(R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1-ethanediyl)]]- bis[5-nitro-1H-benz[de]isoquinoline-1,3-(2H)-dione] dimethanesulfonate (DMP 840), a novel bis-naphthalimide with potent nonselective tumoricidal activity in vitro.

(R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1-ethanediyl)]]- bis[5-nitro-1H-benz[de]isoquinoline-1,3-(2H)-dione] dimethanesulfonate (DMP 840), is a bis-naphthalimide anticancer tumoricidal agent currently in phase I clinical trials. DMP 840 exhibits curative activity in human tumor xenografts, where it shows selectivity for human solid tumors over murine leukemias. In contrast to the selectivity found for DMP 840 in vivo, DMP 840 exhibits potent antiproliferative activity in vitro against a variety of human and murine leukemia and solid tumor cell lines in culture, with inhibitory doses that reduce the number of treated cells to one half (IC50) values ranging from 2.3 to 53 nM. DMP 840 was growth inhibitory to three doxorubicin-resistant cell lines with IC50 values also in the nanomolar range. Clonogenic survival experiments showed that DMP 840 was equally cytotoxic to both exponentially growing and quiescent human clone A colon carcinoma cells. A 1-h incubation of DMP 840 (1.22-12 microM) caused 5-log cell kill in KB-3-1 human epidermoid carcinoma, clone A human colon carcinoma, and L1210 murine leukemia cell lines. The rapid cell killing by DMP 840 in clonogenic survival experiments and initial mechanism of action studies was consistent with a DNA-interactive mechanism for DMP 840 cytotoxicity. Mechanism of action studies in L1210 leukemia cells demonstrated that DMP 840 inhibited the incorporation of thymidine and uridine into DNA and RNA with IC50 values of 0.55 and 0.08 microM, respectively. DMP 840 produced DNA single-strand breaks in a dose-dependent manner. Double-strand breaks were not observed with DMP 840 treatment, even at higher concentrations of compound. Chinese hamster ovary (CHO) and P388 cells resistant to camptothecin and containing a mutant form of topoisomerase I were also used to evaluate whether DMP 840 was cross-resistant with agents active against topoisomerase I. While the CHOR line was 163-fold resistant to camptothecin, the CHOR line was only 1.7-fold resistant to DMP 840. In summary, DMP 840 is a DNA-interactive agent that demonstrates excellent antiproliferative activity in vitro against cultured tumor cells from both human and murine sources. Its mechanism of tumoricidal activity may be novel.

Phleborheography--results of a ten-year experience.

Phleborheography (PRG) is a physiologic volumetric plethysmographic technique that was developed for the diagnosis of lower extremity deep venous thrombosis. During the past 10 years, 21, 626 extremities have been studied with 709 corresponding venograms. Overall data reveal a sensitivity of 92% (247/268) and specificity of 95% (418/441). There were 21 false negative PRG results, and 12 of these were due to isolated calf vein thrombosis. There were 23 false positive results, and 11 of these were considered true errors of the technique. When isolated calf vein thrombosis was disregarded, the sensitivity increased to 95%. PRG detected 45 of 57 (79%) isolated calf vein thrombi. The modified criteria for interpretation included respiratory waves and baseline elevation as the major criteria and prominent arterial pulsation and foot emptying as the minor criteria. PRG has recently been used to monitor the duration of thrombolytic therapy. While data are limited, this appears to be a promising contribution to the quantification of individual response to lytic therapy and may indicate an objective end point for treatment. PRG is a sensitive and specific method of detecting deep vein obstruction. It is a painless, reproducible, repeatable technique that requires minimal patient cooperation. PRG is a versatile laboratory technique that can be used for a variety of applications in addition to the diagnosis of deep vein thrombosis.