Metal-based antitumor compounds: beyond cisplatin.

Despite improvements in the 5-year survival rate to over 80% in cancers, such as Hodgkin lymphoma and testicular cancer, more aggressive tumors including pancreatic and brain cancer still have extremely low survival rates. The establishment of chemoresistance, responsible for the reduction in treatment efficiency and cancer relapse, is one possible explanation for this setback. Metal-based compounds, a class of anticancer drugs, are largely used in the treatment of cancer. Herein, we will review the use of metal-based small molecules in chemotherapy, focusing on recent studies, and we will discuss how new nonplatinum-based agents are prompting scientists to increase drug specificity to overcome chemoresistance in cancer cells.

Mechanistic Investigation into DNA Modification by a RuII ,RhIII Bimetallic Complex.

Despite significant progress in the treatment of cancer, there remains an urgent need for more effective therapies that also have less impact on patient wellbeing. Photodynamic therapy employs targeted light activation of a photosensitizer in selected tissues, thereby reducing off-target toxicity. Our group previously reported a RuII ,RhIII bimetallic architecture that displays multifunctional covalent photomodification of DNA in the therapeutic window in an oxygen-independent manner, features that are essential for treating deep and hypoxic tumors. Herein, we explore the mechanism by which a new analogue, [(phen)2 Ru(dpp)Rh(phen)Cl2 ]3+ , or RuII -RhIII , interacts with DNA. We established that RuII -RhIII exhibits "light switch" behavior in the presence of DNA, undergoing strong electrostatic interactions that might involve groove binding. Furthermore, these noncovalent interactions play a major role in the covalent photobinding and photocleavage of DNA, which occur according to an oxygen-independent mechanism. Polymerase chain reaction (PCR) revealed that covalent modification of DNA by RuII -RhIII , especially photobinding, is critical to inhibiting amplification, thus suggesting that the complex could exert its toxic activity by interfering with DNA replication in cells. This new structural motif, with phenanthroline at all three terminal ligand positions, has a number of properties that are promising for the continued refinement of photodynamic-therapy strategies.

Preparation of Rhodium(III) complexes with 2(1H)-quinolinone derivatives and evaluation of their in vitro and in vivo antitumor activity.

A series of 2(1H)-quinolinone derivatives and their rhodium (III) complexes were designed and synthesized. All the rhodium (III) complexes exhibited higher in vitro cytotoxicity for Hep G2, HeLa 229, MGC80-3, and NCI-H460 human tumor cell lines than their ligands and cisplatin, and among them complex 9 was found to be selectively cytotoxic to tumor cells. Further investigation revealed that complex 9 caused cell cycle arrest at the G2/M phase and induced apoptosis, and inhibited the proliferation of Hep G2 cells by impeding the phosphorylation of epidermal growth factor receptor (EGFR) and its downstream enzymes. Complex 9 also up-regulated the proapoptotic proteins Bak, Bax, and Bim, which altogether activated caspase-3/9 to initiate cell apoptosis. Notably, complex 9 effectively inhibited tumor growth in the NCI-H460 xenograft mouse model with less adverse effect than cisplatin.

Absorbed dose distributions from ophthalmic 106 Ru/106 Rh plaques measured in water with radiochromic film.

PURPOSE: Brachytherapy with 106 Ru/106 Rh plaques offers good outcomes for small-to-medium choroidal melanomas and retinoblastomas. The dose measurement of the plaques is challenging, due to the small range of the emitted beta particles and steep dose gradients involved. The scarce publications on film dosimetry of 106 Ru/106 Rh plaques used solid phantoms. This work aims to develop a practical method for measuring the absorbed dose distribution in water produced by 106 Ru/106 Rh plaques using EBT3 radiochromic film. METHODS: Experimental setups were developed to determine the dose distribution at a plane perpendicular to the symmetry axis of the plaque and at a plane containing the symmetry axis. One CCA and two CCX plaques were studied. The dose maps were obtained with the FilmQA Pro 2015 software, using the triple-channel dosimetry method. The measured dose distributions were compared to published Monte Carlo simulation and experimental data. RESULTS: A good agreement was found between measurements and simulations, improving upon published data. Measured reference dose rates agreed within the experimental uncertainty with data obtained by the manufacturer using a scintillation detector, with typical differences below 5%. The attained experimental uncertainty was 4.1% (k = 1) for the perpendicular setup, and 7.9% (k = 1) for the parallel setup. These values are similar or smaller than those obtained by the manufacturer and other authors, without the need of solid phantoms that are not available to most users. CONCLUSIONS: The proposed method may be useful to the users to perform quality assurance preclinical tests of 106 Ru/106 Rh plaques.

Rhodium complexes as therapeutic agents.

The landscape of inorganic medicinal chemistry has been dominated by the investigation of platinum, and to a lesser extent ruthenium, complexes over the past few decades. Recently, complexes based on other metal centers such as rhodium have attracted attention due to their tunable chemical and biological properties as well as distinct mechanisms of action. This perspective highlights recent examples of rhodium complexes that show diverse biological activities against various targets, including enzymes and protein-protein interactions.

Speciation of precious metal anti-cancer complexes by NMR spectroscopy.

Understanding the mechanism of action of anti-cancer agents is of paramount importance for drug development. NMR spectroscopy can provide insights into the kinetics and thermodynamics of the binding of metallodrugs to biomolecules. NMR is most sensitive for highly abundant I=1/2 nuclei with large magnetic moments. Polarization transfer can enhance NMR signals of insensitive nuclei at physiologically-relevant concentrations. This paper reviews NMR methods for speciation of precious metal anti-cancer complexes, including platinum-group and gold-based anti-cancer agents. Examples of NMR studies involving interactions with DNA and proteins in particular are highlighted.

Calculation of dose distributions for 12 106Ru/106Rh ophthalmic applicator models with the PENELOPE Monte Carlo code.

PURPOSE: For decades, (106)Ru/(106)Rh ophthalmic applicators have been widely used to treat intraocular malignancies with good clinical outcomes. Determining the dosimetry of such applicators is challenging because of their spherical shape, the low range of emitted betas and the steep gradients involved. Furthermore, there is a lack of dose distribution data in the literature for some applicator models. It is crucial to understand the generated dose distributions to improve the treatment planning process. This study aims to calculate the dose distributions in water for 12 commercially available (106)Ru/(106)Rh ophthalmic applicators. METHODS: The applicators were modeled using the Monte Carlo (MC) code PENELOPE-2008.1. A planar nonclinical applicator was also simulated. Depth-dose profiles along the central axis and lateral dose profiles at several depths were calculated and compared with the available published measured and calculated data. In the absence of published data, measurements performed by the manufacturer were used. RESULTS: For some applicators, the calculated results obtained in this work showed improved consistency with the available experimental data compared with previously published calculations. For others, the data calculated in this work represent the first published dose data. CONCLUSIONS: The MC code PENELOPE-2008.1 can accurately calculate the dose distributions for (106)Ru/(106)Rh ophthalmic applicators. The obtained set of tabulated dose distribution values may be useful for quality assurance of treatment planning systems and as a reference for comparison with future measurements and calculations.

Energy deposition by a 106Ru/106Rh eye applicator simulated using LEPTS, a low-energy particle track simulation.

The present study introduces LEPTS, an event-by-event Monte Carlo programme, for simulating an ophthalmic (106)Ru/(106)Rh applicator relevant in brachytherapy of ocular tumours. The distinctive characteristics of this code are the underlying radiation-matter interaction models that distinguish elastic and several kinds of inelastic collisions, as well as the use of mostly experimental input data. Special emphasis is placed on the treatment of low-energy electrons for generally being responsible for the deposition of a large portion of the total energy imparted to matter.

Free Rhodium (II) citrate and rhodium (II) citrate magnetic carriers as potential strategies for breast cancer therapy.

BACKGROUND: Rhodium (II) citrate (Rh(2)(H(2)cit)(4)) has significant antitumor, cytotoxic, and cytostatic activity on Ehrlich ascite tumor. Although toxic to normal cells, its lower toxicity when compared to carboxylate analogues of rhodium (II) indicates (Rh(2)(H(2)cit)(4)) as a promising agent for chemotherapy. Nevertheless, few studies have been performed to explore this potential. Superparamagnetic particles of iron oxide (SPIOs) represent an attractive platform as carriers in drug delivery systems (DDS) because they can present greater specificity to tumor cells than normal cells. Thus, the association between Rh(2)(H(2)cit)(4) and SPIOs can represent a strategy to enhance the former's therapeutic action. In this work, we report the cytotoxicity of free rhodium (II) citrate (Rh(2)(H(2)cit)(4)) and rhodium (II) citrate-loaded maghemite nanoparticles or magnetoliposomes, used as drug delivery systems, on both normal and carcinoma breast cell cultures. RESULTS: Treatment with free Rh(2)(H(2)cit)(4) induced cytotoxicity that was dependent on dose, time, and cell line. The IC(50) values showed that this effect was more intense on breast normal cells (MCF-10A) than on breast carcinoma cells (MCF-7 and 4T1). However, the treatment with 50 µM Rh(2)(H(2)cit)(4)-loaded maghemite nanoparticles (Mag(h)-Rh(2)(H(2)cit)(4)) and Rh(2)(H(2)cit)(4)-loaded magnetoliposomes (Lip-Magh-Rh(2)(H(2)cit)(4)) induced a higher cytotoxicity on MCF-7 and 4T1 than on MCF-10A (p < 0.05). These treatments enhanced cytotoxicity up to 4.6 times. These cytotoxic effects, induced by free Rh(2)(H(2)cit)(4), were evidenced by morphological alterations such as nuclear fragmentation, membrane blebbing and phosphatidylserine exposure, reduction of actin filaments, mitochondrial condensation and an increase in number of vacuoles, suggesting that Rh(2)(H(2)cit)(4) induces cell death by apoptosis. CONCLUSIONS: The treatment with rhodium (II) citrate-loaded maghemite nanoparticles and magnetoliposomes induced more specific cytotoxicity on breast carcinoma cells than on breast normal cells, which is the opposite of the results observed with free Rh(2)(H(2)cit)(4) treatment. Thus, magnetic nanoparticles represent an attractive platform as carriers in Rh(2)(H(2)cit)(4) delivery systems, since they can act preferentially in tumor cells. Therefore, these nanopaticulate systems may be explored as a potential tool for chemotherapy drug development.

Photobiological impact of [{(bpy)2Ru(dpp)}2RhCl2]Cl5 and [{(bpy)2Os(dpp)}2RhCl2]Cl5 [bpy=2,2'-bipyridine; dpp=2,3-Bis(2-pyridyl)pyrazine] on vero cells.

The in vitro photobiology of the supramolecular complexes [{(bpy)2Ru(dpp)}2RhCl2]Cl5 and [{(bpy)2Os(dpp)}2RhCl2]Cl5 [bpy=2,2'-bipyridine; dpp=2,3-bis(2-pyridyl)pyrazine] with African green monkey kidney epithelial (Vero) cells was investigated. Previously, the complexes have been shown to photocleave DNA in the presence or absence of O2. Vero cell replication was uninhibited for cells exposed to the metal complex but protected from light. Vero cells that were exposed to metal complex, rinsed, and illuminated with >460 nm light showed a replication response that was metal complex concentration-dependent. Vero cells exposed to 3.0-120 microM [{(bpy)2Ru(dpp)}2RhCl2]Cl5 and illuminated showed inhibition of cell growth, with evidence of cell death seen for complex concentrations>or=10 microM. Cells exposed to [{(bpy)2Os(dpp)}2RhCl2]Cl5 at concentrations of 5.5-110 microM, rinsed, and illuminated showed only inhibition of cell growth. The impact of [{(bpy)2Ru(dpp)}2RhCl2]Cl5 and [{(bpy)2Os(dpp)}2RhCl2]Cl5 on cell growth following illumination shows the promise of this new structural motif as a photodynamic therapy agent.

Visual outcome, local tumour control, and eye preservation after 106Ru/Rh brachytherapy for choroidal melanoma.

To study the visual outcome, local tumour control, and eye preservation 5 years after ruthenium/rhodium 106 brachytherapy for choroidal melanoma. The study included 55 consecutive patients treated by 106Ru/Rh brachytherapy for a choroidal melanoma during the period 1988-2000 and followed through 2004. The 5-year probability for not losing at least 5 Snellen lines was 59% (n = 45), for retaining a visual acuity of 0.33 or better was 28% (n = 34), and for retaining better than 0.1 was 40% (n = 45). The 5-year probability for no local recurrence was 73% and for eye preservation 72% (n = 55). 106Ru/Rh brachytherapy for choroidal melanoma resulted in a clinically significant vision loss, no local recurrence, and eye preservation in most patients after 5 years. 106Ru/Rh brachytherapy can be regarded as a good treatment option for small and medium-sized tumours but not for large tumours.

A simple calibration method for 106Ru-106Rh eye applicators.

Ru-Rh eye applicators are used for the radiotherapy of eye malignancies such as melanomas. We present a method of dosimetry of these beta particle emitting applicators. Method is based on a Plexiglas phantom (constructed for this purpose) containing spherical shells and very small, 1x1x1mm3 thermoluminescent dosimeters (TLD) as dosimeters. We determined 3-D depth doses and interpolated depth dose functions. Surface dose rate inhomogeneities and the consequences were considered and discussed. A possible influence of photon component of the emission on the results was analysed. The method has overall combined uncertainty + or -6% which is comparable, and slightly better, than other recent dosimetric methods.

The design and the dosimetry of bi-nuclide radioactive ophthalmic applicators.

A novel type of applicator for the treatment of intra-ocular tumors has been developed, based on the two radionuclides 106Ru/106Rh and 125I. The dose distribution of this ophthalmic plaque combines advantageous features of both radionuclides and can be optimally adapted to a tumor thickness in the range 6.5-9 mm, a size which is beyond the dosimetric limitations of the 106Ru/106Rh plaque therapy. Compared with 125I plaques a bi-nuclide plaque allows to maintain the tumor dosage while the dose in the irradiated volume outside of the target volume is significantly reduced. Consequently, radiosensitive structures within the eye can be spared more effectively. Dedicated methods have been developed for the dosimetry of this plaque. These methods are based on our own extensive dosimetric investigations with plastic scintillators. The precondition was the availability, developed in recent years, of a more accurate determination of the absolute dose rate to water of beta- and low energy emitters.

Model of metastatic growth valuable for radionuclide therapy.

The aim was to make a Monte Carlo simulation approach to estimate the distribution of tumor sizes and to study the curative potential of three candidate radionuclides for radionuclide therapy: the high-energy electron emitter 90Y, the medium-energy electron emitter 177Lu and the low-energy electron emitter 103mRh. A patient with hepatocellular carcinoma with recently published serial CT data on tumor growth in the liver was used. From these data the growth of the primary tumor, and the metastatis formation rate, were estimated. Assuming the same tumor growth of the primary and all metastases and the same metastatis formation rate from both primary and metastases the metastatic size distribution was simulated for various time points. Tumor cure of the metastatic size distribution was simulated for uniform activity distribution of three radionuclides; the high-energy electron emitter 90Y, the mean-energy electron emitter 177Lu and the low-energy electron emitter 103mRh. The simulation of a tumor cure was performed for various time points and tumor-to-normal tissue activity concentrations, TNC. It was demonstrated that it is important to start therapy as early as possible after diagnosis. It was of crucial importance to use an optimal radionuclide for therapy. These simulations demonstrated that 90Y was not suitable for systemic radionuclide therapy, due to the low absorbed fraction of the emitted electrons in small tumors (< 1 mg). If TNC was low 103mRh was slightly better than 177Lu. For high TNC values low-energy electron emitters, e.g., 103mRh was the best choice for tumor cure. However, the short half-life of 103mRh (56 min) might not be optimal for therapy. Therefore, other low-energy electron emitters, or alpha emitters, should be considered for systemic targeted therapy.

Rhodium and its compounds as potential agents in cancer treatment.

The antitumor activity of the inorganic complex cis-diammine-dichloroplatinum(II) (cisplatin) led to the development of other types of non-organic cytostatic drugs. Numerous platinum other platinum and non-platinum metal compounds were shown to be effective against animal model tumors as well as tumors in man. However, the introduction of novel transition metal agents in clinical treatment is exceptionally slow. So far, Ru(II) and Ru(III) complexes have shown very promising properties while the Ru(III) compound, [ImH][trans-Cl4(Me2SO)(Im)Ru(III)] (Im=imidazole, NAMI-A), is the first ruthenium compound that successfully entered phase I clinical trials. Rhodium belongs to the same group as platinum and ruthenium. However, rhodium compounds, analogues to the corresponding platinum and ruthenium compounds that possess significant antitumor properties, were found to be less effective as anticancer agents mainly due to their toxic effects. Dimeric mu-Acetato dimers of Rh(II) as well as monomeric square planar Rh(I) and octahedral Rh(III) complexes have shown interesting antitumor properties.

Low-energy electron emitters for targeted radiotherapy of small tumours.

The possibility of using electron emitters to cure a cancer with metastatic spread depends on the energy of the emitted electrons. Electrons with high energy will give a high, absorbed dose to large tumours, but the absorbed dose to small tumours or single tumour cells will be low, because the range of the electrons is too long. The fraction of energy absorbed within the tumour decreases with increasing electron energy and decreasing tumour size. For tumours smaller than 1 g, the tumour-to-normal-tissue mean absorbed dose-rate ratio, TND, will be low, e.g. for 131I and 90Y, because of the high energy of the emitted electrons. For radiotherapy of small tumours, radionuclides emitting charged particles with short ranges (a few microm) are required. A mathematical model was constructed to evaluate the relation between TND and electron energy, photon-to-electron energy ratio, p/e, and tumour size. Criteria for the selection of suitable radionuclides for the treatment of small tumours were defined based on the results of the TND model. In addition, the possibility of producing such radionuclides and their physical and chemical properties were evaluated. Based on the mathematical model, the energy of the emitted electrons should be < or = 40 keV for small tumours (< 1000 cells), and the photon-to-electron energy ratio, p/e, should be < or = 2 to achieve a high TND. Using the selection criteria defined, five low-energy electron emitters were found to be suitable: 58Co, 103mRh, 119Sb, 161Ho, and 189mOs. All of these nuclides decay by internal transition or electron capture, which yields conversion and Auger electrons, and it should be possible to produce most of them in therapeutic amounts. The five low-energy electron-emitting radionuclides identified may be relevant in the radiation treatment of small tumours, especially if bound to internalizing radiopharmaceuticals.

Dosimetry of beta-ray ophthalmic applicators: comparison of different measurement methods.

An international intercomparison of the dosimetry of three beta particle emitting ophthalmic applicators was performed, which involved measurements with radiochromic film, thermoluminescence dosimeters (TLDs), alanine pellets, plastic scintillators, extrapolation ionization chambers, a small fixed-volume ionization chambers, a diode detector and a diamond detector. The sources studied were planar applicators of 90Sr-90Y and 106Ru-106Rh, and a concave applicator of 106Ru-106Rh. Comparisons were made of absolute dosimetry determined at 1 mm from the source surface in water or water-equivalent plastic, and relative dosimetry along and perpendicular to the source axes. The results of the intercomparison indicate that the various methods yield consistent absolute dosimetry results at the level of 10%-14% (one standard deviation) depending on the source. For relative dosimetry along the source axis at depths of 5 mm or less, the agreement was 3%-9% (one standard deviation) depending on the source and the depth. Crucial to the proper interpretation of the measurement results is an accurate knowledge of the detector geometry, i.e., sensitive volume and amount of insensitive covering material. From the results of these measurements, functions which describe the relative dose rate along and perpendicular to the source axes are suggested.

Calculation of beta-ray dose distributions from ophthalmic applicators and comparison with measurements in a model eye.

Dose distributions throughout the eye, from three types of beta-ray ophthalmic applicators, were calculated using the EGS4, ACCEPT 3.0, and other Monte Carlo codes. The applicators were those for which doses were measured in a recent international intercomparison [Med. Phys. 28, 1373 (2001)], planar applicators of 106Ru-106Rh and 90Sr-90Y and a concave 106Ru-106Rh applicator. The main purpose was to compare the results of the various codes with average experimental values. For the planar applicators, calculated and measured doses on the source axis agreed within the experimental errors (<10%) to a depth of 7 mm for 106Ru-106Rh and 5 mm for 90Sr-90Y. At greater distances the measured values are larger than those calculated. For the concave 106Ru-106Rh applicator, there was poor agreement among available calculations and only those calculated by ACCEPT 3.0 agreed with measured values. In the past, attempts have been made to derive such dose distributions simply, by integrating the appropriate point-source dose function over the source. Here, we investigated the accuracy of this procedure for encapsulated sources, by comparing such results with values calculated by Monte Carlo. An attempt was made to allow for the effects of the silver source window but no corrections were made for scattering from the source backing. In these circumstances, at 6 mm depth, the difference in the results of the two calculations was 14%-18% for a planar 106Ru-l06Rh applicator and up to 30% for the concave applicator. It becomes worse at greater depths. These errors are probably caused mainly by differences between the spectrum of beta particles transmitted by the silver window and those transmitted by a thickness of water having the same attenuation properties.

In vitro and in vivo activity of new rhodium (III) complexes against Leishmania donovani.

The activities of 17 new rhodium drug complexes were determined against Leishmania donovani promastigotes. The five most active salts were selected: [Rh(III)(2-amino-6-ethoxybenzothiazole)(4)Br(2)](+)Br(-); [Rh(III)(2-bromothiazole)(4)(Br)(2)](+)Br(-); [Rh(III)(mefloquine)(4)(Cl)(2)](+)Cl(-); [Rh(III)(2-mepacrine)(4)(Cl)(2)](+)Cl(-), and [Rh(III)(oxamniquine)(4)(Cl)(2)](+)Cl(-), which induced growth-inhibition rates of more than 50% at 24 h of treatment and at the maximum dosage tested. The cytotoxicity assays on the macrophage cell line J-774 showed high cytotoxicity for the salts [Rh(III) (mefloquine)(4)(Cl)(2)](+)Cl(-), [Rh(III)(2-mepacrine)(4)(Cl)(2)](+)Cl(-) and [Rh(III)(oxaminquine)(4)(Cl)(2)](+)Cl(-) with a percentage of specific (15)Cr release of 49.3, 64.8 and 53.2% at 24 h of incubation and 100 microg/ml. Meanwhile, assays of the other compounds showed practically no cytotoxicity. The ultrastructural studies in the flagellates treated with the salt [Rh(III)(2-amino-6-ethoxybenzothiazole)(4)Br(2)](+)Br(-) showed some alterations in the nucleus of the parasites with a very condensed chromatin and an electrodense endosome. This compound showed a high in vivo activity in parasitized Wistar rats.

Long-term follow-up of Ru-106/Rh-106 brachytherapy for posterior uveal melanoma.

BACKGROUND: Currently available information about survival, local tumor control rates, secondary enucleation rates, and visual acuity following Ru-106/Rh-106 applicator therapy for choroidal and ciliochoroidal melanomas is limited in terms of duration of follow-up among surviving patients. METHODS: The authors performed a retrospective descriptive study of the rates of survival, local treatment failure, secondary enucleation, and visual acuity decrease in 140 patients (141 eyes) with choroidal or ciliochoroidal melanoma treated by Ru-106/Rh-106 applicator radiotherapy between 1964 and 1976. Median follow-up duration among surviving patients in this series was 17.3 years (mean 18.6 years). The Kaplan-Meier method was used to estimate cumulative survival rates and event rate curves. Multivariate Cox proportional hazards modeling was used to identify prognostic clinical variables associated with the various evaluated outcomes. RESULTS: The 15-year survival rate based on all causes of death was 48.0% (standard error=4.4%), and that based on confirmed and suspected metastatic uveal melanoma was 66.7% (standard error=4.5%). The cumulative 15-year rates of local treatment failure and secondary enucleation were 36.8% (standard error=4.4%) and 34.4% (standard error=4.5%) respectively. The cumulative 10-year rates of visual acuity loss to less than 20/200 and no light perception were 62.8% (standard error=4.4%) and 40.6% (standard error=5.2%) respectively. Prognostic factors associated with death from confirmed and suspected metastatic melanoma were greater tumor diameter and anterior tumor location. Greater tumor diameter was associated with local treatment failure. Baseline visual acuity equal to or worse than 20/200 was associated with profound visual acuity loss. CONCLUSIONS: Although a high proportion of treated eyes eventually lost a great deal of vision, and although many treated eyes ultimately underwent secondary enucleation, a substantial number of patients treated by plaque radiotherapy in this series survived for well over 10 years and retained the tumor-containing eye with a visual decrease of varying severity.