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-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.


OBJECTIVE
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.


METHODS
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.


RESULTS
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%).


CONCLUSIONS
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.


CONCLUSIONS
Further clinical development of DMP 840 is warranted.
Cobb
P W
PW
Hematology/Oncology Clinic, Brooke Army Medical Center, Fort Sam Houston, TX 78234-6200.
Degen
D R
DR
Clark
G M
GM
Chen
S F
SF
Kuhn
J G
JG
Gross
J L
JL
Kirshenbaum
M R
MR
Sun
J H
JH
Burris
H A
HA
Von Hoff
D D
DD
D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008698:Mesylates / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D007546:Isoquinolines; D008698:Mesylates; C084899:bisnafide