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At least 127 records · Page 7Linked to original sources
PubMed1998

Sequential treatment with vindesine-ifosfamide-platinum (VIP) chemotherapy followed by platinum sensitized radiotherapy in stage IIIB non-small cell lung cancer: a phase II trial.

PURPOSE: Daily administration of cisplatin concomitant with radiotherapy improved the overall survival in inoperable non-small cell lung cancer (NSCLC) in one EORTC study. In this study, we prospectively investigated the efficacy and toxicity of a sequential treatment with three cycles of vindesine-ifosfamide-platinum (VIP) induction chemotherapy, followed by daily cisplatin-sensitized radiotherapy. METHODS: Between June 1993 and June 1995, 23 previously untreated patients with stage IIIB NSCLC with World Health Organization performance status 0 or 1 were included. Chemotherapy consisted of platinum 30 mg/m2 and ifosfamide 1200 mg/m2 i.v. on days 1, 2 and 3, and vindesine 3 mg/m2 i.v. on days 1 and 8, every 4 weeks. After three cycles and at least stable disease, radiotherapy was started (30 Gy in 10 fractions, followed by a boost of 22 Gy in 10 fractions). Each fraction was preceded by Platinum 6 mg/m2 i.v. RESULTS: Nineteen patients completed the sequential therapy. One patient died from neutropenic sepsis during the first cycle of chemotherapy, and three patients had progressive disease after chemotherapy. The overall response rate after sequential therapy was 47% (95% confidence interval 24-80), median survival was 10.6 months, 1- and 2-year survival rates were 47 and 16%, respectively. Major toxicity consisted of neurotoxicity grade III-IV in 18% and of leukopenia grade III-IV in 22% of the patients. Acute radiation pneumonitis grade III occurred in 11% of the patients. CONCLUSION: Three-drug VIP induction chemotherapy followed by cisplatin-sensitized radiotherapy is feasible, with acceptable, albeit substantial, toxicity. In spite of the theoretically promising sequence of therapies, survival results remain disappointingly low.

Aged↗
PubMed2003

XANES determination of the platinum oxidation state distribution in cancer cells treated with platinum(IV) anticancer agents.

Here we describe the use of X-ray absorption near edge spectroscopy (XANES) to provide information about the relative proportions of platinum(II) and platinum(IV) complexes by analyzing the XANES edge height. The intracellular reduction of platinum(IV) complexes in cancer cells has been observed directly, and the proportion of reduction after 2 h was found to correlate with the reduction potentials of the complexes.

Antineoplastic Agents↗
PubMed1992

Synthesis, structure and antitumor activity of a water-soluble platinum complex, (1R,3R,4R,5R)-(-)-quinato(1R,2R-cyclohexanediamine)platinum (II).

The reaction of dihydroxo(1R,2R-cyclohexanediamine)platinum(II) with (-)-quinic acid gave a water soluble complex, (-)-quinato(1R,2R-cyclohexanediamine)platinum(II). The crystal structure of the complex was determined by X-ray analysis. The data indicate a chelation of the alpha-hydroxycarboxylic acid part of quinic acid to platinum(II). The complex shows moderate antitumor activity against murine leukemia L1210 at high doses (T/C x 100 = 179% at a dose of 200 mg/kg).

Animals↗
PubMed1986

Mechanism of cytotoxicity of anticancer platinum drugs: evidence that cis-diamminedichloroplatinum(II) and cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II) differ only in the kinetics of their interaction with DNA.

The kinetics of the aquation reactions of cisplatin and carboplatin and their subsequent reactions with DNA, both in vitro and in vivo, have been measured. The results have been extrapolated to indicate the expected cytotoxicity of these compounds in cells obtained from human cancer patients. Rate constants for the aquation at 37 degrees C of cisplatin and carboplatin of 8 X 10(-5) and 7.2 X 10(-7) s-1, respectively, were calculated from the half-life of these compounds in phosphate buffer, pH 7. This difference in their rate of activation was matched by their rates of binding to DNA. By use of a 14C-labeled ligand, carboplatin was shown to bind monofunctionally to DNA, after which there was a time-dependent formation of difunctional interstrand cross-links, formed from some of these initially monofunctional adducts. A similar, although faster, accumulation of cross-links was seen when cisplatin was bound to DNA. The loss of the 14C-CBDCA ligand of carboplatin was calculated to occur with a rate constant of 1.3 X 10(-5) s-1 which was similar to that for the rate of formation of interstrand cross-links and faster than that for the monofunctional reaction with DNA. It was concluded therefore that the CBDCA ligand becomes a more labile leaving group once carboplatin has been monoaquated. In contrast, both chloro-ligands of cisplatin were shown to leave at similar rates. The fact that other difunctional lesions were formed to the same extent, by equal bound doses of cisplatin or carboplatin, was indicated by the unwinding of supercoiled plasmid DNA. The effects of cisplatin and carboplatin on this DNA were the same once bound to the same extent. About a 100-fold larger dose of carboplatin was, as predicted by their rates of aquation, required to produce equivalent binding to plasmid DNA. In vivo, equal binding of the two drugs to DNA of various cell systems resulted in equal cytotoxicity. Again a much larger dose (20- to 40-fold) of carboplatin was required to produce this equal binding. In general a DNA bound platinum level of about 20 nmol/g reduced cell survival by 90%, although certain cell lines were shown to be much more sensitive to DNA bound platinum. Similar binding values, to those above, were obtained in the DNA extracted from cells of human cancer patients treated with cisplatin. It was inferred that the cytotoxic effect of this level of platinum on DNA would be (unless the cells were of a sensitive phenotype) about 90%.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Radiotoxicity of platinum-195m-labeled trans-platinum (II) in mammalian cells.

The chemotoxicity and radiotoxicity of trans-dichlorodiammineplatinum (II) labeled with 195mPt (trans-195mPt) are investigated to ascertain the potential of radioplatinum coordination complexes as antineoplastic agents. Platinum-195m, with a half-life of about 4 days, is a prolific emitter of low-energy Auger electrons because of the high probability of internal conversion in its isomeric transitions. The kinetics of cellular uptake and retention after incubation and the radiotoxicity of this Auger electron emitter in the form of trans-195mPt is investigated using cells of the Chinese hamster V79 cell line. The cellular uptake of 195mPt reaches a plateau in about 3 to 5 h of incubation and varies nonlinearly with the extracellular concentration of radioactivity. The radioactivity is eliminated from the cells after incubation with an effective half-life of 24 h. Cell survival data, when corrected for the chemical toxicity of nonradiolabeled trans-platinum, give a cell survival curve typical for radiations with high linear energy transfer. At 37% survival, the mean lethal cellular uptake is about 1.0 mBq/cell. Dosimetric considerations, based on subcellular distribution of the radionuclide, yield a value of 4.8 for the relative biological effectiveness when compared with 250 kVp X rays. Theoretical Monte Carlo track-structure calculations indicate that the density of radical species produced in liquid water in the immediate vicinity of a 195mPt decay site is substantially greater than the density of species along the track of a 5.3 MeV alpha particle. This explains qualitatively the efficacy of 195mPt in causing high-LET radiation type biological effects. The extreme radiotoxicity of intranuclearly localized 195mPt, in conjunction with the proclivity of platinum chemotherapy agents to bind to DNA in the cell nucleus, suggests that the combination of chemical effects and the effects of Auger electrons that can be obtained with radioplatinum coordination complexes may have potential in the treatment of cancer.

Animals↗
PubMed1989

[1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine] dichloro-platinum(II): an endocrine-active platinum complex with a specific prostatic tumor-inhibiting activity.

[1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]dichloro-platinum (II), (C), a platinum complex with endocrine activity and a specific effect on hormone-dependent mammary tumors, was tested for its tumor-inhibitory activity in the hormone-sensitive R 3327 and Nb prostate carcinoma models of the rat and for its endocrine activities in comparison to the ligand L and diethylstilbestrol (DES). Established tumors of the R 3327 prostate tumor were strongly inhibited by C. Its effect equaled that of DES and was significantly better than that of L. Accessory sex organ weights and testosterone levels were strongly reduced by C as well as L. This antigonadotrophic effect, which is almost comparable to DES, was confirmed in 10 day experiments with intact, mature mice and rats, whereas a direct antiandrogenic activity was not given. A part of the antitumor action of C is therefore due to this antigonadotrophic activity. Affinities to estrogen, progesterone, and androgen receptors, however, were very low. The hormone-sensitive Noble Nb-R prostatic carcinoma was almost completely inhibited by C, whereas L had only a weak effect. As C has no significant effect on the hormone-independent R 3327 HI prostate tumor and as its effect on hormone-dependent tumors is significantly better than that of the ligand L in spite of their similar endocrine properties, an apparently specific antiproliferative effect of C only on hormone-dependent prostate tumors is obvious. This was further shown in a long-term experiment with the R 3327 prostate carcinoma. Whereas tumors in the castration group relapsed from androgen ablation and exerted a progressive tumor growth, therapy with C almost completely prevented this relapse phenomenon. After 25 weeks of treatment, C inhibited tumor growth by 90% compared to castration. Owing to these results, this new endocrine active platinum complex with an apparently specific effect on hormone-dependent prostate tumors can be of value for the therapy of the prostatic carcinoma.

Animals↗
PubMed1996

Intraliposomal conversion of lipophilic cis-bis-carboxylato-trans-R,R-1,2-diaminocyclohexane-platinum (II) complexes into cis-bis-dichloro-trans-R,R-1,2-diaminocyclohexane-platinum (II).

Cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (NDDP) is a lipophilic platinum complex (Pt complex) developed in a liposomal carrier. Prior studies have suggested that NDDP is a prodrug that exerts its biological activity through activation within the liposome bilayers containing dimyristoyl phosphatidylglycerol (DMPG) before in vivo administration. In order to understand the kinetics of the intraliposomal degradation/activation of different liposomal Pt complexes, we studied the effects of their structure, lipid composition, content of acidic phospholipids and size, and the effects of pH, temperature and the presence of residual chloroform on their stability, in vitro cytotoxicity, and in vivo antitumor activity. The following factors were found to enhance the intraliposomal degradation/activation of Pt complexes: (1) the size and spatial configuration of the Pt complex, (2) an acidic pH, (3) a high temperature, (4) the presence and amount of acidic phospholipids, and (5) the presence of residual chloroform. Liposome size did not affect the intraliposomal stability of different Pt complexes. Good inverse relationships between the extent of drug degradation and in vitro cytotoxicity and between the extent of drug degradation and in vivo antitumor potency were observed, thus confirming that the biological activity of these complexes is exerted through the intraliposomal formation of certain active intermediate(s). The only active intermediate that could be identified was cis-bis-dichloro-trans-R,R-1,2-diaminocyclohexane platinum(II) whose structure was confirmed by 1H, 13C, and 195Pt nuclear magnetic resonance (NMR) spectroscopy.

Animals↗
PubMed1999

A new orally active antitumor 1R,2R-cyclohexanediamine-platinum(IV) complex: trans-(n-valerato)chloro(1R,2R-cyclohexanediamine) (oxalato)platinum(IV).

PURPOSE: The authors have previously reported that trans-bis(n-valerato)(1R,2R-cyclohexanediamine) (oxalato)platinum(IV) (C5-OHP), an oxaliplatin derivative, is an orally active antitumor agent in an intraperitoneal (i.p.) L1210 murine leukemia model. In this study, several oxaliplatin derivatives of the general formula trans-(carboxylato)chloro(1R,2R-cyclohexanediamine)(oxala to)platinum(IV) were synthesized in order to find new derivatives with greater oral activity than C5-OHP in a clinically predictive tumor model. In the formula, the carboxylate and chloride ligands are situated in axial positions. METHOD: Four complexes with the axial carboxylate ligands n-butyrate, n-valerate, n-caproate or n-heptanoate were synthesized and designated C4-OHP-Cl, C5-OHP-Cl, C6-OHP-Cl and C7-OHP-Cl, respectively. The oral antitumor activity of the complexes was evaluated against the murine reticulosarcoma M5076 implanted subcutaneoulsy (s.c.) in to male BDF1 mice. The complexes were administered orally daily for 5 days in two cycles initiated on days 5 and 12 postimplantation. The physicochemical properties were examined by measuring the concentrations of the complexes in test solutions at intervals by HPLC. The pharmacokinetic behaviors of C5-OHP-Cl, C6-OHP-Cl and C5-OHP following a single oral administration were studied in non-tumor-bearing male BDFl mice. RESULTS: Of the complexes synthesized in this study, C5-OHP-Cl, which exhibited high activity in the i.p. L1210 model, was found to be orally active in the s.c. M5076 model while C5-OHP was not. The in vitro reduction of the complexes by ascorbate was much more rapid than that of C5-OHP, while the complexes were more stable than C5-OHP in HCl-acidic and alkaline solutions. Pharmacokinetic study showed that Cmax and AUC0 24h values of plasma total and filterable platinum of C5-OHP-Cl were four to six times greater than those of C5-OHP, indicating that C5-OHP-Cl was absorbed more than C5-OHP. CONCLUSION: C5-OHP-Cl was found to be a superior 1-OHP derivative C5-OHP, exhibiting significant oral antitumor activity in the s.c. M5076 model. The enhanced activity of C5-OHP-Cl was considered to be due in part to increased susceptibility to reduction and increased gastrointestinal absorption. C5-OHP-Cl is a suitable candidate for further study as an oral cancer chemotherapy agent.

Administration, Oral↗
PubMed1993

The role of metallothionein, glutathione, glutathione S-transferases and DNA repair in resistance to platinum drugs in a series of L1210 cell lines made resistant to anticancer platinum agents.

The glutathione contents, glutathione S-transferase activities and metallothionein contents have been measured in a series of L1210 cell lines which show decreased sensitivities to platinum drugs. Resistance to cisplatinum cisDDP, cis-diamminedichloroplatinum (II)] and chip [ioproplatin, cisdichloro-bis-isopropylamine-trans dihydroxy platinum IV] was found to correlate with glutathione levels but not metallothionein. Conversely, resistance to tetraplatin was found to be correlated with metallothionein but not glutathione levels. However, depletion of glutathione by buthionine 1-sulphoximine sensitizes all cell lines to the effects of cisDDP, chip and tetraplatin [d,1-trans-tetrachloro-1,2-diamino-cyclohexanplatinum (IV)]. Inhibition of DNA repair by aphidicholin or caffeine also partially restored sensitivity to these platinum drugs. These results indicate the complexity of the changes occurring upon the development of drug resistance.

Animals↗
PubMed1976

Inhibition by caffeine of post-replication repair in Chinese hamster cells treated with cis platinum (II) Diamminedichloride: the extent of platinum binding to template DNA in relation to the size of low molecular weight nascent DNA.

Treatment of Chinese hamster lung V79-379A cells with the anti-tumour agent cis platinum (II) diamminedichloride, (cis Pt(II)), resulted in an immediate recuction in the rate of DNA synthesis. Sedimentation of newly synthesised DNA through alkaline sucrose gradients revealed it to be approximately the same size as that obtained from untreated cells. In contrast, in the presence of 0.75 mM caffeine, the rate of DNA synthesis rapidly returned to control levels, although sedimentation analysis showed the DNA synthesised in cis Pt(II)-treated cells to be of lower molecular weight than in untreated cells. The reduction in molecular weight was directly proportional to the initial dose of the platinum compound. Furthermore, the results of separate binding studies suggested that at several levels of reaction the new DNA was synthesised up to a size approximately equal to the interplatinum distance in the template strand. This has been interpreted as being the result of the formation of a gap in the daughter DNA strand opposite every DNA-platinum product in the template strand. If caffeine was removed from the culture medium, there was a rapid increase in the molecular weight of the nascent DNA strands. However, if caffeine remained in the medium, the DNA remained of lower molecular weight than in untreated cells. It is proposed that this effect of caffeine is the result of the inhibition of a post-replicative DNA repair process which allows the eventual synthesis of a continuous DNA strand on a template containing unexcised lesions. It is further proposed that inhibition of this post-replicative DNA repair process provides a molecular basis for the previously observed potentiation by caffeine of cis Pt(II)-induced chromosomal aberrations and lethality.

Binding Sites↗
PubMed1985

Combined cyclophosphamide, adriamycin and cis-platinum in advanced ovarian cancer resistant to chlorambucil and cis-platinum.

Seventeen patients with advanced ovarian adenocarcinoma recurring or progressing after prior treatment with chlorambucil and cis-platinum were treated with cyclophosphamide, adriamycin, and cis-platinum (CAP) every 3 weeks. In seven patients there was objective tumor response (41%) with a median response duration of 7.6 months and a survival advantage over nonresponders. Patients whose tumors had previously responded to chlorambucil or cis-platinum were less likely to respond to CAP than those who had not responded. Myelosuppression was the main toxicity, febrile neutropenia occurring after 8% of treatments.

Adenocarcinoma↗
PubMed1986

Reaction products from platinum(IV) amine compounds and 5'-GMP are mainly bis(5'-GMP)platinum(II) amine adducts.

The reaction products obtained from mixtures of 5'-GMP and platinum(IV) compounds with formula Pt(IV)Cl4(LL) and Pt(IV)Cl2(OH)2(LL) (LL representing two monodentate or one bidentate amine ligand) have been characterized by proton NMR spectroscopy. The amines used are NH3, H2N-CH2-CH2-NH2 (ethylenediamine, en), H2N-CH2-C(CH3)2-CH2-NH2 (2,2-dimethyl-1,3-diaminopropane, dmdap), and HC(CH3)2-NH2 (isopropylamine, ipa). Conditions varied during the reaction are pH (values of 4, 7, and 10), effect of visible light, and addition of vitamin C as a reducing agent. In all cases, the major product appeared to be the bis(5'-GMP)(LL)Pt(II) compound. The pH effect is limited; i.e., at pH 4 the reactions proceed somewhat faster than at neutral pH, while at pH 10 slower reactions occur. The illumination with visible light also induces only slight differences in the yields of the products. On the other hand, when vitamin C is present, the reactions proceed quite rapidly, resulting in the same main product but in higher yields (up to 80%). The facts that apparently no Pt(IV) adducts with 5'-GMP can be observed under these conditions and that the major products are bis(5'-GMP)(LL)Pt(II) compounds clearly support the hypothesis that the antitumor activity of certain platinum(IV) compounds is based upon in vivo reduction to the corresponding platinum(II) compounds.

Ascorbic Acid↗
PubMed1989

Antitumor activity of a new platinum complex, oxalato (trans-l-1,2-diaminocyclohexane)platinum (II): new experimental data.

Antitumor activity of a new platinum complex, oxalato (trans-l-1,2-diaminocyclohexane) platinum (II) (l-OHP), was studied. This water-soluble platinum complex showed a more prominent life-prolonging effect on a mouse leukemia L1210 than cisplatin (DDP). By an intermittent treatment schedule cured mice were observed at the optimal dose. In addition, a subline of L1210 having a 40-fold resistance to DDP (L1210/DDP) showed lack of cross-resistance to l-OHP both in vivo and in vitro. Especially in vivo l-OHP was more active against L1210/DDP than against the original L1210, and all mice were cured at doses of 6.25 and 3.12 mg/kg. l-OHP was also effective against several mouse tumors such as P388 leukemia, B16 melanoma, Lewis lung carcinoma, colon 26 and colon 38 adenocarcinomas, and M5076 fibrosarcoma, though its antitumor spectrum was somewhat different from that of DDP. The synthesis of both DNA and RNA in L1210 cells was inhibited by about 50% with exposure to 10 microM of l-OHP for 1 h, followed by postincubation in drug-free medium for 6-24 h, while only the inhibition of DNA synthesis was observed by DDP in the same experiment. If severe toxicity is not observed in preclinical study, l-OHP expected to be a new clinically active Pt complex.

Animals↗
PubMed2006

Combined PEG liposomal doxorubicin and gemcitabine are active and have acceptable toxicity in patients with platinum-refractory and -resistant ovarian cancer after previous platinum-taxane therapy: a phase II Austrian AGO study.

OBJECTIVES: Platinum resistance is a significant problem in patients with ovarian cancer. The aim of this phase II study was to define the response rates, the progression-free survival and the toxicity profile of the combination of PEG liposomal doxorubicin (L-DXR) and gemcitabine (GEM). MATERIAL AND METHODS: Thirty one patients with histologically confirmed platinum-refractory or -resistant epithelial ovarian cancer were scheduled to receive 6 cycles of L-DXR 30 mg/m(2) on day 1 as well as GEM 650 mg/m(2) on days 1 and 8 every 28 days. RESULTS: The median number of chemotherapy cycles given was 4. The mean dose intensity for L-DXR and GEM on day 1 was 96% and 97%, respectively. The mean dose intensity for GEM on day 8 was 93%. The overall response rate was 33% (10 of 30 evaluable patients; 20% complete responses). The median progression-free survival was 3.8 months, and the median overall survival was 15.8 months, respectively. Toxicity was acceptable. One quarter of patients developed grade 3 or 4 neutropenia, but none developed febrile neutropenia. Palmoplantar erythrodysesthesia (PPE) grades 2 and 3 occurred in 13% and 3% only, respectively, and no grade 4 PPE was observed. Grades 1 to 3 stomatitis was found in 58% of patients (10% grade 3). CONCLUSION: The combination of L-DXR and GEM is an active and acceptably tolerated option in the treatment of patients with platinum-resistant and -refractory ovarian cancer. Dose reductions seem advisable in the case of > or =grade 2 stomatitis and/or PPE > or =grade 2.

Adult↗
PubMed1983

A comparison of estramustine phosphate versus cis-platinum alone versus estramustine phosphate plus cis-platinum in patients with advanced hormone refractory prostate cancer who had had extensive irradiation to the pelvis or lumbosacral area.

Single and combination chemotherapy was compared in a clinical trial for men with advanced, metastatic prostate cancer who had received prior pelvic irradiation and had had progression of disease despite hormonal therapy. The 149 patients were randomized to receive estramustine phosphate or cis-platinum alone or in combination. Of the 149 patients 25 (17 per cent) were excluded from the study but 124 were evaluated for response and survival. Entry variables were distributed similarly among patients in each treatment arm. There were no complete or partial responders but there were nearly twice as many patients whose disease was stabilized (33 per cent) on the combination regimen compared to estramustine phosphate (18 per cent) and about a third more than for cis-platinum (21 per cent). Analysis of survival revealed some advantage for patients on combination therapy. Major toxicities for all treatments were nausea and vomiting (62 to 88 per cent) and accompanying anorexia (72 to 95 per cent). Azotemia developed in 45 per cent of the patients receiving combination therapy. In addition an elevation in serum creatinine occurred in 22 per cent of the patients receiving combination therapy and in 17 per cent of those receiving cis-platinum alone. Myelosuppression occurred infrequently.

Aged↗
PubMed2001

Novel approaches to polynuclear platinum pro-drugs. Selective release of cytotoxic platinum-spermidine species through hydrolytic cleavage of carbamates.

BBR3464 is a novel trinuclear platinum drug currently in Phase II clinical trials. Polyamine-bridged dinuclear platinum compounds as represented by [[trans-Pt(NH(3))(2)Cl](2)-mu-spermidine-N(1),N(8)]Cl(3) (1) are highly interesting second-generation analogues of BBR3464 because the hydrogen-bonding and electrostatic contributions of the central platinum-amine group in BBR3464 are replicated by the free, noncoordinated "central" quaternary nitrogens of the linear polyamine linker while the presence of two separate Pt-Cl bonds maintains the bifunctional binding mode on the DNA adducts. Preclinical investigations confirm the potency of these species with cytotoxicity in the nanomolar range. This remarkable potency results in a relatively narrow therapeutic index. To enhance the therapeutic index of these drugs, we investigated the potential for "pro-drug" delivery of less toxic and better tolerated derivatives such as the compounds [[trans-Pt(NH(3))(2)Cl](2)-mu-N(4)-R-spermidine-N(1),N(8)]Cl(2) where N(4)-R represents BOC (tert-butyl), CBz (benzyl), and Fmoc (fluorenylmethyl) carbamate blocking groups, 2-4, respectively. The bulky Fmoc derivative showed evidence for conformational isomers by (1)H NMR spectroscopy due to the inequivalence of the two n-propyl and n-butyl side chains of the spermidine moiety. The rate constants for hydrolysis and release of 1 were calculated. Release of cytotoxic 1 at physiologically relevant pH followed the order 4 > 2 > 3. The calculated values for 4 (pH 5, 6.0(+/-3.9) x 10(-10) s(-1); pH 6, 6.5(+/-0.2) x 10(-9) s(-1); pH 7, 6.0(+/-0.2) x 10(-8) s(-1); pH 8, 1.6(+/-0.1) x 10(-7) s(-1)) show a more pronounced pH dependence compared to 2 (pH 5, 4.6(+/-0.1) x 10(-8) s(-1); pH 6, 4.2(+/-0.1) x 10(-8) s(-1); pH 7, 3.2(+/-0.1) x 10(-8) s(-1)). Preliminary biological assays of cellular uptake and cytotoxicity confirm the utility of the pro-drug concept. While blocked-polyamine compounds such as 2-4 are, in general, 2-3 orders of magnitude less cytotoxic than 1, there is significant cell type variability. Specifically, the Fmoc derivative 4 showed significantly enhanced cytotoxicity warranting further study of the pro-drug concept for greater selectivity and/or oral delivery.

Animals↗
PubMed2004

Inhibition of cell growth, induction of apoptosis and mechanism of action of the novel platinum compound cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N(4)]-chloride platinum (II) monohydrochloride monohydrate.

Cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N(4)]-chloride platinum (II) monohydrochloride monohydrate (DPR) is a new platinum triamine complex obtained from the synthesis of cisplatin and procaine. In this paper we analyzed, adopting a disease-oriented strategy, the tumour selectivity of this compound, its ability to induce apoptosis and its mechanism of interaction with DNA. The inhibition of cell proliferation was evaluated by the MTT assay using a panel of 51 tumour cell lines. Some of them were also evaluated for the induction of apoptosis by 4'-6-diamidine-2'-phenylindole (DAPI) staining, Western blot of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, interstand cross-links (ISCL) were evaluated by ethidium bromide fluorescence technique. When evaluated by the MTT assay, DPR showed a high selective activity for neuroblastoma, small cell lung cancer (SCLC), ovarian cancer and leukemia cell lines. The comparison of mean graphs of DPR and cisplatin suggested that our compound possesses a mechanism of action similar to that, at least in part, of its parent compound. Moreover, DPR showed itself to be a good trigger of programmed cell death, as demonstrated by DAPI staining, activation of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, the study of the formation of ISCLs demonstrated that DPR, despite being a monofunctional platinum compound, is able to form bifunctional adducts through the release of procaine residue. Data presented here suggest that DPR is an antitumour agent able to trigger apoptosis, and that it is endowed with a peculiar mechanism(s) of action and a special selective activity against two tumours, namely neuroblastoma and SCLC, which are still characterized by a low incidence of long-term survivors.

Animals↗
PubMed1991

Comparison of the antitumour effects and nephrotoxicity-inducing activities of two new platinum complexes, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato+ ++)-platinum (II) monohydrate, and its enantiomeric isomer.

New platinum complexes, (-)-(R)-2-aminomethylpyrrolidine(1,1- cyclobutanedicarboxylato)platinum(II) monohydrate (DWA2114R) and its enantiomeric isomer, (+)-(S)-2-aminomethylpyrrolidine(1,1- cyclobutanedicarboxylato)platinum(II) monohydrate (DWA2114S), were compared in their antitumour effects and nephrotoxicity-inducing activities. Both compounds were effective against the murine tumours L1210 and Colon 26 by i.p. injection of 20-100 mg kg-1. While DWA2114S showed marked increases in blood urea nitrogen (BUN) and urinary protein and sugar in BDF1 mice treated i.p. at the maximum tolerated dose, DWA2114R showed no increases in these parameters. To clarify the difference of nephrotoxicity between the isomers, tissue distribution was examined. Renal Pt concentration in DWA2114S-treated mice was more than 5-fold higher compared with that in DWA2114R-treated mice 2h after i.p. injection of 80 mg kg-1. However, there were no such marked differences in the lung, liver, heart, spleen and plasma. The low content of Pt in the kidneys of DWA2114R-treated mice could explain its lower nephrotoxicity. The in vitro experiments for uptake of the drugs into the cultured normal rat kidney cells and fresh splenocytes revealed that the Pt amount in the cells treated with DWA2114S, especially in the kidney cells, was much higher than DWA2114R.

Animals↗