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PubMed2005

Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes.

PURPOSE: Gemcitabine-platinum combination activity has been clearly established in a number of phase II studies. It has also been compared against other combinations in many phase III trials. It is generally believed that all such regimens have an equivalent impact on survival. This meta-analysis aims to quantify the treatment effect of gemcitabine plus a platinum agent in the treatment of advanced NSCLC and compare the combination to other regimens used globally. DESIGN: Data from a total of 4556 patients from 13 randomized trials investigating gemcitabine in combination with a platinum agent versus any other platinum-containing regimen were included in a meta-analysis of time-to-event outcomes. RESULTS: A significant reduction in overall mortality in favor of gemcitabine-platinum regimens was observed, hazard ratio (HR) 0.90 (95% CI: 0.84-0.96) with an absolute benefit at 1 year of 3.9%. Median survival was 9.0 months for the gemcitabine-platinum regimens and 8.2 months for the comparator regimens. Sub-group analysis of the first- and second-generation platinum-based comparator regimens also indicated a significant benefit for gemcitabine-platinum regimens, HR 0.84 (CI: 0.71-0.9985). Analysis of third-generation agent plus platinum regimens showed a non-significant trend favoring gemcitabine-platinum regimens, HR 0.93 (CI: 0.86-1.01). There was a significant decrease in the risk of disease progression in favor of gemcitabine-platinum regimens, HR 0.88 (CI: 0.82-0.93). An absolute benefit of 4.2% at 1 year was estimated. Median progression-free survival was 5.1 months for gemcitabine-platinum regimens compared with 4.4 months for the comparator regimens. Sub-group analysis indicated a statistically significant progression-free survival benefit for patients assigned to gemcitabine-platinum treatment compared to first- and second-generation platinum regimens, HR 0.85 (CI: 0.77-0.94), and third-generation agent plus platinum regimens, HR 0.89 (CI: 0.82-0.96).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Urinary excretion of platinum from platinum industry workers.

OBJECTIVES: Assessment of level of exposure to platinum and platinum concentration in urine from platinum industry workers to evaluate internal exposures and excretion kinetics. METHODS: Platinum concentrations in urine samples from 34 workers were measured by adsorptive voltammetry after UV-photolysis. Morning and evening samples were taken two to six times during six months. Individual exposures were assessed by personal air sampling. Also, two male volunteers were exposed to platinum dust for four hours at a typical platinum refinery workplace. RESULTS: Urinary platinum excretion after a shift in platinum industry workers was found to be up to 6270 ng/g creatinine--that is, 1000 times above the median value of unexposed people. Urinary excretion reached the maximum nearly 10 hours after inhalative exposure to dust containing platinum. Elimination corresponded to a first half life of about 50 (95% confidence interval (95% CI) 36 to 66) hours, but there were indications that a part of the incorporated platinum is stored longer. The amount of urinary platinum excretion showed a close correlation with the exposure level monitored by personal air sampling. CONCLUSIONS: A newly developed analytical method enabled the detection of even natural background concentrations of platinum. Thus, increased urinary platinum concentrations could be detected early, which is important to avoid damaging health of exposed workers.

Adult↗
PubMed1991

cis-platinum ototoxicity in children.

Despite the recognized ototoxicity of cis-platinum, a clinical outline for the audiologic evaluation of patients receiving this drug has not been clearly defined. In a practical approach to this problem, the audiograms of 48 pediatric patients referred for monitoring during planned cis-platinum therapy were reviewed. Eleven patients tested with auditory brain-stem response (ABR) audiometry demonstrated several limitations of this modality. Fourteen children underwent initial ABR testing followed by at least two pure-tone audiograms. The remaining 23 patients had their hearing evaluated by pure-tone audiometry only. Various factors such as patient age, cis-platinum dosage, and cranial radiation exposure were analyzed for apparent effect. Younger patients tended to be more susceptible to audiologic changes with the administration of cis-platinum. The proportion of patients who demonstrated a hearing loss increased with successive dosing as did the severity of the hearing loss. Prior exposure to cranial radiation was strongly linked to the development of hearing loss following cis-platinum therapy. Guidelines are presented regarding the use of clinical audiometry in the screening of these pediatric oncology patients.

Adolescent↗
PubMed1994

Tetravalent platinum complexes with ammine/amine carrier ligand configuration: circumvention of platinum resistance in vivo.

A platinum(II) and three platinum(IV) ammine/cycloalkylamine homologous series, the latter possessing either chloro, acetato or hydroxo axial ligands, were evaluated for efficacies in mice bearing tumor cells sensitive (leukemia L.1210/0 and reticulosarcoma M5076) or resistant to cisplatin (L1210/DDP) and tetraplatin (L1210/DACH). Within each series, which contained four homologs, potency increased (optimal dose decreased) as alicyclic ring size increased incrementally from cyclopropane to cyclohexane. All analogs were active at maximally tolerated doses against L1210/0 (%T/C = 125-426), with good associated therapeutic ratios of 2 to > 8 that, like the therapeutic index, provided indications of the drug's safety margin. Most complexes had activities that were similar to cisplatin (%T/C = 239) and tetraplatin (%T/C = 310). Antitumor activities were seen for all four platinum(II) complexes against L1210/DDP cells (%T/C = 133-167). In the three platinum(IV) series, on the other hand, only cyclopentane (C5) and cyclohexane (C6) analogs met or exceeded the minimum criterion for activity. These activities were similar to that seen with the positive control agent tetraplatin (%T/C = 133), but higher than that of cisplatin (%T/C = 94). Long-term survivors, which were frequently observed with these complexes in the L1210/0 model, were also seen in the L1210/DDP model, but to a lesser extent. Against L1210/DACH cells, which were sensitive to cisplatin (%T/C = 155), but resistant to tetraplatin (%T/C = 113), the C5 and C6 congeners in the platinum(IV) series were effective with %T/C in the range 148-189, while corresponding members in the platinum(II) series were only marginally active. In the solid M5076 model, complexes C5 in platinum(II) and in the acetato- and hydroxoplatinum(IV) series, and C6 from the hydroxo-platinum(IV) series, were as effective or more effective than cisplatin, which itself gave a tumor growth delay of 27.5 days. In summary, the results indicate that alicyclic ring size and, in the platinum(IV) series, axial ligand, are important modulators of efficacies of ammine/cycloalkylamine platinum congeners in both sensitive and platinum-resistant models. However, the cyclopentylamine or cyclohexylamine carrier ligand with acetato or hydroxo axial ligands in the platinum(IV) configuration are optimal combinations for circumventing both cisplatin and tetraplatin resistances.

Amines↗
PubMed1986

Small intestinal mucosal toxicity of cis-platinum--comparison of toxicity with platinum analogues and dexamethasone.

Cis-platinum causes profound gastrointestinal symptoms in patients and these may persist for many days after drug administration. Gut mucosal toxicity may be a factor in the pathogenesis of such prolonged nausea, vomiting and anorexia. The effects of cis-platinum on mouse ileal mucosal architecture, villus epithelial cell influx and disaccharidase activity are described in comparison with dhe effects of two platinum analogues, CBDCA and CHIP. In addition the effect of dexamethasone, a useful drug in the palliation of cis-platinum-induced emesis, in combination with cis-platinum is described. Cis-platinum, CBDCA and CHIP cause profound reduction in crypt cell production rate (CCPR) and thus villus epithelial cell influx within hours of administration leading to villus stunting and diminished function. CBDCA showed the least profound effect with early rebound in CCPR by day 3. Cis-platinum and CHIP were roughly equitoxic to ileal crypts with rebound in CCPR being delayed until day 7. Similarly, CBDCA caused least reduction in disaccharidase activity with cis-platinum and CHIP being equitoxic. The addition of dexamethasone had no protective effect on the effects of cis-platinum on murine ileal mucosa and mice given the combination chronically had no weight gain over 18 weeks, their weight paralleling those receiving cis-platinum alone. The platinate compounds have differing degrees of intestinal mucosal toxicity but no direct inference can be drawn in respect to the clinical situation where CBDCA causes less gastrointestinal symptomatology than CHIP but where both cause less than cis-platinum. Dexamethasone does not act by mucosal protection to provide its useful effects in prolonged cis-platinum-induced gastrointestinal symptoms.

Animals↗
PubMed2005

Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature.

PURPOSE: This meta-analysis was performed to compare the activity, efficacy and toxicity of platinum-based versus non-platinum-based chemotherapy in patients with advanced non-small-cell lung cancer. METHODS: Randomized phase II and III clinical trials comparing first-line palliative platinum-based chemotherapy with the same regimen without platinum or with platinum replaced by a nonplatinum agent were identified by electronic searches of Medline, Embase, and Cancerlit, and hand searches of relevant abstract books and reference lists. Response rates, 1-year survival, and toxicity were analyzed. Subgroups of trials using third-generation agents were compared. RESULTS: Thirty-seven assessable trials were identified including 7,633 patients. A 62% increase in the odds ratio (OR) for response was attributable to platinum-based therapy (OR, 1.62; 95% CI, 1.46 to 1.8; P < .0001). The 1-year survival rate was increased by 5% with platinum-based regimens (34% v 29%; OR, 1.21; 95% CI, 1.09 to 1.35; P = .0003). No statistically significant increase in 1-year survival was found when platinum therapies were compared to third-generation-based combination regimens (OR, 1.11; 95% CI, 0.96 to 1.28; P = .17). The toxicity of platinum-based regimens was significantly higher for hematologic toxicity, nephrotoxicity, and nausea and vomiting, but not for neurotoxicity, febrile neutropenia rate, or toxic death rate. CONCLUSION: Response is significantly higher with platinum-containing regimens. One-year survival was not significantly prolonged when platinum-based therapies were compared with third-generation-based combination regimens. Toxicity is generally higher for platinum-based regimens.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

The cellular distribution and oxidation state of platinum(II) and platinum(IV) antitumour complexes in cancer cells.

The cellular distribution of platinum in A2780 ovarian cancer cells treated with cisplatin and platinum(IV) complexes with a range of reduction potentials has been examined using elemental analysis (synchrotron radiation-induced X-ray emission). The cellular distribution of platinum(IV) drugs after 24 h is similar to that of cisplatin, consistent with the majority of administered platinum(IV) drugs being reduced. Micro-X-ray absorption near-edge spectra of cells treated with cisplatin and platinum(IV) complexes confirmed the reduction of platinum(IV) to platinum(II). In cells treated, the most difficult to reduce complex, cis, trans, cis-[PtCl(2)(OH)(2)(NH(3))(2)], platinum(IV) was detected in the cells along with platinum(II). The observations are in accordance with the relative ease of reduction of the platinum(IV) complexes used and support the requirement of reduction for activation of platinum(IV) complexes.

Antineoplastic Agents↗
PubMed1990

Cold air challenge and platinum skin reactivity in platinum refinery workers. Bronchial reactivity precedes skin prick response.

An investigation of a platinum refinery operation consisted of an administered questionnaire, spirometry, skin prick testing with platinum salts and common aeroallergens, serum total IgE, radioallergosorbent test for platinum salts, and measurement of nonspecific airway hyperresponsiveness by cold air challenge testing. Among 136 employees examined, there were 107 current and 29 medically terminated workers; 23 (17 percent) subjects had a positive platinum salts prick skin test and 19 (14 percent) displayed a positive cold air challenge. RAST binding for platinum salts IgE antibodies showed a high level of agreement with platinum skin prick test results. A proportion (63 percent) of the population (74 current and 12 terminated workers) underwent repeat platinum skin testing one year later. Among current workers, there was conversion of the platinum skin test from negative to a positive test in five employees, with three conversions occurring in workers who showed only a positive cold air challenge test the year before. Platinum skin sensitivity, asthma symptoms, and nonspecific airway hyperresponsiveness persisted for years after termination of exposure in some medically terminated workers presumably because of a delay in removal from work of employees who became sensitized to platinum salts. It is suggested that proper surveillance for occupational asthma involves the use of several testing procedures. Prompt removal from work of individuals found to become sensitized to platinum salts is important in this industry.

Adult↗
PubMed1994

Total platinum dose versus platinum dose intensification in ovarian cancer treatment.

Multiple in vitro and in vivo studies demonstrate the importance of platinum dose intensity in chemotherapy of advanced ovarian cancer. The relevant areas discussed in this report include (1) retrospective analysis of platinum dose intensity and outcome of ovarian cancer therapy, (2) in vitro human tumor cell line drug assay data, (3) fresh human ovarian tumor cloning data, (4) platinum pharmacokinetics with an emphasis on the relationship between the platinum concentration x time product and cytotoxicity, and (5) prospective clinical studies designed to test the importance of platinum dose intensity alone or platinum dose intensity and total dose. When attempting to design optimal platinum-based therapies for ovarian cancer, it is important to bear in mind the following considerations: (1) both platinum dose intensity and total dose should be increased; (2) to achieve exponential cytotoxicity (eg, up to 10-fold increases in tumor cell kill) by increasing the platinum dose, it is critical to select a platinum dose capable of overcoming inherent drug resistance; (3) carboplatin may be the platinum analogue of choice for dose intensification studies since, unlike cisplatin, it is rarely associated with cumulative nonhematologic toxicity (and as a result can be escalated up to five to six times the standard dose); and (4) the Calvert formula should be used for determining carboplatin dose to safely and accurately target desired drug exposure (as measured by the concentration x time product) and degree of hematologic toxicity.

Clinical Trials as Topic↗
PubMedDate not supplied

Pharmacokinetics of platinum in cancer patients following intravenous infusion of cis-diammine(glycolato)platinum, 254-S.

The pharmacokinetics of platinum in cancer patients were examined following an intravenous infusion of cis-diammine(glycolato) platinum, 254-S. The plasma concentrations of total platinum, which decreased biexponentially after the infusion, were proportional to the dose over the range of 10 to 120 mg/m2, suggesting linearity of the pharmacokinetics. The plasma concentrations of ultrafilterable platinum were similar to those of total platinum and there was little difference in the pharmacokinetic parameters between total platinum and ultrafilterable platinum. These findings show that almost all of the platinum derivative is unbound, which is thought to be the active form, in plasma after administration of 254-S. Platinum was eliminated from blood faster when given as 254-S rather than as cisplatin because of the low protein binding. The urinary recovery within 24 hours was about half of the dose, suggesting that platinum given as 254-S was distributed to various tissues and organs in an active form.

Adolescent↗
PubMed1989

Pharmacokinetics of (glycolate-0,0')-diammine platinum (II), a new platinum derivative, in comparison with cisplatin and carboplatin.

The pharmacokinetics of (glycolato-0,0')-diammine platinum (II) (254-S; NSC 375101D), one of the new platinum analogues, was examined in a phase I study of this drug and compared with that of cisplatin and carboplatin. All drugs were given in short-term (30-min) i.v. drip infusions; the doses of 254-S, cisplatin, and carboplatin were 100, 80, and 450 mg/m2, respectively. Platinum concentrations in whole plasma, plasma ultrafiltrate, and urine were determined by atomic absorption spectrometry. After the infusion, the plasma concentration of total platinum for the three agents decayed biphasically. Ultrafilterable platinum in plasma decreased in a biexponential mode after infusions of 254-S and carboplatin, whereas the free platinum of cisplatin showed a monoexponential disappearance. The peak plasma concentrations and AUC for free platinum were 5.31 micrograms/ml and 959 micrograms/min per ml for 254-S, 3.09 micrograms/ml and 208 micrograms/min per ml for cisplatin, and 19.90 micrograms/ml and 3446 micrograms/min per ml for carboplatin, respectively. The mean ratio of plasma ultrafilterable platinum to total platinum were calculated, and the results showed that the protein-binding abilities of 254-S and carboplatin were almost identical. More than 50% of the 254-S was excreted in the urine within the first 480 min after its administration. Thrombocytopenia was reported as a dose-limiting toxicity for both 254-S and carboplatin. This similarity in side effects may mainly be due to the comparable pharmacokinetic behavior of these two platinum compounds.

Antineoplastic Agents↗
PubMedDate not supplied

Gemcitabine reverses platinum resistance in platinum-resistant ovarian and peritoneal carcinoma.

Platinum compounds are the key components of chemotherapy for ovarian cancer. Preclinical models in an ovarian cancer cell line (A2780) have demonstrated synergistic activity when gemcitabine is added to cisplatin compared with either single agent alone. Furthermore, the combination leads to increased platinum-adduct retention as a result of decreased DNA repair compared with cisplatin alone. Inhibition of specific exonucleases, such as excision repair cross-complementation group 1 (ERCC1), is integral to the platinum-gemcitabine synergy. In platinum-sensitive recurrent ovarian cancer patients (defined as those patients whose cancer recurs after > 6 months following primary therapy), platinum and gemcitabine have demonstrated an improvement in progression-free survival compared with platinum alone. This is also true for the patients who are only moderately platinum sensitive (defined as those patients who have cancer recurring 6-12 months after primary therapy). Increasing numbers of phase II experiences have demonstrated the activity of the platinum-gemcitabine combination in patients defined as platinum resistant (those with disease progression on therapy or whose disease recurs within 6 months of a platinum-based regimen).

Antimetabolites, Antineoplastic↗
PubMedDate not supplied

Novel trans platinum complexes: comparative in vitro and in vivo activity against platinum-sensitive and resistant murine tumours.

Two pairs of cis/trans platinum complexes, JM118 (cis-ammine(cyclohexylamine) dichloro platinum(II)) and its trans counterpart, JM334 and JM149 (cis-ammine(cyclohexylamine) dichloro-dihydroxo platinum(IV)) and its trans counterpart JM335 have been evaluated (both in vitro and in vivo) against two murine tumour models of historical importance in the discovery of novel platinum drugs; the ADJ/PC6 plasmacytoma and the L1210 leukaemia and sublines selected for resistance to platinum drugs. In vitro, results showed that the trans complexes induced comparable growth inhibitory properties to those observed for cisplatin and their respective cis isomers. Moreover, retention of activity was observed in a series of 5 acquired platinum drug (cisplatin, carboplatin, iproplatin, tetraplatin and JM149)-resistant L1210 sublines whereas at least partial cross-resistance was observed to the cis isomer JM149 in the acquired carboplatin and iproplatin-resistant lines (in addition to being 11-fold resistant in the line selected for resistance to JM149 itself). In vivo, JM355 showed activity against both the ADJ/PC6 and L1210 models of acquired cisplatin resistance. Furthermore, JM355 was active against an ADJ/PC6 subline possessing resistance to iproplatin and a L1210 subline possessing resistance to its cis isomer JM149. Interestingly, the trans platinum(II) counterpart of JM335(JM334) was inactive in vivo. These data indicate that the trans platinum(IV) complex JM335 possess several in vitro growth inhibitory- and in vivo antitumour properties which are distinct from those observed for cisplatin (or its cis isomer). Thus, JM335 contravenes the original structure-activity rules determined for platinum-containing compounds and, because of its level of activity against cisplatin-resistant tumours, establishes the complex as of interest in the search for new platinum drugs active against cisplatin-resistant disease.

Animals↗
PubMedDate not supplied

Platinum levels in human erythrocytes following intravenous administration of cisplatin: importance of erythrocytes as a distribution site for platinum species.

Recent reports of the extent of uptake of cisplatin and possible biotransformation products of cisplatin by red blood cells of humans receiving this drug have been conflicting. In vitro and in vivo studies of the platinum content of washed red blood cells following exposure to cisplatin have been conducted. Low levels of platinum were found in the red cell lysate of the erythrocytes of humans receiving cisplatin. The platinum was primarily associated with red cell lysate and little, if any, platinum appeared to be associated with the cell membrane. The in vivo studies indicated that the intracellular platinum levels are rapidly achieved following cisplatin administration and the platinum concentration appears to be linearly related to the administered dose. However, the fraction of platinum found within the erythrocytes is slight, representing only about 1 per cent of the administered dose. In light of the reactivity of cisplatin with compounds containing divalent sulphur and the millimolar glutathione levels present within erythrocytes, it is unlikely that the platinum released from the red blood cell is in the form of cisplatin. Therefore, it is doubtful that the red blood cell is a major site for cisplatin distribution and the anticancer activity of the platinum released from red blood cells is questionable.

Biotransformation↗
PubMed1994

Urinary platinum in hospital personnel occupationally exposed to platinum-containing antineoplastic drugs.

Urinary platinum levels of 21 nurses and hospital pharmacy personnel occupationally exposed to platinum containing antineoplastic drugs were determined in 24-h urine by voltammetric analysis after UV photolysis. All study participants applied standard safety measures, including a vertical laminar air-flow cabinet and latex gloves. The amount of platinum-containing drugs prepared for intravenous application ranged from 40-3260 mg/day. Urinary platinum was detected in 9 of 52 urine samples collected on days when platinum-containing drugs were mixed (limit of determination 4 ng/l). In comparison with a non-exposed control group, elevated urinary platinum levels were found in one pharmacist (35 ng/g creatinine) and one pharmacy technician (28 ng/g creatinine). The pharmacist's urinary platinum remained elevated after 2 days without occupational exposure to antineoplastic drugs. The urinary platinum level of the pharmacy technician dropped considerably after several weeks without handling cytostatic drugs. Voltammetric detection of urinary platinum is a highly sensitive method suitable for biological and environmental monitoring.

Adult↗
PubMed1995

Platinum concentrations in uterus and serum after internal iliac arterial infusion of platinum compounds in rabbits.

OBJECTIVE: To compare three platinum compounds, and study the pharmacokinetics of these compounds after systemic and intra-arterial infusion. METHODS: Adult female rabbits received infusions of 1.7 mg/kg cisplatin, 10 mg/kg carboplatin, or 6 mg/kg cisdiammine(glycolato)platinum (254-S) via the internal iliac artery or jugular vein. The doses were equitoxic. Platinum tissue concentration in uterus and platinum serum levels were measured after internal iliac arterial or intravenous (i.v.) infusion with these platinum compounds. RESULTS: Platinum uterine concentration after intra-arterial infusion was significantly higher than that after i.v. infusion for each drug (P < .05). The ratios of platinum uterine concentration after intra-arterial infusion to those after i.v. infusion were 2.24 for cisplatin, 1.83 for carboplatin, and 1.67 for 254-S measured 20 minutes after drug administration. The area under the curve of filtrated platinum (micrograms/mL.hours) was significantly lower for cisplatin compared with carboplatin and 254-S in both infusion methods (1.5 for cisplatin, 32.1 for carboplatin, and 16.0 for 254-S after i.v. administration, and 0.8, 30.9, and 15.2 after intra-arterial administration, respectively). CONCLUSION: Cisplatin produced the highest ratio of uterine to serum concentration of platinum after intra-arterial infusion.

Animals↗
PubMed2003

Platinum(II) catalysis and radical intervention in reductions of platinum(IV) antitumor drugs by ascorbic acid.

Reductions of four platinum(IV) amine complexes, cis-diamminetetrachloroplatinum(IV), tetraammine-cis-dichloroplatinum(IV), cis,cis,trans-diamminedichlorodihydroxoplatinum(IV), and cis,trans,cis-dichloro-dihydroxo-bis(isopropylamine)platinum(IV) by ascorbic acid were catalyzed by platinum(II) at pH 7.3 and 22 degrees C. Except for the first mentioned compound, initial slow uncatalyzed reductions yielded platinum(II) products which served as catalyst as revealed by the presence of induction periods and their disappearance by the addition of the platinum(II) products. The platinum(II) catalysis generated ascorbate bound platinum(IV) intermediates. An internal electron transfer process within these intermediates led to the formation of platinum(II) complexes. Although the rate constants for the uncatalyzed reductions vary greatly depending on the nature of the ligands and their spatial arrangements, the magnitudes of the platinum(II) catalyzed rate constants fall in the narrow range, 100 to 300 M(-2) s(-1). The values of the uncatalyzed reductions lie in the range 5 x 10(-2) to 15 M(-1) s(-1), the tetrachloroplatinum(IV) complex suffered the faster reduction. The reduction of iproplatin with two hydroxide ligands in trans configuration was the slowest. The internal electron transfer rate constants span two orders of magnitude, from 0.15 to 4 x 10(-3) s(-1). These reactions were accompanied by the formation of the ascorbate radical which persists throughout the entire reaction. Although the tetrachloro species exhibited simple second order reduction, first order in each of the reactants, the rate of reduction was also accelerated by the addition of cis-diamminedichoroplatinum(II) indicating the presence of catalysis in this reaction as well.

Antineoplastic Agents↗
PubMed1999

Bis[platinum(II)] and bis[platinum(IV)] complexes with optically active bis(vicinal-1,2-diamines) and their interaction with DNA.

Bis[platinum(II)] [Cl2Pt(LL)PtCl2] complexes 2,5 and 8 with chiral non-racemic ligands: 1a-c (LL = (R,R), (S,S) and (R,S) N,N'-bis(3,4-diaminobutyl)hexanediamide); 4a,b (LL = (R,R) and (S,S) N,N'-bis[3,4-bis(diaminobutyl)] urea); 7a-d (LL' = (R,R), (S,S), (R,S) and (S,R) 4,5-diamino-N-(3,4-diaminobutyl) pentanamide) and bis[platinum(IV)] complex 10-13 with ligands 1a,b and 4a,b have been prepared and characterized by IR, 1H, 13C and 195Pt NMR spectra. The interactions of 2a-c, 5a, 5b, 8a-d and 10a with dsDNA were investigated with the goal of examining whether the chirality, the nature of the spacer and the oxidation state have an influence on platinum-DNA binding properties. All the bis[platinum(II)] complexes form with dsDNA intra- and interstrand crosslinks and crosslinks over sticky ends, whereas the bis[platinum(IV)] complex 10a only forms intra- and interstrand crosslinks. The platinum-DNA coordination sites were determined by the T4 DNA polymerase footprinting method. The results show that all investigated bis(platinum) complexes have high preference towards distinct purines. All isomeric bis(amide) 2a-c and mono(amide) 8a-d complexes exhibit nearly the same binding pattern, whereas the ureide complexes 5a and 5b have other coordination sites with higher sequence preference. Interestingly, the ureides 5a and 5b differ in their coordination sites not only in comparison to the bis(amides) 2a-c and mono(amides) 8a-d, but also between each other. The bis[platinum(IV)] complex 10a also differs in coordination sites in comparison to all the bis[platinum(II)] compounds.

Animals↗