Isophosphoramide mustard-lysine (ZIO-201): A potential new alkylator for bone marrow transplants

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Cyclophosphamide (CPA) and ifosfamide (IFOS) are widely used anti-cancer drugs. High-dose CPA has a special role in bone marrow transplants but its use is associated with substantial toxicities (kidney, bladder, and CNS) that mandate special interventions like use of Na-2-mercaptoethane sulfonate (mesna) and IV hydration. CPA and IFOS are pro-drugs which must be metabolized before they cross-link DNA via phosphoramide (PM) and isophosphoramide mustards (IPM). Adverse effects of CPA and IFOS result from the metabolites acrolein (ACR) and chloroacetaldehyde (CCA), which is not directly involved in DNA-cross-linking. Recently, a lysine-stabilized form of IPM (IPM-lysine; ZIO-201) was developed. ZIO-201 directly cross-links DNA and is active against human cancer cell lines and in mice with human cancer xenografts. To evaluate kidney toxicity of ZIO-201, we used an in vitro primary rabbit kidney proximal tubule (RPT) cell culture system, which retains many of the characteristics of renal proximal tubule cells including a polarized morphology, a Na+/glucose co-transport system and a p-aminohippurate transport system, glutathione state, and hormone responses. We studied effects of ZIO-201, ACR, and CAA on confluent monolayers of primary rabbit kidney proximal tubule (RPT) cells at 15–100 μM. Viability was determined by neutral red dye uptake. ZIO-201 did not significantly reduce viability; LD₅₀ for CAA was about 40 μM with complete inhibition at 75 μM. These data show that ZIO-201 avoids the kidney toxicity caused by metabolites of pro-drugs like CPA and IFOS. Also, because there is also no inter-subject variability in metabolism of ZIO-201 (unlike CPA and IFOS) and because CPA/IFOS-resistant cells are sensitive to ZIO-201, ZIO-201 may be a useful substitute for CPA and/or IFOS in bone marrow transplant conditioning regimens.