ACTIVITY OF DMP-840, A NEW BIS-NAPHTHALIMIDE, ON PRIMARY HUMAN TUMOR COLONY-FORMING-UNITS

Background: DMP 840 {(R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1- -1H-benz[de]iso[quinoline-1,3(2H)-dione]dimethane- sulfonate; NSC-D64 0430} is one in a series of bis-naphthalimides that binds DNA with hig h 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. Purpose: We evalua ted 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 f or initial phase II studies. Methods: A soft-agar cloning system assay was used to determine the in vitro effects of DMP 840 against cells f rom biopsy specimens of colorectal, breast, lung, ovarian, renal cell, stomach, and bladder cancers and from other tumor types. A total of 2 60 human tumor specimens were exposed continuously during the assay to DMP 840; 103 were assessable (20 colonies or more on control plates a nd 30% or less survival for the positive control). An in vitro respons e was defined as at least a 50% decrease in tumor colony formation res ulting from drug exposure compared with controls. Results: In vitro re sponses 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 m u g/mL of DMP 840, respectively. At a concentration of 0.1 mu g/mL, sp ecific activity was seen against melanoma (80%) and against renal ce11 (80%), ovarian (63%), breast (54%), non-small-cell lung (42%), and co lorectal cancers (33%). DMP 840 demonstrated activity in tumor specime ns resistant in vitro to methotrexate (88%), doxorubicin (58%), platin um (57%), cyclophosphamide (53%), vinblastine (53%), etoposide (53%), fluorouracil (37%), and paclitaxel (36%). Conclusions: At in vitro con centrations of 0.1 mu g/mL as a continuous exposure, DMP 840 has activ ity against a variety of human tumors, including a subgroup resistant in vitro to standard antineoplastic agents. Implications: Further clin ical development of DMP 840 is warranted.