Koppán M, Nagy A, Schally A V, Plonowski A, Halmos G, Arencibia J M, Groot K
Endocrine, Polypeptide and Cancer Institute, Veterans Administration Medical Center, New Orleans, Louisiana 70112-1262, USA.
Prostate. 1999 Feb 1;38(2):151-8. doi: 10.1002/(sici)1097-0045(19990201)38:2<151::aid-pros9>3.0.co;2-#.
Receptors for luteinizing hormone-releasing hormone (LH-RH) found in prostate cancers might be used for targeting of chemotherapeutic agents. Doxorubicin derivative 2-pyrrolinodoxorubicin (AN-201) can be linked to carrier analog [D-Lys6]LH-RH to form the targeted cytotoxic analog of LH-RH, AN-207.
We evaluated the effects of AN-207 and its components on the growth of LH-RH receptor-positive human prostate cancer PC-82 xenografted into nude mice. Analog AN-207, radical AN-201, carrier [D-Lys6]LH-RH, or a mixture of [D-Lys6]LH-RH and AN-201 were injected intravenously once at doses of 200 nmol/kg. Tumor growth, body weight, total WBC counts, and serum prostate-specific antigen (PSA) were determined. Receptors for LH-RH on PC-82 tumors were evaluated, and the expression of mRNA for LH-RH receptors was assessed by RT-PCR.
Eight weeks after administration of cytotoxic analog AN-207, there was a 67.8% reduction in tumor volume (P < 0.01), 70.7% decrease in tumor burden (P < 0.01), and 36.5% decrease in serum PSA levels (P < 0.01) as compared with controls. Only one of 8 animals treated with AN-207 died. Cytotoxic radical AN-201 caused a 34.2% (not significant, NS) reduction in tumor volume with no change in serum PSA, and killed 3 of 8 mice due to toxicity. Carrier [D-Lys6]LH-RH and the unconjugated mixture of [D-Lys6]LH-RH and AN-201 had no effect on tumor growth. LH-RH receptors as well as the expression of their mRNA were found in PC-82 tumors.
在前列腺癌中发现的促黄体生成激素释放激素（LH-RH）受体可用于靶向化疗药物。阿霉素衍生物2-吡咯啉阿霉素（AN-201）可与载体类似物[D-Lys6]LH-RH连接，形成LH-RH的靶向细胞毒性类似物AN-207。
我们评估了AN-207及其成分对移植到裸鼠体内的LH-RH受体阳性人前列腺癌PC-82生长的影响。以200 nmol/kg的剂量静脉注射一次类似物AN-207、自由基AN-201、载体[D-Lys6]LH-RH或[D-Lys6]LH-RH与AN-201的未结合混合物。测定肿瘤生长、体重、白细胞总数和血清前列腺特异性抗原（PSA）。评估PC-82肿瘤上的LH-RH受体，并通过逆转录聚合酶链反应（RT-PCR）评估LH-RH受体的mRNA表达。
给予细胞毒性类似物AN-207八周后，与对照组相比，肿瘤体积减少67.8%（P<0.01），肿瘤负荷降低70.7%（P<0.01），血清PSA水平下降36.5%（P<0.01）。用AN-207治疗的8只动物中只有1只死亡。细胞毒性自由基AN-201使肿瘤体积减少34.2%（无统计学意义，NS），血清PSA无变化，并且由于毒性导致8只小鼠中有3只死亡。载体[D-Lys6]LH-RH以及[D-Lys6]LH-RH与AN-201的未结合混合物对肿瘤生长没有影响。在PC-82肿瘤中发现了LH-RH受体及其mRNA表达。
