Cobb P W, Degen D R, Clark G M, Chen S F, Kuhn J G, Gross J L, Kirshenbaum M R, Sun J H, Burris H A, Von Hoff D D
Hematology/Oncology Clinic, Brooke Army Medical Center, Fort Sam Houston, TX 78234-6200.
J Natl Cancer Inst. 1994 Oct 5;86(19):1462-5. doi: 10.1093/jnci/86.19.1462.
DMP 840 ((R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1-ethanediyl)]]- bis[5-nitro-1H-benz[de]-iso[quinoline-1,3(2H)-dione]dimethane- sulfonate; NSC-D640430) is one in a series of bis-naphthalimides that binds DNA with high affinity and has sequence specificity to multiple G and C bases. It is also a potent inhibitor of RNA synthesis. DMP 840 has been selected for clinical evaluation on the basis of a broad spectrum of activity (including cures) in human tumors in murine models.
We evaluated DMP 840 in a human tumor clonogenic assay to estimate what plasma concentrations may be necessary for clinical cytotoxic activity and to determine what types of tumors potentially might be primary targets for initial phase II studies.
A soft-agar cloning system assay was used to determine the in vitro effects of DMP 840 against cells from biopsy specimens of colorectal, breast, lung ovarian, renal cell, stomach, and bladder cancers and from other tumor types. A total of 260 human tumor specimens were exposed continuously during the assay to DMP 840; 103 were assessable (20 colonies or more on control plates and 30% or less survival for the positive control). An in vitro response was defined as at least a 50% decrease in tumor colony formation resulting from drug exposure compared with controls.
In vitro responses were seen in 10% (one of 10), 54% (55 of 101), 80% (82 of 103), and 89% (82 of 92) of specimens tested at 0.01, 0.1, 1.0, and 10.0 micrograms/mL of DMP 840, respectively. At a concentration of 0.1 microgram/mL, specific activity was seen against melanoma (80%) and against renal cell (80%), ovarian (63%), breast (54%), non-small-cell lung (42%), and colorectal cancers (33%). DMP 840 demonstrated activity in tumor specimens resistant in vitro to methotrexate (88%), doxorubicin (58%), platinum (57%), cyclophosphamide (53%), vinblastine (53%), etoposide (53%), fluorouracil (37%), and paclitaxel (36%).
At in vitro concentrations of 0.1 microgram/mL as a continuous exposure, DMP 840 has activity against a variety of human tumors, including a subgroup resistant in vitro to standard antineoplastic agents.
Further clinical development of DMP 840 is warranted.
DMP 840（(R,R)-2,2'-[1,2 - 乙二基双[亚氨基(1 - 甲基 - 2,1 - 乙二基)]] - 双[5 - 硝基 - 1H - 苯并[de]异喹啉 - 1,3(2H) - 二酮]二甲磺酸盐；NSC - D640430）是一系列双萘酰亚胺中的一种，它能与DNA高亲和力结合，并且对多个鸟嘌呤和胞嘧啶碱基具有序列特异性。它还是RNA合成的强效抑制剂。基于在小鼠模型中对人类肿瘤具有广泛的活性（包括治愈效果），DMP 840被选用于临床评估。
我们在人类肿瘤克隆形成试验中评估了DMP 840，以估计临床细胞毒性活性可能需要的血浆浓度，并确定哪些类型的肿瘤可能是初始II期研究的主要靶标。
采用软琼脂克隆系统试验来确定DMP 840对来自结直肠癌、乳腺癌、肺癌、卵巢癌、肾细胞癌、胃癌和膀胱癌活检标本以及其他肿瘤类型细胞的体外作用。在试验过程中，总共260个人类肿瘤标本持续暴露于DMP 840；其中103个标本可评估（对照平板上有20个或更多集落，阳性对照的存活率为30%或更低）。体外反应定义为与对照相比，药物暴露导致肿瘤集落形成至少减少50%。
在分别以0.01、0.1、1.0和10.0微克/毫升的DMP 840测试的标本中，体外反应分别见于10%（10个中的1个）、54%（101个中的55个）、80%（103个中的82个）和89%（92个中的82个）。在0.1微克/毫升的浓度下，对黑色素瘤（80%）、肾细胞癌（80%）、卵巢癌（63%）、乳腺癌（54%）、非小细胞肺癌（42%）和结直肠癌（33%）有特异性活性。DMP 840在体外对甲氨蝶呤（88%）、多柔比星（58%）、铂（57%）、环磷酰胺（53%）、长春碱（53%）、依托泊苷（53%）、氟尿嘧啶（37%）和紫杉醇（36%）耐药的肿瘤标本中显示出活性。
在体外浓度为0.1微克/毫升持续暴露时，DMP 840对多种人类肿瘤具有活性，包括体外对标准抗肿瘤药物耐药的一个亚组。
有必要对DMP 840进行进一步的临床开发。
