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Enhanced Antitumor Activity of SarCNU in Comparison to BCNU in an Extraneuronal Monoamine Transporter Positive Human Glioma Xenograft Model

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Abstract

A novel analogue of nitrosoureas, 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU), has demonstrated increased anticancer effects in vitro and in vivo. Our previous work suggested that SarCNU enters cells via the extraneuronal monoamine transporter (EMT), that contributes to its enhanced cytotoxicity. In the present study, comparative activities of SarCNU and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) were evaluated in an EMT positive human glioma xenograft model. Athymic nude mice implanted subcutaneously or intracranially with human glioma SHG-44, a cell line that has been confirmed EMT positive by using reverse-transcription polymerase chain reaction (RT-PCR) assay, were treated with SarCNU at an optimal dose of 167 mg/kg, or BCNU at 20 mg/kg or 30 mg/kg, q4d×3 intraperitoneally (i.p.). In 17 animals with subcutaneous tumor grafts treated with SarCNU, 9 animals became tumor free and 8 demonstrated tumor regression. While in the BCNU treated group, there were only 2 out of 10 mice in the 20 mg/kg group and 2 out of 7 in the 30 mg/kg group, which demonstrated some tumor regression. There were 4 drug related deaths in the BCNU (30 mg/kg) group, while there were no drug related deaths in the SarCNU group. In the intracranially implanted mice, the median survival time in the SarCNU group was more than 130 days, while in the BCNU treated group it was only 22 days which was similar to the control group (18 days). This is the first demonstration that SarCNU, in comparison to BCNU, has enhanced anticancer activity in an EMT positive human glioma xenograft model.

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Authors and Affiliations

  1. Department of Neurosurgery, Second Affiliated Hospital of Suzhou Medical College, Suzhou, People's Republic of China

    Zhong-Ping Chen, Gang Wang & Qiang Huang

  2. Department of Brain Tumor Laboratory, Second Affiliated Hospital of Suzhou Medical College, Suzhou, People's Republic of China

    Zhi-Fang Sun, Li-Ying Zhou & An-Dong Wang

  3. Lady Davis Institute for Medical Research, Sir Mortimer B. Davis – Jewish General Hospital, McGill University, Montreal, Quebec, Canada

    Zhong-Ping Chen & Lawrence C. Panasci

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  1. Zhong-Ping Chen
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  2. Gang Wang
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  3. Qiang Huang
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  4. Zhi-Fang Sun
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  7. Lawrence C. Panasci
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Chen, ZP., Wang, G., Huang, Q. et al. Enhanced Antitumor Activity of SarCNU in Comparison to BCNU in an Extraneuronal Monoamine Transporter Positive Human Glioma Xenograft Model. J Neurooncol 44, 7–14 (1999). https://doi.org/10.1023/A:1006245724456

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