ski-2053r and Lung-Neoplasms

A phase II trial of a novel platinum analog, SKI 2053R, was performed in patients with previously untreated extensive-stage disease (ED) small-cell lung cancer (SCLC). SKI 2053R was administered at the dose of 400 mg/m2 every 3 to 4 weeks as a 1-h infusion. After the first cycle, the dose was escalated to 440 mg/m2 based on toxicity. Thirty-eight patients (31 male) were enrolled between June 1995 and August 1997. The median age was 61 years (range, 36-70 years). Six of 37 evaluable patients achieved a partial response (16.2%; 95% confidence interval [CI], 4.4-28.0%). The durations of response were 1.1, 1.5, 1.7, 1.9, 3.4, and 4.6 months. The estimated median survival time was 7.4 months (95% CI, 5.1-9.7 months). Grade 3 or 4 toxicities were not observed. Grade 1 to 2 leukopenia, anemia, and thrombocytopenia were seen in 5 of 68 cycles, 16 of 68, and 2 of 68, respectively. Nonhematologic toxicities included grade 1 to 2 nausea or vomiting (30 of 68 cycles), nephrotoxicity (27 of 68), and hepatotoxicity (13 of 68). SKI 2053R showed a modest antitumor activity with limited toxicities in patients with ED SCLC. Further clinical trials are warranted in SCLC with a higher dose of SKI 2053R.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Small Cell; Female; Hematologic Diseases; Humans; Korea; Lung Neoplasms; Male; Malonates; Middle Aged; Nausea; Organoplatinum Compounds; Survival Rate

Heptaplatin, cis-malonato [(4R,5R)-4,5-bis (amino-methyl)-2-isopropyl-1,3-dioxolane] platinum(II) (SKI-2053R, Sunpla) is a new platinum derivative with anti-tumor activity comparable to cisplatin on various cancer cell lines. Preclinical studies suggest that it is less nephrotoxic than cisplatin. This study was undertaken to examine the combined effect of heptaplatin and ionizing radiation on two established human squamous carcinoma cell lines (NCI-H520, SQ20B). The cytotoxic activity of heptaplatin was concentration-dependent in both cell lines. When low dose heptaplatin was combined with high dose ionizing radiation, there was an additive cytotoxic effect on NCI-H520 cells (P < 0.05), while a moderate dose of heptaplatin and a low dose of ionizing radiation had an additive cytotoxic effect on the growth of SQ20B cells (P < 0.05). FACS analysis and DAPI staining showed that their additive cytotoxic effects were correlated with the induction of apoptosis. Further studies are warranted using heptaplatin and ionizing radiation in squamous cell carcinoma as a substitute for cisplatin.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Cisplatin; Combined Modality Therapy; Drug Screening Assays, Antitumor; Humans; Laryngeal Neoplasms; Lung Neoplasms; Malonates; Organoplatinum Compounds; Radiation-Sensitizing Agents; Radiation, Ionizing

The effect of exposure time on the in vitro cytotoxicity of a new platinum complex, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolan e]platinum(II) (SKI 2053R) and cisplatin (CDDP) toward two human lung-adenocarcinoma cell lines (PC-9, PC-14) and two human stomach-adenocarcinoma cell lines (KATO III, MKN-45) was investigated by variation of the exposure time (1, 4, 12, and 24 h) and drug concentration to yield a constant product of drug concentration times exposure time (C x T). Exposure of cancer cells to low concentrations of SKI 2053R for 12 or 24 h resulted in a greater killing effect than did 1- or 4-h exposure to 24- or 6-fold higher concentrations; the inhibitory effects of SKI 2053R on the colony formation of all tumor cell lines except for KATO III were significantly increased with increasing exposure time (P < 0.05). However, the inhibitory effects of CDDP against all tumor cell lines tested except for PC-14 were inversely correlated with increasing exposure time (P < 0.05). The intracellular accumulation of SKI 2053R and CDDP was measured under the same conditions used in the cell-survival assay using MKN-45 cells. The amount of platinum accumulated from SKI 2053R into MKN-45 cells was greater for the treatment involving low concentrations and long-term exposures (12 and 24 h) than for that using high concentrations and short-term exposures (1 and 4 h) at the constant C x T values; however, the increased accumulation of CDDP was more prominent as the concentration was increased, even if the exposure time became shorter. The pharmacokinetics studies of SKI 2053R following 1-, 4-, 12-, and 24-h infusions were performed in beagle dogs. A single dose of SKI 2053R (5.0 mg/kg) was successively given over various infusion periods to three beagle dogs at 3-week intervals. The peak levels of ultrafiltrable platinum observed for SKI 2053R at the 1-, 4-, 12-, and 24-h infusions were 3.10+/-0.49 (mean +/- SD), 1.24+/-0.06, 0.43+/-0.07, and 0.25+/-0.04 microg/ml, respectively. The mean binding ratios of platinum from SKI 2053R to plasma protein at the end of 1-, 4-, 12-, and 24-h infusions were approximately 91%, 73%, 53%, and 51%, respectively. The steady-state level of free platinum was maintained during long-term infusions (12 and 24 h) after short periods (1-3 h) from the start of the infusion. This study strongly suggests that the therapeutic efficacy of SKI 2053R given by continuous long-term infusion should be investigated in future

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Area Under Curve; Cisplatin; Dogs; Dose-Response Relationship, Drug; Humans; Infusions, Intravenous; Lung Neoplasms; Malonates; Organoplatinum Compounds; Stomach Neoplasms; Tumor Cells, Cultured

The in vitro and in vivo antitumor activity of a new antitumor platinum complex, cis-malonato[(4R, 5R)-4,5- bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI2053R, NSC D644591), were evaluated and compared with those of cisplatin (CDDP) and carboplatin (CBDCA) using murine tumors. SKI 2053R was highly active in vitro against both L1210 murine leukemia and its CDDP-resistant subline, L1210/DDP; the relative resistances were 20.0-, 14.5-, and 2.7-fold for CDDP, CBDCA, and SKI 2053R, respectively. SKI 2053R showed activity comparable with or superior to either CDDP or CBDCA in mice implanted with L1210. In mice implanted with L1210/DDP, as compared with CBDCA, SKI 2053R showed high values for the percentage of treated survivors relative to controls and for numbers of cured mice, whereas CDDP had virtually no activity. In mice implanted with P388, all three drugs were highly active, but the intensity of activity was shown to be ranked in the following order: SKI 2053R > CDDP > CBDCA. The antitumor activity of SKI 2053R against Lewis lung carcinoma was comparable with that of both CDDP and CBDCA. The antitumor activity of SKI 2053R was further investigated against two human tumor xenografts, KATO III (stomach adenocarcinoma) and WiDr (colon adenocarcinoma), implanted s.c. in nude mice and was compared with that of CDDP. In SKI 2053R-treated groups, the time required for a mean tumor weight of 1,000 mg was 33.1 days in KATO III xenografts and 35.0 days in WiDr xenografts as compared with 30.2 and 27.2 days in CDDP-treated groups, respectively. SKI 2053R achieved growth-inhibition rates comparable with those of CDDP against KATO III (65% versus 59%) and WiDr xenografts (64% versus 54%) on day 35. These results indicate that SKI 2053R is an attractive candidate for further development as a clinically useful anticancer drug.

Topics: Adenocarcinoma; Analysis of Variance; Animals; Antineoplastic Agents; Carboplatin; Cell Division; Cisplatin; Colonic Neoplasms; Disease Models, Animal; Drug Evaluation; Humans; Leukemia L1210; Leukemia P388; Lung Neoplasms; Male; Malonates; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Nude; Neoplasm Transplantation; Organometallic Compounds; Organoplatinum Compounds; Stomach Neoplasms; Transplantation, Heterologous; Tumor Cells, Cultured