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• W2126306520 abstract "Purpose/Objective(s)Onrigen (also called laromustine, cloretazine, VNP4101M, 101M) a sulfonylhydrazine prodrug first synthesized in the Sartorelli laboratory, undergoes a base-catalyzed activation, generating two reactive electrophiles, one with chloroethylating activity and the other with carbamoylating activity. Assays in biochemical systems and intact cells showed that the chloroethylating species primarily alkylates DNA at the O-6 position of guanine, ultimately resulting in the formation of interstrand crosslinks with cytosine on the opposite strand. Onrigen has activity across a broad spectrum of tumor cell culture models and showed promise in Phase I/II trials for the treatment of leukemia. The studies reported here extend preclinical studies of this novel anticancer agent to explore additional questions related to the potential use of onrigen in the treatment of solid tumors and in combination with radiotherapy.Materials/MethodsThese studies used human Fanconi anemia C fibroblasts and control fibroblasts, VC8 (deficient in BRCA2) cells and the parental control Chinese hamster cells in cell culture, and EMT6 cells in vitro and growing as solid tumors in BALB/c Rw mice.ResultsSevere hypoxia at the time of exposure to onrigen did not alter the response of either EMT6 cells or normal human fibroblasts. The proliferative status of the cells was important, with proliferating cells in exponentially-growing cultures being more sensitive to onrigen than cells in quiescent plateau phase cultures. Fanconi anemia C cells and VC8 cells showed marked hypersensitivity to the cytotoxic effects of onrigen, confirming the importance of crosslinks as the lethal lesion produced by this agent. Regimens combining radiation and onrigen in vitro, analyzed using full dose-response curves for the two individual agents, showed additive cytotoxicities for the combined modality regimens. In vivo, onrigen was effective against EMT6 tumors, as measured using both clonogenic assays for tumor cell survival and tumor growth delay assays. Regimens combining radiation with onrigen showed increased effects over those seen with radiation alone, and were compatible with additive effects of the two agents. Regimens combining radiation and onrigen were well tolerated by the hosts.ConclusionsThe results reported here support the potential use of origen for solid tumors and provide preclinical data that will be useful in the design of regimens combining onrigen with radiotherapy.AcknowledgmentThis work was supported by NCI grants P01 CA129186 and CA129186 - 03S2 and used core facilities supported by the Yale Cancer Center and NCI grant 16359. Purpose/Objective(s)Onrigen (also called laromustine, cloretazine, VNP4101M, 101M) a sulfonylhydrazine prodrug first synthesized in the Sartorelli laboratory, undergoes a base-catalyzed activation, generating two reactive electrophiles, one with chloroethylating activity and the other with carbamoylating activity. Assays in biochemical systems and intact cells showed that the chloroethylating species primarily alkylates DNA at the O-6 position of guanine, ultimately resulting in the formation of interstrand crosslinks with cytosine on the opposite strand. Onrigen has activity across a broad spectrum of tumor cell culture models and showed promise in Phase I/II trials for the treatment of leukemia. The studies reported here extend preclinical studies of this novel anticancer agent to explore additional questions related to the potential use of onrigen in the treatment of solid tumors and in combination with radiotherapy. Onrigen (also called laromustine, cloretazine, VNP4101M, 101M) a sulfonylhydrazine prodrug first synthesized in the Sartorelli laboratory, undergoes a base-catalyzed activation, generating two reactive electrophiles, one with chloroethylating activity and the other with carbamoylating activity. Assays in biochemical systems and intact cells showed that the chloroethylating species primarily alkylates DNA at the O-6 position of guanine, ultimately resulting in the formation of interstrand crosslinks with cytosine on the opposite strand. Onrigen has activity across a broad spectrum of tumor cell culture models and showed promise in Phase I/II trials for the treatment of leukemia. The studies reported here extend preclinical studies of this novel anticancer agent to explore additional questions related to the potential use of onrigen in the treatment of solid tumors and in combination with radiotherapy. Materials/MethodsThese studies used human Fanconi anemia C fibroblasts and control fibroblasts, VC8 (deficient in BRCA2) cells and the parental control Chinese hamster cells in cell culture, and EMT6 cells in vitro and growing as solid tumors in BALB/c Rw mice. These studies used human Fanconi anemia C fibroblasts and control fibroblasts, VC8 (deficient in BRCA2) cells and the parental control Chinese hamster cells in cell culture, and EMT6 cells in vitro and growing as solid tumors in BALB/c Rw mice. ResultsSevere hypoxia at the time of exposure to onrigen did not alter the response of either EMT6 cells or normal human fibroblasts. The proliferative status of the cells was important, with proliferating cells in exponentially-growing cultures being more sensitive to onrigen than cells in quiescent plateau phase cultures. Fanconi anemia C cells and VC8 cells showed marked hypersensitivity to the cytotoxic effects of onrigen, confirming the importance of crosslinks as the lethal lesion produced by this agent. Regimens combining radiation and onrigen in vitro, analyzed using full dose-response curves for the two individual agents, showed additive cytotoxicities for the combined modality regimens. In vivo, onrigen was effective against EMT6 tumors, as measured using both clonogenic assays for tumor cell survival and tumor growth delay assays. Regimens combining radiation with onrigen showed increased effects over those seen with radiation alone, and were compatible with additive effects of the two agents. Regimens combining radiation and onrigen were well tolerated by the hosts. Severe hypoxia at the time of exposure to onrigen did not alter the response of either EMT6 cells or normal human fibroblasts. The proliferative status of the cells was important, with proliferating cells in exponentially-growing cultures being more sensitive to onrigen than cells in quiescent plateau phase cultures. Fanconi anemia C cells and VC8 cells showed marked hypersensitivity to the cytotoxic effects of onrigen, confirming the importance of crosslinks as the lethal lesion produced by this agent. Regimens combining radiation and onrigen in vitro, analyzed using full dose-response curves for the two individual agents, showed additive cytotoxicities for the combined modality regimens. In vivo, onrigen was effective against EMT6 tumors, as measured using both clonogenic assays for tumor cell survival and tumor growth delay assays. Regimens combining radiation with onrigen showed increased effects over those seen with radiation alone, and were compatible with additive effects of the two agents. Regimens combining radiation and onrigen were well tolerated by the hosts. ConclusionsThe results reported here support the potential use of origen for solid tumors and provide preclinical data that will be useful in the design of regimens combining onrigen with radiotherapy. The results reported here support the potential use of origen for solid tumors and provide preclinical data that will be useful in the design of regimens combining onrigen with radiotherapy." @default.
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• W2126306520 date "2011-10-01" @default.
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• W2126306520 title "Preclinical Studies of Onrigen in Combination with Radiation" @default.
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