Li-Ying Yang

The synergistic lethal interaction of Cis-diamminedichloroplatinum and natural nucleosides is related to increased DNA cross-links

Human tumor cells were treated in vitro with combinations of cis- or trans-dichlodiammineplatinum (DDP) and natural nucleosides (thymidine, uridine, cytidine and adenosine). Effects were measured by inhibition of colony-formation (cell survival) and DNA alkaline elution (DNA cross-links). No increments in cell lethality or DNA cross-links were elicited by any combination of trans-DDP and nucleosides. In contrast, every combination of cis-DDP and nucleoside was eminently synergistic with 5- and 10-fold increases in cell lethality over the predicted sum of each agent alone. These increments in cell kill correlated linearly with increases in DNA crosslinks suggesting that the nucleosides interact with cis-DDP to enhance its cytotoxic crosslinking mode of action.

The activity of flavone acetic acid (NSC 347512) on human colon cancer cells in vitro

Flavone acetic acid (FAA) was incubated for 1 to 48 hr with 3 established human colon cancer cell lines endowed with distinct degrees of phenotypic properties. All 3 lines responded to FAA in almost identical fashion; when incubated with the drug for only 1 hr, an initial decrease in survival was observed for concentrations of 250 μg/ml but no further increments in cytotoxicity were elicited when the concentration of FAA was augmented. Increasing the length of treatment yielded relatively modest increments (about 1 log) in cell killing only after an interval of 48 hr and only at the highest concentration (1000 μg/ml). Because of these relatively poor cytotoxic effects and because the therapeutic range of FAA is so narrow, we conclude that this agent will not be a valuable contribution to the antitumor arsenal, at least for colon cancer.

Serum CEA levels in a human colonic adenocarcinoma (LOVO) xenograft system

The relationship between tumor size and circulating CEA titers was examined for a human colonic adenocarcinoma xenografted in Balb/C athymic mice. Xenograft material was derived from line LoVo, which produces moderate amounts of CEA, both in vitro and in vivo. No correlation was found between tumor size and serum CEA levels.

Comparative cytotoxicity between cisplatin and second generation platinum analogs

The cytotoxic activity of cis-DDP and four second generation platinum coordination complexes (TNO-6; JM-82; JM-8; and JM-9) was compared on six established human colon carcinoma cell lines with different degrees of differentiation. Cytotoxicity was evaluated by the inhibition of colony formation technique. Cis-DDP was uniformity active against all lines. JM-8 and JM-9 were virtually ineffective for all cell lines, even at concentrations as high as 50 μg/ml. JM-82 was slightly more active although (with the exception of LoVo cells) still about 10-fold less efficacious than cis-DDP. TNO-6 was the only derivative with appreciable cytotoxic activity although about 2 to 5-fold less than cis-DDP for lines SW48, 620, 480, and 1116. For LoVo and SW403, TNO-6 was slightly more active than cis-DDP. In both such instances, increased efficacy resulted from abrogation of the shoulder region of the survival curve while the slope remained essentially intact. Thus any enhancement in therapeutic efficacy with these second generation analogues can only be expected from possible decreases in toxic effects but not from superior tumor cell kill activity.

Ligands of second generation platinum analogs decrease both platinum-induced DNA cross-linking and its ability to interact with 1-β-D-arabinofuranosyl cytosine to potentiate cytotoxic efficacy☆

We evaluated the cytotoxic and DNA cross-linking (CL) ability of four second generation platinum coordination complexes (TNO-6, JM-89, JM-8 and JM-9) delivered alone or in combination with 1-beta-D-arabinofuranosyl cytosine (ara-C) to human colon cancer cells (LoVo). Cell survival varied markedly as a function of the particular substitution moiety. JM-8 and JM-9 were virtually ineffective, even at concentrations as high as 50 micrograms/ml. At that concentration cis-diamminedichloroplatinum(II) (cis-DDP) killed greater than 99.99% of the cells. JM-82 was slightly more active while TNO-6 was the only derivative with appreciably higher cytotoxic activity due to an abrogation of the shoulder region of the type C survival curve. The highest CL effect was observed for cis-DDP followed closely by TNO-6. Very little CL effects were demonstrated for the other three analogs JM-82, JM-8 and JM-9 when measured 6 h after treatment. The combination of cis-DDP and ara-C augmented 10-fold the cytotoxic activity of cis-DDP alone, an effect accompanied by an almost 2-fold increase in CL; every other analog failed to interact in a potentiating manner (either cytotoxicity, or CL at 6 h) with the antimetabolite. Thus, it appears clear that the associated moieties of the Pt coordination complex play a fundamental role in reducing the interaction of the analogs with DNA (as reflected by the decreased CL and cytotoxic effects produced by each agent alone) and in totally preventing their interaction with ara-C to yield a potentiating lethal effect.

The lethal activity and repair inhibition capacity of 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea

SummaryThe survival response of human colorectal carcinoma cells treated in vitro for 1 h with PCNU was characterized by a threshold exponential curve, Dq = 8 μg/ml (1 h) and D0 = 22 μg/ml (1 h). Continuous treatment induced decreasing degrees of cell kill although PCNU was biologically stable in solution for at least 24 h. Cells treated with PCNU were unable to recover from potentially lethal damage but were quite capable of repairing PCNU-induced sublethal damage. Thus, PCNU with different alkylating and carbamoylating than other nitrosourea congeners had similar cytotoxic and repair inhibition capacities. Any therapeutic gain in the clinical use of PCNU must derive only from its lipophilic properties and not from its superior activity at the cellular level.