nk-121 and Leukemia

The purpose of the study was to define the maximally tolerated dose (MTD), major toxicities, and possible antitumor activity of CI-973 a new platinum analogue, in patients with refractory or relapsed acute leukemia. CI-973 was given as a 5-day continuous infusion every 3 to 4 weeks to patients with refractory or relapsed acute leukemia, at doses ranging from 150 mg/m2 to 1350 mg/m2 per course. Thirty-six patients were treated including 18 patients with acute myelogenous leukemia (AML), four with acute lymphocytic leukemia (ALL) and 14 with chronic myelogenous leukemia in blastic phase (CML-BP). Severe gastrointestinal and renal side-effects were the dose-limiting toxicities occurring in four of five patients treated with CI-973 1200 to 1350 mg/m2 per course. At the MTD of 1000 mg/m2 per course, three of 13 patients treated (23%) had moderate to severe nausea and vomiting, three (23%) had moderate diarrhea and one had moderate mucositis. Among 21 patients treated at > or = 1000 mg/m2 (15 AML, 6 CML-BP) no objective complete or partial responses were observed. Twelve of 18 patients (66%) with evaluable marrows on day 14 showed significant suppression of marrow blasts percentage and marrow leukemic infiltrate percentage. Tests for measurement of DNA adduct formation in leukemic cells in vivo after CI-973 therapy, and in vitro following exposure of leukemic cells to CI-973 were developed. This study defined the MTD of CI-973 to be 1000 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Gastrointestinal and renal side-effects were dose-limiting. No objective responses were noted in this heavily resistant population. Correlations between CI-973-induced DNA adduct formation and individual patient response to CI-973 will help to define its role in leukemia subsets.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Agents; Blast Crisis; Carboplatin; DNA Adducts; DNA, Neoplasm; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Remission Induction; Tumor Cells, Cultured

We examined the effects of CI-973 (supplied by Parke-Davis) on several human leukemia cell lines and a Chinese hamster ovary (CHO) line and their drug-resistant counterparts. The cell lines used were HL-60, HL-60/mAMSA, HL-60/DOX, KBM3, KBM3/mAMSA 6, KBM3/mAMSA 6(85), CHO, and CHO/AC-7. DOX, mAMSA, and AC-7 indicate resistance to doxorubicin, amsacrine, or 1-beta-D-arabinofuranosylcytosine, respectively. Cells were incubated with CI-973, and the effect was evaluated by two methods: growth inhibition assay and inhibition of colony formation. All cell lines examined were inhibited by CI-973; two of three amsacrine-resistant lines and the one cytarabine-resistant line demonstrated collateral sensitivity. At equivalent dosages, a 4-day exposure provided much greater cell kill than a 1-h exposure. Clonogenic assay showed exponential killing over 3 log units. Maximum CI-973 levels required to kill 50% of cells were 10-fold lower than the peak plasma levels achieved in a phase I solid tumor study. A continuous infusion phase I study in acute leukemia has been initiated.

Topics: Animals; Antineoplastic Agents; Carboplatin; Cell Division; Cell Line; Cell Survival; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Drug Resistance; Drug Screening Assays, Antitumor; Humans; Leukemia; Leukemia, Promyelocytic, Acute; Tumor Stem Cell Assay

(R)-(-)-1,1-(2-amino-methylpyrrorodine)-platinum(II) (DWA2114R), cis-1,1-cyclobutanedicarboxylato(2R)-2-methyl-1,4-butanediammin eplatinum(II) (NK121; CI-973) and glycolate-o,-o'-diammine platinum(II) (254-S; NSC375101D) are new platinum compounds developed in Japan. We studied the antitumor effects of these compounds on the cisplatin (cis-diamminedichloroplatinum, DDP)-resistant human leukemia cell line, K562/DDP. K562/DDP cells were 10-fold resistant to DDP, while the cells showed minimal cross-resistance to carboplatin (2.1-fold) and DWA2114R (3.3-fold), and were as sensitive to NK121 (1.6-fold) and 254-S (1.0-fold) as the parent cells. Increases in exposure time of K562 cells to DWA2114R resulted in progressive shifting of the dose-response curve to the left, or more effective cell growth inhibition of the cells. Time dependency indices (ID80 obtained from dose-response curve after 1 hr-exposure of K562 cells to drug followed by 72 hr-culture without drug/ID80 after 24 hr-exposure) of DDP, NK121 and 254-S were 10, 8 and 20, respectively. A multidrug resistant cell-line, MOLT-3/TMQ200, was as sensitive to platinum compounds as the parent MOLT-3 cells. Little or no influence of tumor cell density was observed in the growth inhibition of MOLT-3 or K562 cells induced by these new compounds even if cells were concentrated to a density of 10(8) cells/ml. These results indicate that NK121 and 254-S may overcome the drug resistance developed in the patients after treatment with DDP. The antitumor effect of DWA2114R is more dependent not only on drug-concentration but also on exposure time than that of DDP, suggesting that continuous infusion rather than bolus administration appears the favorable schedule in clinical trials.

Topics: Antineoplastic Agents; Carboplatin; Cell Count; Cell Division; Cisplatin; Drug Resistance; Drug Screening Assays, Antitumor; Drugs, Investigational; Humans; Leukemia; Molecular Structure; Organoplatinum Compounds; Tumor Cells, Cultured