Short-Term Treatment with Novel Ribonucleotide Reductase Inhibitors Trimidox and Didox Reverses Late-Stage Murine Retrovirus-Induced Lymphoproliferative Disease with Less Bone Marrow Toxicity Than Hydroxyurea

Abstract

We evaluated the ability of a short course of treatment with the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU) and two novel RR inhibitors Trimidox (TX) and Didox (DX) to influence late-stage murine retrovirus-induced lymphoproliferative disease. LPBM5 murine leukaemia virus retrovirus-infected mice were treated daily with HU, TX or DX for 4 weeks, beginning 9 weeks post-infection, after development of immunodeficiency and lymphoproliferative disease. Drug effects on disease progression were determined by evaluating spleen weight and histology. Effects on haematopoiesis were determined by measuring peripheral blood indices (white blood cells and haematocrit) and assay of femur cellularity and femoral and splenic content of colony-forming units granulocyte-macrophage (CFU-GM) and burst-forming units-erythroid (BFU-E). HU, TX and DX partially reversed late-stage retrovirus-induced disease, resulting in spleen weights significantly below pre-treatment values. Spleen histology was also improved by RR inhibitor treatment (DX>TX>HU). However, as expected, HU was significantly myelosuppressive, inducing a reduction in peripheral indices associated with depletion of femoral CFU-GM and BFU-E. In contrast, although TX and DX were moderately myelosuppressive, both drugs were significantly better tolerated than HU. In summary, short-term treatment in late-stage murine retroviral disease with HU, TX or DX induced dramatic reversal of disease pathophysiology. However, the novel RR inhibitors TX and DX had more effective activity and significantly less bone marrow toxicity than HU.

Didox, a ribonucleotide reductase inhibitor, induces apoptosis and inhibits DNA repair in multiple myeloma cells

“…Didox belongs to a unique class of more specific and more potent inhibitors of RR enzyme activity than hydroxycarbamide. Already Didox has demonstrated anti‐tumour activity in several tumour models in both in vitro studies and in vivo models (Elford et al , 1979; Mayhew et al , 1997, 2002; Horvath et al , 2004a,b; Sumpter et al , 2004; Wakisaka et al , 2005). Phase I trials, as well as phase II clinical studies, in patients with advanced breast cancer showed minimal toxicity (Veale et al , 1988; Carmichael et al , 1990; Rubens et al , 1991).…”

Ribonucleotide Reductase Inhibitors and Future Drug Design

“…Trimidox and didox have shown efficacy in combination with Temozolomide (an alkylating agent) in the treatment of human malignant glioma cell lines [279]. Trimidox and didox suppress retrovirus-induced murine AIDS with more effectiveness and less bone marrow toxicity than hydroxyurea [280][281][282]. Both of the agents also showed the ability to improve the efficacy of the reverse transcriptase inhibitor didanosine (2,3-didoxyinosine; ddI) and abacavir in murine AIDS model.…”

Two Proteins Mediate Class II Ribonucleotide Reductase Activity in Pseudomonas aeruginosa

“…All three RNR classes also share a sophisticated allosteric regulation mediated by different deoxyand ribonucleotides, which guarantees an adequate and bal-anced supply of DNA precursors during DNA replication and repair. The essentiality of this enzyme makes it a good candidate for anticancer, antiviral, and antibacterial drug therapy (15)(16)(17). In P. aeruginosa, the investigation of the expression and physiological function of the three different classes of RNR is important from a biomedical and physiological point of view, since such studies might contribute to a better understanding of the pathogenicity and the metabolic diversity of this species.…”