normal saline only as a control, group B was given 5FU (100 mg/kg i.p.) only, and group C was given FA (100 mg/kg i.p.) and 5FU simultaneously and group D was given FA and one hour later 5FU. Before treatment and after treatment tumor volumes were measured and tumor growth ratio (TGR) of each group was calculated. TGRs of group A, B, C, and D were 6.1+/-0.6, 3.8+/-0.3, 3.8+/-0.4, and 3.0+/-0.2, respectively.No difference in cytotoxicity was seen if 5FU was given simultaneously with FA (group C). However, pretreatment with FA one hour prior to 5FU resulted in statistically significant potentiation of 5FU efficacy (group D) (p<0.05). Using this preferred dose schedule, DU4184 vs. DU4284 (+/- FA) was evaluated. Comparative sensitivity of the two lines revealed that DU4284 is relatively resistant to 5FU. FA significantly enhanced the cytotoxicity of 5FU on both DU4184 and DU4284 xenografts (p<0.05, and p<0.01, respectively) and had a substantially greater impact in the intrinsically more 5FU-resistant tumor (DU4284). It is concluded that FA is an effective chemosensitizer of 5FU in vivo against human TCC. Nevertheless, dose schedule is critical; pre-loading of the tumor with FA prior to 5FU is essential. However, as yet undefined intrinsic biochemical differences between tumors [such as thymidine salvage pathways (not generally assessable by standard in vitro assays)] may modulate the extent of such efficacy. Further preclinical study with an expanded TCC xenograft battery is necessary and should be linked with a study of biochemical correlates to identify phenotypic differences in FA chemosensitivity of those benefiting from this regimen.