nk-121 and nedaplatin

New cisplatinum derivatives of 254-S, DWA2114R and NK121 developed in Japan were reviewed. These three compounds have less nephrotoxicity and nausea/vomiting than cisplatinum, but have more myelotoxicity. 254-S showed activities against carcinomas of the head and neck, lung, esophagus, urinary tract, prostate, testis, ovary and cervix. DWA2114R showed activities against carcinoma of the ovary, prostate, testis and breast. NK121 is under phase II study. A randomized controlled study of 254-S for non-small-cell lung cancer and DWA2114R for ovarian cancer was performed compared to cisplatinum. The antitumor activity of these compounds was not different from cisplatinum, however the hydration was much less than cisplatinum. These cisplatinum derivatives of 254-S and DWA2114R were thought to be useful for QOL of the patients treated with cisplatinum compound.

Topics: Adult; Aged; Antineoplastic Agents; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Female; Humans; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Ovarian Neoplasms; Prostatic Neoplasms; Testicular Neoplasms

A number of platinum compounds have been synthesized and screened on the basis of structure-activity strategy. In Japan, clinical trials of three analogues (NK-121, DWA-2114R and 254-S) have been undertaken. NK-121, which have the same leaving group as carboplatin, the dose limiting factor (DLF) was leukopenia, while renal toxicity was extremely mild. DWA-2114R, also with the same leaving group, was less nephrotoxic than CDDP or less marrow toxic than CBDCA. DLF was also leukopenia. Phase II study revealed 29% and 12% response rates for small cell carcinoma (SCLC) and non-small cell carcinoma (NSCLC), respectively. In 254-S which has the same carrier ligand (NH2) as CDDP and CBDCA. DLF was thrombocytopenia with mild nephrotoxicity. Response rates of 41% and 21% were obtained for SCLC and NSCLC, respectively. In a randomized study comparing 254-S plus VDS with CDDP plus VDS, equivalent response rate and milder toxicity were observed for the 254-S group. Since highly active agents other than platinum compounds have been currently evaluated for the cases of lung cancer, preclinical screening for substantially active compounds is essential in developing new platinum analogues.

Topics: Antineoplastic Agents; Carboplatin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Female; Humans; Lung Neoplasms; Male; Organoplatinum Compounds

Nine platinum analogs are currently in clinical development, including three that contain the diaminocyclohexane substituent and five that contain the cyclobutanedicarboxylato leaving group. Many of them have shown activity in at least one cisplatin (CDDP)-resistant cell line, most commonly L1210 murine leukemia. In addition, most were less nephrotoxic than CDDP in preclinical evaluations. While these agents share certain key structural similarities, there are important differences in their toxicity profiles that may be exploitable in future combination therapies. Though neuropathy has been a troubling toxicity with two of the three diaminocyclohexane (DACH) compounds, it differs in that it appears to be less chronic and cumulative with oxaliplatin (I-OHP), which is also associated with much less myelosuppression. Of the cyclobutanedicarboxylato compounds that are structurally related to carboplatin (CBDCA), there are several notable differences. For several compounds, isolated neutropenia has been dose-limiting and thrombocytopenia, which is common with CBDCA, has been uncommon. Like CBDCA, neurotoxicity has not been an issue with this group. Therefore, the potential for dose escalation with a colony stimulating factor (CSF) appears enhanced. Furthermore, promising early clinical leads, such as the substantial response rates in cervix and head and neck cancers with 254-S and in patients with colon cancer using circadian modulation of I-OHP, require careful evaluation. Preclinical synergy data are also cited that suggest other potential clinical leads. The development of a number of these agents has been complicated by unanticipated issues, including unexpected chronic dose-limiting neurotoxicity with ormaplatin (OP), formulation and stability problems with liposomal-neodecanoato-diaminocyclohexane platinum (II) (L-NDDP), and problematic nephrotoxicity with zeniplatin (ZP). However, several of these new compounds are likely to enter broader phase II and III development and should provide important information not only about the utility of the agents themselves but also about the predictive value of some of these preclinical models of CDDP resistance.

Topics: Animals; Antineoplastic Agents; Carboplatin; Chemistry, Pharmaceutical; Cyclobutanes; Drugs, Investigational; Forecasting; Humans; Neoplasms; Organoplatinum Compounds; Oxaliplatin

New cisplatinum derivatives of 254-S, DWA2114R and NK121 developed in Japan were reviewed. These three compounds have less nephrotoxicity and nausea/vomiting than cisplatinum, but have more myelotoxicity. 254-S showed activities against carcinomas of the head and neck, lung, esophagus, urinary tract, prostate, testis, ovary and cervix. DWA2114R showed activities against carcinoma of the ovary, prostate, testis and breast. NK121 is under phase II study. A randomized controlled study of 254-S for non-small-cell lung cancer and DWA2114R for ovarian cancer was performed compared to cisplatinum. The antitumor activity of these compounds was not different from cisplatinum, however the hydration was much less than cisplatinum. These cisplatinum derivatives of 254-S and DWA2114R were thought to be useful for QOL of the patients treated with cisplatinum compound.

Topics: Adult; Aged; Antineoplastic Agents; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Female; Humans; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Ovarian Neoplasms; Prostatic Neoplasms; Testicular Neoplasms

A number of platinum compounds have been synthesized and screened on the basis of structure-activity strategy. In Japan, clinical trials of three analogues (NK-121, DWA-2114R and 254-S) have been undertaken. NK-121, which have the same leaving group as carboplatin, the dose limiting factor (DLF) was leukopenia, while renal toxicity was extremely mild. DWA-2114R, also with the same leaving group, was less nephrotoxic than CDDP or less marrow toxic than CBDCA. DLF was also leukopenia. Phase II study revealed 29% and 12% response rates for small cell carcinoma (SCLC) and non-small cell carcinoma (NSCLC), respectively. In 254-S which has the same carrier ligand (NH2) as CDDP and CBDCA. DLF was thrombocytopenia with mild nephrotoxicity. Response rates of 41% and 21% were obtained for SCLC and NSCLC, respectively. In a randomized study comparing 254-S plus VDS with CDDP plus VDS, equivalent response rate and milder toxicity were observed for the 254-S group. Since highly active agents other than platinum compounds have been currently evaluated for the cases of lung cancer, preclinical screening for substantially active compounds is essential in developing new platinum analogues.

Topics: Antineoplastic Agents; Carboplatin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Female; Humans; Lung Neoplasms; Male; Organoplatinum Compounds

Topics: Adenocarcinoma; Antineoplastic Agents; Carboplatin; Cell Division; Cisplatin; Humans; Organoplatinum Compounds; Stomach Neoplasms; Tumor Cells, Cultured

cis-1,1-Cyclobutanedicarboxylato(2R)-2-methyl-1,4-butanediammin eplatinum(II) (NK121) and cis-diammine(glycolato)platinum (254-S), analogues of cis-diamminedichloroplatinum (II) (CDDP) with reduced nephrotoxicity, are under clinical phase trial in Japan. Since CDDP has been shown to be more cytotoxic under conditions of an elevated temperature, we tested the cytotoxicity and cellular uptake of these analogues at 37 degrees and 43 degrees C using EMT6/KU cells in vitro. The cytotoxicity of CDDP was enhanced at 43 degrees C, and that of NK121 and 254-S was also enhanced, in a dose- and time-dependent manner. The 90% cytotoxic concentration (IC90) of each drug was reduced 2.9-fold for CDDP, 2.5-fold for NK121, and 2.2-fold for 254-S. Cytotoxicity was maximal when the two modalities were used simultaneously for all three drugs. The intracellular platinum concentration was assayed using flameless atomic absorption spectrophotometry. When exposed to IC90 drug concentration at 43 degrees C for 2 h simultaneously, the intracellular platinum concentration increased to 0.095 +/- 0.007 micrograms/10(7) cells (a 1.9-fold increase) for CDDP, to 0.198 +/- 0.012 micrograms/10(7) cells (a 1.3-fold increase) for NK121, and to 0.090 +/- 0.014 micrograms/10(7) cells (a 1.3-fold increase) for 254-S; respectively, as compared with the level measured after drug exposure at 37 degrees C (P < 0.05 for all drugs). The elevation in platinum concentration may be one of mechanism related to a synergistic effect of the two treatment modalities. The concomitant use of CDDP analogues and heat shows potential for possible clinical application.

Topics: Animals; Antineoplastic Agents; Carboplatin; Cell Survival; Cisplatin; Female; Hot Temperature; Mammary Neoplasms, Experimental; Mice; Organoplatinum Compounds; Tumor Cells, Cultured; Tumor Stem Cell Assay

The cytotoxic properties of hyperthermia combined with cis-diammine-dichroloplatinum(II) (CDDP), and recently developed platinum complexes, (Glycolato-O-O')diammineplatinum(II) (254-S), cis-1-1-cyclobutane-dicarboxylate-(R)-2-methyl-1-4-butanediammine platinum(II) (NK-121), cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA), and (-)-R-[2-(aminomethyl)pyrrolodine](1,1- cyclobutanedicarboxylato)-platinum(II)monohydrate (DWA-2114R) were studied in vitro in monolayer cultures and multicellular spheroids of HMV-I human malignant melanoma cells. Hyperthermia at 44 degrees C for 30 min was applied during the latter part of 1 hr drug exposure. Cell survival was compared after drug treatments in cells exposed or not exposed to heat. Cytotoxicity was assessed by clonogenic assays. In exponentially growing monolayer cultures, marked hyperthermic sensitization was observed by each of the five platinum complexes studied. The dose modifying factors obtained were almost the same in these drugs. Unlike monolayer cells, the spheroids were appreciably different with regard to hyperthermic sensitization among platinum complexes. The order of the magnitude was as follows: CDDP, DWA-2114R, 254-S, CBDCA, and NK-121. In the low dose region, however, 254-S was the most thermally sensitized. These results suggest that the microenvironment factor within spheroids may significantly affect the cytotoxicity of platinum complexes combined with hyperthermia. On the basis of these findings using spheroids, CDDP, DWA2114R, and 254-S appear to be promising platinum complexes for use with hyperthermia clinically as far as hyperthermic sensitization is concerned.

Topics: Antineoplastic Agents; Carboplatin; Cell Survival; Cisplatin; Hot Temperature; Humans; Melanoma; Organoplatinum Compounds; Radiation-Sensitizing Agents; Tumor Cells, Cultured

(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

The antitumor activities of CDDP analogs (CBD-CA, NK-121, 254-S) were evaluated preclinically by subrenal capsule assay (SRCA) with cyclophosphamide pretreatment. In the fundamental study, the antitumor activities against serially transplanted human esophageal cancer xenograft (IMEs-1) were compared with subcutaneous transplantation assay in nude mice and SRCA. The antitumor activities in SRCA were similar to those of in nude mice assay system (CBDCA greater than CDDP greater than 254-S greater than NK-121). Thus SRCA was considered to be useful for the evaluation of the activities of these agents. The activities were also tested against 10 human esophageal tumors obtained clinically. The sensitivity rate of these agents were 50% in CDDP, 30% in CBDCA, 30% in NK-121, and 30% in 254-S, respectively. These analogs seemed to be less effective than CDDP. However, in two cases, analogs were active though CDDP were inactive. The results suggest that these analogs are useful for the cases in which CDDP can not be given due to the toxicities and also for outpatient use.

Topics: Animals; Antineoplastic Agents; Carboplatin; Cisplatin; Esophageal Neoplasms; Humans; Mice; Mice, Nude; Organoplatinum Compounds; Subrenal Capsule Assay

Topics: Antineoplastic Agents; Carboplatin; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Line; Cisplatin; Humans; In Vitro Techniques; Lung Neoplasms; Organoplatinum Compounds; Tumor Cells, Cultured; Tumor Stem Cell Assay

In the present study, comparison of the therapeutic effects of CDDP and the analogues (CBDCA, 254S, DWA2114R and NK121) on human gynecological carcinomas transplanted into nude mice (uterine cervical cancer; UZ-1-N, endometrial cancer; UE-1-N, ovarian cancer; OCl-1-N, OS-4-N and OS-8-N) was made. CDDP (5 mg/kg), CBDCA (50 mg/kg), 254S (25 mg/kg), DWA (50 mg/kg) and NK121 (18 mg/kg) were administered intraperitoneally every four days at three doses. Simultaneously the tumor size and the body weight were measured and the peripheral WBC and BUN were examined. The results were as follows: 1) The administration of 254S caused a marked inhibition of the tumor growth against all xenografts into nude mice. 2) CDDP and CDDP analogues except 254S were not effective against UE-1-N, but in this xenograft antitumor activity of 254S was remarkable. 3) With 254S, there were a decrease in body weight and the peripheral leukopenia and the elevation of BUN level were more severe. Although 254S has severe side effects, 254S is seemed to be recommendable for the treatment of gynecological malignancies.

Topics: Animals; Antineoplastic Agents; Carboplatin; Cisplatin; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Organoplatinum Compounds; Ovarian Neoplasms; Prognosis; Transplantation, Heterologous; Uterine Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Cell Survival; Cisplatin; Fluorouracil; Humans; In Vitro Techniques; Organoplatinum Compounds; Pharyngeal Neoplasms; Tumor Cells, Cultured

An equi-toxic dose of CDDP and its analogues (254-S, NK-121, CBDCA and DWA-2114 R) was administered to rabbits and S.180 bearing mice, and the pharmacokinetics were studied. Blood levels: Plasma total platinum (Pt) curves of 5 drugs decreased, showing a biphasic function. The shortest t 1/2 alpha and the longest t 1/2 beta were observed in CDDP group, which correlated with the rate of protein binding (CDDP greater than DWA-2114R greater than NK-121 greater than CBDCA greater than 254-S). Tissue distribution: The tissue levels of Pt decreased slowly, and showed a similar pattern among 5 drugs. The highest level was observed in the kidney, liver and skin, with a moderate high level in the tumor, lung, spleen and thymus, followed by the heart, pancreas, stomach, intestine, muscle and testis in that order. The lowest level was in the brain in S.180 bearing mice.

Topics: Animals; Antineoplastic Agents; Carboplatin; Cisplatin; Mice; Organoplatinum Compounds; Platinum; Protein Binding; Rabbits; Sarcoma 180; Tissue Distribution

CDDP is an extremely active antineoplastic agent, yet has severe renal, upper GI and neurotoxicity. Therefore, extremely careful supportive care is necessary to administer this agent to patients. There are two ways to improve this agent. The first is to improve the activities of this agent, including widening the spectrum. The other is to reduce toxicity. By these two ways, the therapeutic window or efficacy of the agents will be increased. In these two factors in mind, 4 analogues, CBDCA, 254S, DWA 2114R and NK-121 are in clinical trials in Japan. These 4 agents are different from mother compound CDDP, that is the DLF is bone marrow depression with rather mild renal and upper GI toxicities with different degrees among analogues, compared with those of CDDP. Therefore, these 4 agents do not need hydration before and after the administration. The extensive studies of pharmacokinetics and dynamics are studied including plasma levels, protein bindings and urinary excretions. These above studies indicate some correlations in efficacy and toxicity, but not perfectly correlated. The experiences of the above 4 analogues are still too short to predict the possibility of neurotoxicity, however, it seems to be 4 analogues also neurotoxic. Above findings strongly suggests that the more clinical experiences are necessary to evaluate these analogues.

Topics: Antineoplastic Agents; Carboplatin; Chemical Phenomena; Chemistry; Cisplatin; Female; Humans; Kidney; Leukopenia; Nervous System; Organoplatinum Compounds; Platinum; Protein Binding; Thrombocytopenia

Since the introduction of Cisplatin (CDDP) into clinical practice in 1972, CDDP has assumed an important role in the treatment of various tumors. But its renal toxicity has been proved to be a dose limiting factor. Thus the total number of courses which may be given is limited. For this reason, efforts have been made to develop CDDP analogues with reduced toxicities, especially renal toxicity, and more enhanced antitumor activity, and they are now reaching the clinical testing phase. Among them Carboplatin (CBDCA), 254-S, DWA 2114R and NK 121 have been well studied. These analogues were noted to be less nephrotoxic, but more myelosuppressive than CDDP in preclinical analysis. As for cytotoxicity, their inhibitory effects on tumor growth in murine experimental system were similar or more to that of CDDP. Due to these data clinical trials have been carried out. Phase I studies have shown that these analogues are relatively free of renal toxicity as evaluated in preclinical studies and that their dose limiting factor is myelosuppression. Estimation of cross resistance to CDDP and antitumor spectrum have been studied at phase II trials which are ongoing. Interim reports have not shown that enhanced tumor activity or enlarged antitumor spectrum are expected.

Topics: Animals; Antineoplastic Agents; Bone Marrow; Carboplatin; Cisplatin; Drug Evaluation; Drug Screening Assays, Antitumor; Humans; Kidney; Leukopenia; Mice; Neoplasms; Neoplasms, Experimental; Organoplatinum Compounds; Thrombocytopenia

Topics: Animals; Antineoplastic Agents; Carboplatin; Carcinoma, Squamous Cell; Cisplatin; Female; Head and Neck Neoplasms; Mice; Mice, Nude; Organoplatinum Compounds