Formaldehyde-releasing prodrugs in combination with Adriamycin in resistant tumour cells

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Adriamycin is widely used in cancer chemotherapy and is classified as a topoisomerase II inhibitor. In the presence of formaldehyde, the drug efficiently forms DNA adducts. In this study, a new series of formaldehyde-releasing drugs related to AN-9 (Pivanex^TM) were assessed for their ability to inhibit proliferation (MTT assay) and facilitate formation of Adriamycin-DNA adducts in the Adriamycin sensitive and resistant isogenic cell lines HL60 and HL60/MX2, and MES-SA and MES-SA/Dx5. As single agents, the formaldehyde-releasing prodrugs affected the sensitive and resistant cell lines in a similar manner indicating that they are not substrates for the drug resistance mechanisms involved. Drugs that release two molar equivalents of formaldehyde were superior in inhibiting cell proliferation and enhancing adduct formation, in the presence of Adriamycin, compared to those that released one molar equivalent. Adduct formation was always lower in the resistant cell lines compared to the sensitive, however prodrug combinations were able to overcome Adriamycin resistance to some extent. Moreover, the combination of Adriamycin with selected prodrugs that release two moles of formaldehyde were able to completely overcome resistance in HL60/MX2 cells (that express altered levels of topoisomerase II compared to the HL60 parental cell line). A combination of Adriamycin with selected prodrugs that release one or two moles of formaldehyde was able to partially overcome p-glycoprotein–mediated resistance in MES-SA/Dx5 cells. Collectively these results suggest that changing the mechanism via which Adriamycin exerts its anticancer effect by dramatically increasing adduct levels in the presence of formaldehyde-releasing prodrugs may be useful in chemotherapy.