carboxyphthalato-1-2-diaminocyclohexaneplatinum and Colonic-Neoplasms

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.

Topics: Carboplatin; Cell Line; Cell Survival; Colonic Neoplasms; Cytarabine; DNA; Humans; Organoplatinum Compounds

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 uniformily active against all lines. JM-8 and JM-9 were virtually ineffective for all cell lines, even at concentrations as high as 50 micrograms/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.

Topics: Antineoplastic Agents; Carboplatin; Cell Line; Cell Survival; Cisplatin; Colonic Neoplasms; Humans; Organoplatinum Compounds

In an effort to investigate the antitumor activity of new cisplatin analogues, 1,2-diaminocyclohexane-(4-carboxyphthalato) platinum (II) (DACCP) was administered in a phase II disease-oriented trial to patients with advanced colorectal carcinoma. Six patients had not received prior chemotherapy, while four had received one drug, and two had received more than one drug. Primary sites of disease were in the liver only (8 patients), liver and lung (2 patients), and intra-abdominal (2 patients). Liver radionuclide scans and CT scans were the main parameter for evaluation. The drug was administered intravenously every 4 weeks at a dose of 640 mg/m2. There were no responses in 12 adequately treated patients. One patient had stable disease for 5 months. Nausea and vomiting was milder than that seen with cisplatin. A peripheral neuropathy was seen in four patients. Fever occurred in two patients and urticaria in one patient. No patient had significant drug-induced anemia, and renal dysfunction was not observed. DACCP at this dose and schedule demonstrated no efficacy as a single agent in the treatment of colorectal carcinoma.

Topics: Adult; Aged; Colonic Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Middle Aged; Organoplatinum Compounds; Rectal Neoplasms