Laromustine, a sulfonyl hydrolyzing alkylating prodrug for cancer therapy.
ABSTRACT Laromustine (Onrigin), under development by Vion Pharmaceuticals Inc, belongs to the sulfonylhydrazine class of alkylating agents and is in clinical development for the treatment of malignancies. Laromustine is a prodrug that yields a chloroethylating compound (VNP-4090-CE) and a carbamoylating compound (methyl isocyanate). The antineoplastic effect of laromustine is attributed primarily to the chloroethylating species, which causes the preferential alkylation of DNA at the O6 position of guanine, a lesion that results in interstrand crosslinks and, eventually, cell death. The carbamoylating species contributes to antitumor activity by inhibiting the DNA repair protein O6-alkylguanine transferase. Early phase I clinical trials in patients with solid tumors indicated that laromustine was associated with myelosuppression; few extramedullary toxicities were observed, indicating potential efficacy for the treatment of hematological malignancies. Phase II trials have been completed in patients with previously untreated acute myelogenous leukemia (AML), high-risk myelodysplastic syndrome (MDS) and relapsed AML. The most encouraging results were observed in patients over 60 years of age with poor-risk de novo AML for which no standard treatment exists. Laromustine is currently in phase II/III trials for AML and phase II trials for MDS and solid tumors. Laromustine appears to be a promising agent that will add to the armamentarium of drugs available to treat patients who do not respond to, or are not fit for, intensive chemotherapy, such as elderly individuals.
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ABSTRACT: To most effectively treat cancer it may be necessary to preferentially destroy tumor tissue while sparing normal tissues. One strategy to accomplish this is to selectively cripple the involved tumor resistance mechanisms, thereby allowing the affected anticancer drugs to gain therapeutic efficacy. Such an approach is exemplified by our design and synthesis of the intracellular hypoxic cell activated methylating agent, 1,2-bis(methylsulfonyl)-1-methyl-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS900) that targets the O-6 position of guanine in DNA. KS900 is markedly more cytotoxic in clonogenic experiments under conditions of oxygen deficiency than the non-intracellularly activated agents KS90, and 90M, when tested in O(6)-alkylguanine-DNA alkyltransferase (AGT) non-expressing cells (EMT6 mouse mammary carcinoma, CHO/AA8 hamster ovary, and U251 human glioma), and than temozolomide when tested in AGT expressing cells (DU145 human prostate carcinoma). Furthermore, KS900 more efficiently ablates AGT in HL-60 human leukemia and DU145 cells than the spontaneous globally activated methylating agent KS90, with an IC(50) value over 9-fold lower than KS90. Finally, KS900 under oxygen-deficient conditions selectively sensitizes DU145 cells to the chloroethylating agent, onrigin, through the ablation of the resistance protein AGT. Thus, under hypoxia, KS900 is more cytotoxic at substantially lower concentrations than methylating agents such as temozolomide that are not preferentially activated in neoplastic cells by intracellular reductase catalysts. The necessity for intracellular activation of KS900 permits substantially greater cytotoxic activity against cells containing the resistance protein O(6)-alkylguanine-DNA alkyltransferase (AGT) than agents such as temozolomide. Furthermore, the hypoxia-directed intracellular activation of KS900 allows it to preferentially ablate AGT pools under the oxygen-deficient conditions that are present in malignant tissue.Biochemical pharmacology 03/2011; 81(10):1201-10. · 4.25 Impact Factor
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ABSTRACT: 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119) is a prodrug of the 1,2-bis(sulfonyl)hydrazine class of antineoplastic agents designed to exploit the oxygen-deficient regions of cancerous tissue. Thus, under reductive conditions in hypoxic cells this agent decomposes to produce the reactive intermediate 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE), which in turn generates products that alkylate the O(6)-position of guanine in DNA. Comparison of the cytotoxicity of KS119 in cultured cells lacking O(6)-alkylguanine-DNA alkyltransferase (AGT) to an agent such as Onrigin, which through base catalyzed activation produces the same critical DNA G-C cross-link lesions by the generation of 90CE, indicates that KS119 is substantially more potent than Onrigin under conditions of oxygen deficiency, despite being incompletely activated. In cell lines expressing relatively large amounts of AGT, the design of the prodrug KS119, which requires intracellular activation by reductase enzymes to produce a cytotoxic effect, results in an ability to overcome resistance derived from the expression of AGT. This appears to derive from the ability of a small portion of the chloroethylating species produced by the activation of KS119 to slip through the cellular protection afforded by AGT to generate the few DNA G-C cross-links that are required for tumor cell lethality. The findings also demonstrate that activation of KS119 under oxygen-deficient conditions is ubiquitous, occurring in all of the cell lines tested thus far, suggesting that the enzymes required for reductive activation of this agent are widely distributed in many different tumor types.Biochemical pharmacology 12/2009; 79(11):1553-61. · 4.25 Impact Factor