Cytotoxic effects of a doxorubicin-transferrin conjugate in multidrug-resistant KB cells

Prodrug chemotherapeutics bypass p-glycoprotein resistance and kill tumors in vivo with high efficacy and target-dependent selectivity

“…With respect to in vitro data on pgp resistance, both positive and negative data have been reported (Fritzer et al, 1996;Munns et al, 1998;Matsui et al, 2002). The present report is the first direct demonstration of efficient bypassing of pgp in vivo using a targeted chemotherapeutic.…”

Doxorubicin-transferrin conjugate selectively overcomes multidrug resistance in leukaemia cells

“…3B), probably by MDRassociated proteins [14]. In the fibroblasts [29], the conjugated DOX remained at low concentrations for up to 72 h. Our results demonstrate that the conjugation of doxorubicin to transferrin significantly increased the intracellular drug accumulation in HL60 and resistant HL60ADR cells after a longer incubation time.…”

“…Therefore, transferrin can deliver drugs directly to neoplastic cells with a reduced injury to normal tissue cells [6,25]. Coupling doxorubicin to transferrin may alter the drug disposition, improve the therapeutic index and overcome resistance to conventional therapy [14]. In this study, we used a DOX-TRF conjugate and compared its ability to induce DNA damage, apoptosis and viability in three cell lines with that of the free drug.…”

“…The influence of DOX-TRF conjugate on DSBs formation and apotosis in DOX-resistant leukaemia cells was not previously demonstrated, although it was demonstrated that apoptotic rates after doxorubicin therapy correlate with theraputic success [30]. DOX-TRF is toxic against a variety of human cell lines including HL60 [10,11,19,20] and cell lines resistant to DOX: KB [14], HL60ADR [19], and MCF-7 [9]. Due to the targeted delivery of DOX into tumour cells, the conjugate was 3-to 10-fold more cytotoxic than the free drug, depending on the cell line [27].…”

“…A number of studies have indicated that the conjugation of doxorubicin with the serum protein transferrin significantly increased the cytotoxic effect against tumour cells both in vitro [6,8,9] and in vivo [10]. DOX-TRF is toxic against a variety of human cell lines including HL60-promyelocytic leukemia [11], K562-erythroleukemia [11], Hep2-liver carcinoma [10], HeLa-cervical adenocarcinoma [12], SBC-3-small cell lung cancer [13] and cell lines resistant to DOX: KB-oral carcinoma [14], MCF-7-breast cancer [9], and SBC-3/ADM [13]. In this study, we used a transferrin-doxorubicin conjugate to compare the effect of the free drug and the conjugate on human promyelocytic cell lines HL60 and the doxorubicin-resistant HL60ADR, both overexpressing the TRF receptor.…”