Relationship between folate-binding protein expression and cisplatin sensitivity in ovarian carcinoma cell lines

Abstract

Summary It has been suggested that sensitivity of ovarian carcinomas to cisplatin is in part related to an endogenous folate deficiency. In this work, we investigated whether overexpression of the folate-binding protein (FBP), a receptor involved in folate transport, might be associated with cisplatin sensitivity. The results obtained on a panel of ten ovarian carcinoma cell lines that overexpress different levels of the FBP showed a statistically significant relationship between FBP overexpression and cisplatin responsiveness, with the most sensitive cell lines expressing higher FBP levels on their membrane than the less sensitive ones. The relationship was observed both in cells growing in standard medium-containing high-folate concentrations (2.3 gM) and in cells adapted to growth in low-folate (20 nM) medium. Analysis of two cisplatin-resistant cell lines derived from the cisplatin-sensitive IGROV1 ovarian carcinoma cell line indicated that resistance was associated with a significant decrease in FBP expression. However, the receptor does not appear to be directly responsible for drug sensitivity per se as different cell lines transfected with FBP cDNA did not become more sensitive to the drug. Together, the data suggest the possible predictive value of FBP in ovarian carcinoma, as higher levels of expression can be indirectly but significantly associated with increased drug sensitivity.Keywords: ovarian carcinoma; folate receptor; cisplatin Platinum-derived compounds have occupied a dominant place in cancer therapy, particularly for the treatment of ovarian malignancies (Rosenberg, 1985;Ozols, 1992). Unfortunately, not all tumours are responsive, and initially sensitive tumours often become resistant in a short time Ozols et al, 1991).Various mechanisms have been proposed to contribute to cisplatin resistance, including altered drug accumulation (Loh et al, 1992;Nakagawa et al, 1993;Jekunen et al, 1994;Misawa et al, 1995), enhanced drug detoxification by elevated metallothionein or glutathione levels (Andrews et al, 1987;Morrow et al, 1990;Tedeschi et al, 1990;Mistry et al, 1991), enhanced DNA repair capability (Masuda et al, 1988;Eastman et al, 1988) or upregulation of specific biochemical pathways . Concerning, in particular, the last possibility, an association between cisplatin resistance and changes in folate metabolism has been observed. Indeed, cisplatin can stimulate endogenous methionine and folate metabolism (Gross et al, 1986;Shionoya et al, 1986;Scanlon et al, 1989a). Enhanced 5,10-methylenetetrahydrofolate (5,10-methylene THF) and THF pools and enhanced gene expression of enzymes of the dTMP synthase cycle, which is the sole source of de novo dTMP, have been observed in drug-resistant cells (Scanlon et al, , 1989bNewman et al, 1988;Lu et al, 1988 Correspondence to: S Miotti increased dTMP synthase activity might be required for the repair of cisplatin-induced DNA damage.Previous reports have shown that the 38-KDa folate-binding protein (FBP) is overexpressed in a majority of non-mucinous ovaria...

Expression of folate binding protein as a prognostic factor for response to platinum-containing chemotherapy and survival in human ovarian cancer

“…Experiments we previously performed in vitro on ovarian carcinoma cell lines did not address this issue, giving conflicting results (Ottone et al, 1997). Some hypotheses could be proposed: FBP, by increasing cellular uptake of folates, could render cells more prone to repair DNA damage caused by platinum.…”

“…A significant relationship between FBP overexpression and cisplatinum responsivity was observed; however, the receptor did not appear to be directly responsible for drug sensitivity. It is noteworthy that we found that the human ovarian cancer cells SKOV-3 transfected with FBP required cisplatinum concentrations about 3-fold higher in culture medium than control cells for equitoxic effects (Ottone et al, 1997).…”

The impact of GGH -401C>T polymorphism on cisplatin-based chemoradiotherapy response and survival in cervical cancer

“…Although weekly cisplatin at 40 mg/m 2 for six weeks is the standard of care for locally advanced cervical carcinoma in many cancer centers as ours, its optimal scheduling and dosing have yet to be established due to the frequent development of therapy resistance (Candelaria et al, 2006). Different mechanisms have been proposed to reduce cisplatin response, including altered drug accumulation, enhanced drug detoxification and DNA repair, or upregulation of specific biochemical pathways (Ottone et al, 1997;Siddik, 2003). Thus, the identification of molecular predictors of response urges (Siddik, 2003).…”

Antitumor Effects of a Human Dimeric Antibody Fragment 131I-AFRA-DFM5.3 in a Mouse Model for Ovarian Cancer

“…FR expression, on normal epithelial cells such as in kidney proximal tubules, breast, and choroid plexus (32), is restricted to the apical (luminal) surface of polarized cells, on which it is not exposed to the bloodstream and not accessible to antibody (33). Moreover, expression of FR is associated with tumor progression in ovarian carcinoma (34); and, importantly, on the basis of published (35) and unpublished data, the expression of the FR is stable or even upmodulated during acquisition of drug resistance. In support of the mentioned preclinical and clinical data, the humanized anti-FR mAb farletuzumab is now in phase II and III clinical trials in combination with chemotherapy (36).…”