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At least 19 recordsLinked to original sources
PubMed1988

[Organoplatinum compounds. 1987 update].

Cisplatin is one of the best available cytotoxic agents particularly in testicular, ovarian and head and neck cancer. However gastrointestinal and renal toxicities preclude greater utilisation. High dose cisplatin (200 mg/m2) has serious neurological side effects. Carboplatin gives the same therapeutic results as cisplatin in ovarian, small cell lung and head and neck cancers with a better tolerance, the main toxicity being haematological. Iproplatin seems to have no advantage over carboplatin. New derivates such as diaminocyclo-hexane-platinum seem to be promising in preclinical and phase I studies.

Carboplatin↗
PubMed1992

Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer: activity in platinum-resistant disease.

PURPOSE: There is a critical need to find new antineoplastic drugs that are active in platinum-refractory ovarian cancer. We conducted a phase II trial of single-agent ifosfamide with mesna uroprotection in patients with ovarian cancer previously treated with an organoplatinum compound to assess its activity in this clinical setting. PATIENTS AND METHODS: Ifosfamide (1.0 or 1.2 g/m2/d for 5 days, delivered on a monthly schedule) was administered to the 57 patients entered onto this trial. Dose reductions were permitted for unacceptable toxicities. RESULTS: Toxicity included severe bone marrow suppression (WBC count less than 1,000/microL and/or platelet count less than 50,000/microL), renal dysfunction (serum creatinine level greater than 2.0 mg/dL), and reversible CNS dysfunction (disorientation, hallucinations, somnolence, and agitation), which occurred in 20%, 14%, and 12% of patients, respectively. Of 41 patients with strictly defined platinum-refractory ovarian cancer, five (12%) demonstrated a partial (four) or complete (one) response to this treatment program. CONCLUSION: Single-agent ifosfamide has modest but unequivocal activity in platinum-resistant ovarian cancer. Further studies of this drug used as a front-line agent along with an organoplatinum compound or as part of a dose-intensification program with bone marrow, peripheral stem cell, or colony-stimulating factor support are indicated. In addition, single-agent ifosfamide is a reasonable standard second-line treatment strategy in appropriately selected patients with platinum-refractory ovarian cancer.

Acute Kidney Injury↗
PubMedDate not supplied

Paclitaxel plus ifosfamide in advanced ovarian cancer: a multicenter phase II study.

BACKGROUND: While ovarian cancer is one of the most sensitive cancers to cytotoxic drugs, with objective response rates of 60-80% routinely being reported in previously untreated patients, the majority of individuals with advanced disease ultimately relapse. Paclitaxel, a new and novel antimicrotubule agent, has shown activity as a salvage therapy in epithelial ovarian cancer. More importantly, in a prior study, it has been shown to be active in tumors that have displayed resistance to platinum compounds, with a reported response rate of 20%. Ifosfamide has shown activity in the treatment of patients who previously demonstrated clinical resistance to a platinum-cyclophosphamide combination. Recently, a synergistic activity of Taxol combined with ifosfamide has been reported in ovarian cell lines. Based on these data, a phase I/II study of a combination treatment with paclitaxel and ifosfamide was performed. PATIENTS AND METHODS: Thirty-one patients with recurrent ovarian cancer or ovarian cancer refractory to cisplatin (CDDP)-containing regimens were treated with paclitaxel at a dose of 135 mg/m2 on day 1; ifosfamide was administered at 1 g/m2 on days 2 and 3 for the first cycle and 1.5 and 2 g/m2 with the same schedule in cycles 2 and 3, respectively. In the absence of toxicity, the dose of ifosfamide was maintained at 2 g/m2 for the last three cycles. Cytotoxic therapy was repeated every 3 weeks. RESULTS: A 30% overall objective response rate was achieved in the 30 patients assessable for response. Among 21 platinum-resistant patients, 4 partial responses (19%) were observed, while in the 9 platinum-sensitive patients 2 complete responses and 3 partial responses (55%) were observed. Myelosuppression was the predominant toxicity. Leukopenia (WHO grade 3-4) occurred in 10% of patients who received ifosfamide at a dose of 1 g/m2 and in 18% of patients treated with ifosfamide at 1.5 g/m2. CONCLUSION: Our results confirmed a low activity of paclitaxel in platinum-resistant patients. The results of this combination treatment with paclitaxel-ifosfamide in our platinum-sensitive patients support further investigations in a randomized study of the combination regimen against paclitaxel alone or retreatment with organoplatinum compounds.

Aged↗
PubMed2004

Synthesis and properties of para-substituted NCN-pincer palladium and platinum complexes.

A variety of para-substituted NCN-pincer palladium(II) and platinum(II) complexes [MX(NCN-Z)] (M=Pd(II), Pt(II); X=Cl, Br, I; NCN-Z=[2,6-(CH(2)NMe(2))(2)C(6)H(2)-4-Z](-); Z=NO(2), COOH, SO(3)H, PO(OEt)(2), PO(OH)(OEt), PO(OH)(2), CH(2)OH, SMe, NH(2)) were synthesised by routes involving substitution reactions, either prior to or, notably, after metalation of the ligand. The solubility of the pincer complexes is dominated by the nature of the para substituent Z, which renders several complexes water-soluble. The influence of the para substituent on the electronic properties of the metal centre was studied by (195)Pt NMR spectroscopy and DFT calculations. Both the (195)Pt chemical shift and the calculated natural population charge on platinum correlate linearly with the sigma(p) Hammett substituent constants, and thus the electronic properties of predesigned pincer complexes can be predicted. The sigma(p) value for the para-PtI group itself was determined to be -1.18 in methanol and -0.72 in water/methanol (1/1). Complexes substituted with protic functional groups (CH(2)OH, COOH) exist as dimers in the solid state due to intermolecular hydrogen-bonding interactions.

Hydrocarbons, Aromatic↗
PubMed2003

Sequence-selective metalation of double-helical oligodeoxyribonucleotides with PtII, MnII, and ZnII ions.

Reactions of [PtCl(dien)](+) (dien=diethylenetriamine), Mn(2+) and Zn(2+) ions with three different double-helical oligodeoxyribonucleotides, which contain the central sequence GGXY (XY=AT, TA or CC) have been monitored by NMR spectroscopy. 2 D [(1)H, (15)N] HSQC/HMQC NMR spectroscopy using (15)N-labeled Pt(dien) shows that the rate of formation of 3'-G-N 7 and 5'-G-N 7 platinated adducts is highly sequence dependent. The relative rates of platination of 5'-G versus 3'-G are largest for the sequence -GGCC-, for which only a small fraction of the 3'-G adduct is formed; for -GGTA-, the rate of 5'-G platination is about eight times that of 3'-G, and for -GGAT- the ratio is 1.2. These values are in qualitative agreement with those obtained for G-N 7/Mn(2+) selectivity as determined by paramagnetic line broadening of the adjacent G-H 8, and also G-N 7/Zn(2+) selectivity as determined by G-H 8 chemical shift changes. Fluctuation in the nucleophilicity of G-N 7 may be explained by variation of the pi-stacking interaction between base residues along the double helix. The reaction mixtures containing platinated 3'-G and 5'-G fractions were separated by HPLC. Since the duplexes are self-complementary, the platinated single strands were readily annealed to duplexes with twofold symmetry and analyzed by 2 D [(1)H, (1)H] NOESY NMR spectroscopy. Unexpectedly, the 5'-G-H 8 resonance signals of both 5'-G and 3'-G platinated duplexes showed large downfield shifts in the range delta=0.3-0.6 ppm, while the 3'-G-H 8 resonance signals in both cases exhibited no, or only slight, upfield shifts. Resonance signals for several other protons in the central region undergo large chemical shift variations induced by platination, indicating that monofunctional binding to DNA leads to appreciable conformational changes.

Base Sequence↗
PubMed2006

Flexibility of inorganic tennis ball structures inducing anion selectivity.

Inorganic tennis balls (ITBs), [[{Pt(betmp)(dach)}(2)Cu](2)(X)][X](3) (in which X=ClO(4) (-) (3), NO(3) (-) (4), Cl(-) (5) and Br(-) (6); dach=trans-1,2-diaminocyclohexane and betmp=bisethylthiomethylidenepropanedioate) and [[{Pt(dteym)(dach)}(2)Cu](2)(PF(6))][PF(6)](3) (7; dteym=1,3-dithiepane-2-ylidenemalonate), were prepared as crystals. Investigation of their X-ray crystal structures revealed that shapes of the cavities in ITBs show significant distortions that depend on the properties of the encapsulated anions. The CuCu* distance was observed to be longest in 7 and shortest in 5, the difference between them being 2.05 A. The flexibility of cavity structures of ITBs makes it possible to encapsulate various anions inside the cavity, while their distortions may be a reason for the difference in the encapsulating ability for anions, that is, anion selectivity. Especially, the distortions observed in 7 are so severe that the encapsulating ability of the cavity for PF(6) (-) is very low compared to other anions. The shapes of ITBs with ClO(4) (-) and BF(4) (-) ions inside their cavities are very similar; however, ClO(4) (-) is encapsulated by the cavity better than BF(4) (-), which is explicable by the difference of metal-anion interactions. This structural study on ITBs gives a clue to the origin of the anion selectivity of the cavity in ITBs previously investigated by (19)F NMR spectroscopy of the ITBs in methanol.

Anions↗
PubMed2006

Mass spectrometry assisted assignments of binding and cleavage sites of copper(II) and platinum(II) complexes towards oxidized insulin B chain.

Interaction of cis-[Pt(en)(H2O)2]2+ and [CuL(H2O)]2+, where L is 2-[bis(2-aminoethyl)amino]ethanol, with oxidized insulin B chain in molar ratio of 1 : 1, 1 : 2 and 1 : 3 at pH 2.5 and 40 degrees C has been investigated by electrospray ionization mass spectrometry (ESI-MS) and tandem mass spectrometry (MS/MS). The results show that the binding sites of the two complexes with oxidized insulin B chain are terminal NH2, imidazole groups of His5 and His10. The hydrolytic cleavage studies show that the [CuL(H2O)]2+, upon a pendant hydroxyl group of the ligand, selectively cleaves the peptide bonds at Gly8-Ser9, Asn3-Gln4 and Phe1-Val2, and the cis-[Pt(en)(H2O)2]2+ only cleaves the peptide bond at His10-Leu11. This is the first report of cis-[Pt(en)(H2O)2]2+-promoted cleavage of His-X peptide bond.

Copper↗
PubMed1986

[Cytostatic platinum complexes: an unexpected discovery with considerable consequences].

Antineoplastic platinum complexes represent new-developed inorganic cytostatics, which interfere with intracellular nucleic acids, especially with DNA. The main representative is cis-diamminedichloroplatinum (II) (cis-platin, DDP). It has proven effective against human urogenital tumors and against carcinomas of the head and neck. The most severe side effects are nephrotoxicity and gastrointestinal irritation. Stimulated by the clinical success of cisplatin, a series of platinum complexes of the second generation has been recently developed. Moreover, anti-tumor properties were detected for various organometallic complexes containing titanium, vanadium, tin, or iron as central atoms.

Antineoplastic Agents↗
PubMed1992

Activity of two platinum-linked phosphonic acids against autochthonous rat colorectal cancer as well as in two human colon-cancer cell lines.

Two new platinum-containing phosphonate compounds, cis-diammine[nitrilotris(methylphosphonato)(2-)- O1,N1]platinum(II) (AMDP) and cis-cyclohexane-1,2-diamine[nitrilotris(methylphosphonato) (2-)-O1,N1]platinum(II) (DADP) were investigated in acetoxy-methyl-methylnitrosamine-induced autochthonous colorectal rat adenocarcinoma in vivo as well as in two human colon-cancer cell lines (SW707 and SW948) in vitro. In the in vivo model, the two compounds were given i.v. at doses of 8 and 13 mg/kg as well as p.o. at 16 and 26 mg/kg twice a week for 10 weeks, respectively. AMDP produced more intensive toxicity at both doses but showed higher antitumour activity only following i.v. administration. On the other hand, DADP caused significant tumour-growth inhibition after both modes of application, but as it produced only low toxicity, its use should be favoured. The in vitro assays were performed using two cell lines derived from human colorectal adenocarcinomas. According to the microculture tetrazolium test (MTT) AMDP (IC50, 34 and 59 microM in SW707 and SW948, respectively) was more effective than DADP (IC50, 412 and 660 microM in SW707 and SW948, respectively) in inhibiting cell growth. Based on cell counts AMDP (IC50, 8 and 11 microM in SW707 and SW948, respectively) and DADP (IC50, 266 and 285 microM in SW707 and SW948, respectively) showed more intensive antiproliferative efficacy as determined by the Coulter Counter method vs the MTT assay. The promising activities of these new platinum-linked phosphonic acids in autochthonous rat colorectal carcinoma and in human colorectal cancer cell lines warrant further investigations of compounds of this class to elucidate their role in the treatment of colorectal cancer.

Adenocarcinoma↗
PubMed1990

Anticancer-agent-linked phosphonates with antiosteolytic and antineoplastic properties: a promising perspective in the treatment of bone-related malignancies?

Bisphosphonates are compounds with a high affinity for bone and other calcified tissues. They inhibit tumor-induced bone destruction and the associated hypercalcemia by hindering the activity of the osteoclasts. Owing to a long biological half-life of bisphosphonates in the bone, a treatment using a prophylactic regimen seems possible. This paper summarizes preclinical studies with the bisphosphonate 3-amino-1-hydroxypropylidene-1,1-diphosphonic acid and two methyl derivatives; 3-N,N-dimethylamino-1-hydroxypropylidene-1,1-diphosphonic acid and 4-N,N-dimetyhlamino-1-hydroxybutylidene-1,1-diphosphonic acid with respect to their bone-protecting activity in therapy as well as in prophylaxis. To find substances that are useful for the treatment of primary tumor, as well as bone metastasis, we synthesized and tested cis-diammine[nitrilotris(methylphosphonato)(2-)-O1,N1]platin um(II) and cis-diammine[( bis-(phosphonatomethyl)amino]acetato(2-)-O1,N1)platinum(II), which contain both an osteotropic and an antineoplastic moiety. Experiments were carried out: (a) in the intratibial transplanted Walker carcinosarcoma 256B of the rat, which mimics osteolytic bone metastasis, and (b) in the transplantable osteosarcoma of the rat, which shows a histology and metastatic pattern similar to that found in man. These investigations indicate that it is possible to effect adjuvant therapy of bone metastases by combination of two compounds with different properties into one structure without losing the therapeutic characteristics of the parent compounds. They thus provide evidence that it may be possible to design compounds well suited for the therapeutic or prophylactic treatment of bone-related malignancies.

Animals↗
PubMed1990

Sensitivity of rodent osteosarcoma clones to platinum-containing phosphonic acid complexes in vitro.

Osteosarcoma treatment still is unsatisfactory owing to the development of metastases. This situation causes many problems for the patients as well as the clinicians. Tumor heterogeneity is made responsible for the development of cell lines resistant to chemotherapy. As the transplantable osteosarcoma of the rat resembles the human metastasizing osteosarcoma, studies on clones of this tumor were started. The following compounds were investigated: AMDP, cis-diammine[nitrilotris-(methylphosphonato)(2-)-O1,N1]plati num II; DADP, cis-cyclohexane-1,2-diamine[nitrilotris(methylphosphonato)(2 -)-O1,N1]- platinum II; IMD, cis-diammine[imino-bis(methylphosphonato)(2-)-O1,N1]platinum II; DIMD, cis-cyclohexane-1,2-diamine[iminobis(methylphosphonato) (2-)-O1,N1]platinum II. In vitro assays were performed with cell lines derived from a lung metastasis with the limited-dilution method. The clones varied in modal chromosome number, growth kinetics and tumorigenicity. AMDP was the most potent compound in all three clones resulting in a concentration- and time-dependent effect while IMD was somewhat less active. The diamminocyclohexane derivatives were considerably less effective, inhibiting cell growth especially in clone C10. In contrast, clone C36 was more sensitive than C25 and did not recover within the observation period of 5 days. Viability was reduced significantly only in C10, when treated with AMDP. Differences between the clones and the various compounds in inhibiting cell growth could be observed. Therefore, further experiments on the heterogeneity and sensitivity of these cell lines seem promising.

Animals↗
PubMedDate not supplied

Therapeutic efficacy of two different cytostatic-linked phosphonates in combination with razoxane in the transplantable osteosarcoma of the rat.

Two new compounds, 4-[4-[bis-(2-chloroethyl)-amino-]phenyl]-1- hydroxybutane-1,1-bisphosphonic acid (BAD) and aminotris-(methylenephosphonato)-diamminoplatinum(II) (ADP) that both have cytostatic and osteotropic properties, have shown good therapeutic efficacy against an osteosarcoma which metastasizes and kills by lung metastases. We therefore combined each of these drugs with the antimetastic agent razoxane. Razoxane (20 mg/kg i.p., 5 days/week for 6 weeks) was administered in combination with either BAD (30 mg/kg i.p.) or ADP (37.5 mg/kg i.v.) twice weekly for 3 weeks. Tumour volumes, body weight, survival time and occurrence of metastases were recorded, in addition to the measurement of the metastasis area compared to the total lung area in serial histological lung samples. In both experiments, razoxane effected a significant increase in life span while being ineffective in tumour inhibition. Razoxane in combination with BAD displayed an enhanced anticancer activity which was not significant. ADP had a good antineoplastic activity and a large increase in survival time (144 per cent ILS). Razoxane used in combination with ADP did not influence antitumour efficacy. Median survivals of both ADP-treated groups were significantly longer than the razoxane-treated group. Analysis of the lung metastasis area showed a maximum of 57 per cent for the controls while all treated groups occupied a lesser area. The lowest metastases area was found with the combination treatment BAD + RAZ (18 per cent). This was considered an antimetastatic effect, while ADP treatment effected a time delay only. No change in metastatic pattern was observed in any of the treatment groups. Histological examination showed no effect on the capillaries in the proliferating region of the tumours that could account for the lower occurrence of metastases.

Animals↗
PubMed1995

Antitumor activity of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2- isopropyl-1,3-dioxolane]platinum(II), a new platinum analogue, as an anticancer agent.

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.

Adenocarcinoma↗
PubMed2007

Interventional management of gastroduodenal lesions complicating intra-arterial hepatic chemotherapy.

Herein we report the efficacy of embolization of small patent gastric or duodenal vessels for treating gastroduodenal complications after hepatic arterial infusion therapy (HAIC). Catheter ports were implanted percutaneously from a femoral approach in three cases or surgically in the gastroduodenal artery in two cases. Acute abdominal pain developed on average after four HAIC courses of 5FU-oxaliplatin, mytomycin, oxaliplatin or fotemustine. Esophagogastroduodenoscopy showed gastroduodenal lesions (gastroduodenitis with or without ulcerations) in all cases. Despite the interruption of the HAIC, symptoms persisted and led to selective hepatic arteriography showing a patent right gastric artery (n = 4) or a recanalized gastroduodenal artery (n = 1) responsible for gastroduodenal misperfusion. Successful embolizations of the arteries responsible for gastroduodenal misperfusion (right gastric artery in four cases and gastroduodenal artery in one case) using 0.018 platinium coils relieved the patients' symptoms and allowed the HAIC to continue. In gastroduodenal complications of HAIC, a selective hepatic arteriography should be performed to search any artery responsible for the misperfusion of the toxic agent in the gastroduodenal area. Embolization of these arteries allowed the HAIC to be restored.

Adult↗
PubMed1992

Incorporation of new amphiphilic perfluoroalkylated bipyridine platinum and palladium complexes into liposomes: stability and structure-incorporation relationships.

New perfluoroalkylated side-chain (formed by a perfluoroalkyl tail grafted onto a hydrocarbon spacer) bipyridine complexes of platinum, palladium and their hydrocarbon analogs, when dispersed in aqueous solutions in the presence of egg yolk phospholipids (EYP), are incorporated into EYP vesicles. Most complexes retain their chemical and structural integrity when entrapped into liposomes, thermally sterilized under the FDA norms and stored for 3 months at 25 degrees C. All complex/liposome preparations consist mainly of small unilamellar vesicles (size less than 100 nm) together with a population of larger uni- or multilamellar vesicles (100 to 230 nm). These preparations are remarkably stable with respect to particle size and size distribution evolution and complex leakage: no precipitate of drug was detected even after 7 months of storage at 25 degrees C. The impact of the perfluoroalkyl tail and of the other structural features of the complexes on their incorporation efficiency into EYP liposomes is assessed. A high fluorophilic character (long perfluoroalkyl tail), when tempered by an equally lipophilic one (long hydrocarbon spacer) is not detrimental to the incorporation efficiency of a perfluoroalkylated drug into hydrocarbon vesicles. This incorporation efficiency is considerably improved by the introduction of a double bond between the perfluoroalkyl tail and the hydrocarbon spacer, forming the bipyridine side-chains.

Drug Carriers↗
PubMed1979

Biological activity of metal complexes. I. Interaction of pt(II), pd(II) and rh(I) complexes with E. coli strains and with mice LS fibroblasts in vitro.

The effects of a number of Pt(II, Pd(II) and Rh(I) complexes against cultures of Escherichia coli (strains B, H10178, uvra-, recA-) and cultures of mice LS Fibroblasts were tested. Most of the compounds showed higher cytotoxic activity than the cis-Pt(NH3)2Cl2, the compound at present on clinical trial as antittumour drug. A new model of active compound is proposed.

Anti-Bacterial Agents↗