Luminescent Rhenium(I)-Polypyridine Complexes Appended with a Perylene Diimide or Benzoperylene Monoimide Moiety: Photophysics, Intracellular Sensing, and Photocytotoxic Activity.

This communication reports novel luminescent rhenium(I)-polypyridine complexes appended with a perylene diimide (PDI) or benzoperylene monoimide (BPMI) moiety through a non-conjugated linker. The photophysical and photochemical properties originating from the interactions of the metal polypyridine and perylene units were exploited to afford new cellular reagents with thiol-sensing capability and excellent photocytotoxic activity.

The effects of rhenium accumulation on Indian mustard.

Rhenium (Re) is one of Earth's scarcest and more largely scattered elements, with an estimate concentration of 0.4-0.6 µg kg-1 in the upper crust. Still, considerable concentrations of bioavailable ReO4- ions are often found, particularly in copper-molybdenum mines, where their uptake by plants of these regions has been reported. Yet, the impact of Re on plants remains a question mark, as the only available knowledge derives from a limited investigation carried out over 60 years ago. The aim of this study was to evaluate the ecophysiological response of Brassica juncea, a species known to endure and accumulate various metals, to a broad range of Re concentrations. B. juncea plants were allowed to grow and on a substrate amended with KReO4 to attain soil Re levels ranging from 0 to 80 mg kg-1. Plants were collected 45 days after sowing for analysis. The results have shown that greater Re levels reduce growth, photosynthetic activity, soluble carbohydrate mobilization, and protein contents, and increase the plant's oxidative stress (anthocyanins, H2O2, lipid peroxidation) and corresponding response (ascorbic acid, superoxide dismutase activity). Nevertheless, B. juncea exhibited a remarkable ability to endure and uptake Re, featuring shoot Re concentrations that ranged from 1615 to 24,987 mg kg-1 among the 5 and 80 mg kg-1 treatments.

Evaluation of chromosomal aberrations induced by 188Re-dendrimer nanosystem on B16f1 melanoma cells.

PURPOSE: To study the rhenium-188 labeling of polyamidoamine (PAMAM) generation 4 (G4) dendrimer and its evaluation on biodistribution and chromosomal aberrations in melanoma cells induced by ionizing radiation as potential treatment agent. MATERIALS AND METHODS: Dendrimers were first conjugated with Suc-HYNIC (succinimidyl 6-hydrazinopyridine-3-carboxylic acid hydrochloride). Dendrimer-HYNIC was then incubated with 188ReO4-. Biodistribution was performed administrating 188Re-dendrimer to normal (NM) or melanoma-bearing mice (MBM). Chromosome aberration test was conducted in order to measure treatment capacity of 188Re-dendrimer in melanoma cells. RESULTS: Radiolabeling yield of dendrimer was approx. 70%. Biodistribution studies in NM showed blood clearance with hepatic and renal depuration. MBM showed a similar pattern of biodistribution with tumor uptake of 6% of injected dose. Aberrant metaphases quantified in control cells were 7%, increasing to 29.5% in cells treated with 15µCi (0.555 MBq) of 188Re-dendrimer for 24 h. CONCLUSIONS: 188Re-dendrimer can produce double-stranded breaks in DNA induced by ionizing radiation in melanoma cells in vitro.

Cellular internalization and morphological analysis after intravenous injection of a highly hydrophilic octahedral rhenium cluster complex - a new promising X-ray contrast agent.

The octahedral cluster compound Na2 H8 [{Re6 Se8 }(P(C2 H4 CONH2 )(C2 H4 COO)2 )6 ] has been shown to be highly radio dense, thus becoming a promising X-ray contrast agent. It was also shown that this compound had low cytotoxic effect in vitro, low acute toxicity in vivo and was eliminated rapidly from the body through the urinary tract. The present contribution describes a more detailed cellular internalization assay and morphological analysis after intravenous injection of this hexarhenium cluster compound at different doses. The median lethal dose (LD50 ) of intravenously administrated compound was calculated (4.67 ± 0.69 g/kg). Results of the study clearly indicated that the cluster complex Hn [{Re6 Se8 }(P(C2 H4 CONH2 )(C2 H4 COO)2 )6 ]n-10 was not internalized into cells in vitro and induced only moderate morphological alterations of kidneys at high doses without any changes in morphology of liver, spleen, duodenum, or heart of mice. Copyright © 2016 John Wiley & Sons, Ltd.

Studying the Effect of a Composition of the Cluster Core in High-Radiopacity Cluster Complexes of Rhenium on Their Acute Toxicity In Vivo.

An in vivo study was performed to evaluate the dependence of acute toxicity of high-radiopacity and luminescent octahedral cluster complexes of rhenium after intravenous injection on a composition of the cluster core. Changes in mouse body weight, water and food consumption, degree of intoxication, and morphological changes in the visceral organs were studied after intravenous injection of the following cluster complexes with various internal ligands (S, Se, or Te): Na4[{Re 6 Te 8 }(CN)6], Na4[{Re 6 Se 8 }(CN)6], and Na4[{Re 6 S 8 }(CN)6]. The Na4[{Re 6 S 8 } (CN)6] cluster complex was shown to be the safest for animals.

A luminescent and biocompatible photoCORM.

The water-soluble rhenium(I) complex fac-[Re(bpy)(CO)(3)(thp)](+) (1) [CF(3)SO(3)(-) salt; bpy = 2,2'-bipyridine, thp = tris(hydroxymethyl)phosphine] is both strongly luminescent and photoactive toward carbon monoxide release. It is stable in aerated aqueous media, is incorporated into cells from the human prostatic carcinoma cell line PPC-1, and shows no apparent cytotoxicity. Furthermore, the solvated Re(I) photoproduct of CO release (2) is also luminescent, a feature that allows one to track the transformation of 1 to 2 inside such cells using confocal fluorescence microscopy. In this context, 1 is a very promising candidate as a photoactivated CO releasing moiety (photoCORM) with potential therapeutic applications.

Combination of three metals for the treatment of cancer: gallium, rhenium and platinum. 1. Determination of the optimal schedule of treatment.

Platinum is well known for its anticancer activity, firstly used as cis-diaminedichloroplatinum (II) (CDDP), with a wide range of activity. Its main mechanism of action involves its binding to DNA. Gallium, another metal, has also demonstrated apoptotic effects on malignant cells, but through interaction with targets other than DNA, such as the membrane, cytoskeleton and proteasome, and on enzyme activities. An antitumor synergism between CDDP and both gallium and rhenium compounds has been demonstrated. For these reasons, we proposed to combine these three metals and to determine at which doses each compound could be administered without major toxicity. CDDP, tetrakis(1-octanol) tris(5-aminosalicylate)gallium(III), and a diseleno-ether rhenium(I) complex were used in this experimental study in breast cancer MCF-7 tumor-bearing mice. CDDP was administered intraperitoneally (i.p.) twice a week at the dose of 3 mg/kg. Tetrakis(1-octanol) tris(5-aminosalicylate) gallium (III) and rhenium(I) diseleno-ether complexes were administered orally, daily, five days a week for three weeks, at doses ranging from 20 to 100 mg/kg for the gallium compound and from 10 to 50 mg/kg for the rhenium compound. Doses of 10 mg/kg of rhenium(I) diseleno-ether, and 100 mg/kg of the salicylate gallium compound, in combination with CDDP induced a significant decrease of 50% of the tumor volume, by comparison with the control group. In contrast, the decrease of the tumor volume in mice treated by CDDP alone was less than 25%. Changes in the sequence of administration of the three metals will be discussed to improve the therapeutic index.

Treatment of early and established Cryptococcus neoformans infection with radiolabeled antibodies in immunocompetent mice.

We investigated the utility of radioimmunotherapy (RIT) in early and established cryptococcal infection in immunocompetent mice. RIT with (213)Bi-18B7 antibody completely eliminated fungus from mouse lungs and brains for early infection, while (188)Re-18B7 significantly reduced CFU in the lungs or both lungs and brains during early and established infection, respectively. The results point to the independence of RIT of the immune status of the host, which is encouraging for translation of this strategy into the clinic.

Chemoradionuclide therapy with 186re-labeled liposomal doxorubicin: toxicity, dosimetry, and therapeutic response.

This study was performed to determine the maximum tolerated dose (MTD) and therapeutic effects of rhenium-186 ((186)Re)-labeled liposomal doxorubicin (Doxil), investigate associated toxicities, and calculate radiation absorbed dose in head and neck tumor xenografts and normal organs. Doxil and control polyethylene glycol (PEG)-liposomes were labeled using (186)Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA) method. Tumor-bearing rats received either no therapy (n=6), intravenous Doxil (n=4), or escalating radioactivity of (186)Re-Doxil (185-925 MBq/kg) or (186)Re-PEG-liposomes (1110-1665 MBq/kg) and were monitored for 28 days. Based on body weight loss and systemic toxicity, MTD for (186)Re-Doxil and (186)Re-PEG-liposomes were established at injected radioactivity/body weight of 740 and 1480 MBq/kg, respectively. (186)Re-injected radioactivity/body weight for therapy studies was determined to be 555 MBq/kg for (186)Re-Doxil and 1295 MBq/kg for (186)Re-PEG-liposomes. All groups recovered from their body weight loss, leucopenia, and thrombocytopenia by 28 days postinjection. Normalized radiation absorbed dose to tumor was significantly higher for (186)Re-Doxil (0.299±0.109 Gy/MBq) compared with (186)Re-PEG-liposomes (0.096±0.120 Gy/MBq) (p<0.05). In a separate therapy study, tumor volumes were significantly smaller for (186)Re-Doxil (555 MBq/kg) compared with (186)Re-PEG-liposomes (1295 MBq/kg) (p<0.01) at 42 days postinjection. In conclusion, combination chemoradionuclide therapy with (186)Re-Doxil has promising potential, because good tumor control was achieved with limited associated toxicity.

Interventional therapy of head and neck cancer with lipid nanoparticle-carried rhenium 186 radionuclide.

PURPOSE: Minimally invasive interventional cancer therapy with drug-carrying lipid nanoparticles (ie, liposomes) via convection-enhanced delivery by an infusion pump can increase intratumoral drug concentration and retention while facilitating broad distribution throughout solid tumors. The authors investigated the utility of liposome-carrying beta-emitting radionuclides to treat head and neck cancer by direct intratumoral infusion in nude rats. MATERIALS AND METHODS: Four groups of nude rats were subcutaneously inoculated with human tongue cancer cells. After tumors reached an average size of 1.6 cm(3), the treatment group received an intratumoral infusion of liposomal rhenium-186 ((186)Re) (185 MBq [5 mCi]/cm(3) tumor). Three control groups were intratumorally infused with unlabeled liposomes, unencapsulated (186)Re-perrhenate, or unencapsulated intermediate (186)Re compound ((186)Re-N,N-bis[2-mercaptoethyl]-N',N'-diethyl-ethylenediamine [BMEDA]). In vivo distribution of (186)Re activity was measured by planar gamma-camera imaging. Tumor therapy and toxicity were assessed by tumor size, body weight, and hematology. RESULTS: Average tumor volume in the (186)Re-liposome group on posttreatment day 14 decreased to 87.7% +/- 20.1%, whereas tumor volumes increased to 395.0%-514.4% on average in the other three groups (P< .001 vs (186)Re-liposome). The (186)Re-liposomes provided much higher intratumoral retention of (186)Re activity, resulting in an average tumor radiation absorbed dose of 526.3 Gy +/- 93.3, whereas (186)Re-perrhenate and (186)Re-BMEDA groups had only 3.3 Gy +/- 1.2 and 13.4 Gy +/- 9.2 tumor doses, respectively. No systemic toxicity was observed. CONCLUSIONS: Liposomal (186)Re effectively treated head and neck cancer with minimal side effects after convection-enhanced interventional delivery. These results suggest the potential of liposomal (186)Re for clinical application in interventional therapy of cancer.

Cellular uptake and cytotoxicity of octahedral rhenium cluster complexes.

Cellular uptake behavior of a novel class of octahedral rhenium cluster compounds, hexahydroxo complexes K(4)[{Re(6)S(8)}(OH)(6)].8H(2)O (1) and K(4)[{Re(6)Se(8)}(OH)(6)].8H(2)O (2), was evaluated in human cervical adenocarcinoma HeLa cells. Confocal microscopy and flow cytometry studies demonstrated that rhenium cluster 1 was not internalized into cell, while rhenium cluster 2 was. Conjugation of a polymer to rhenium cluster 1, namely the derivative K(4)[{Re(6)S(8)}(OH)(5)L] (3) (L is amphiphilic diblock copolymer MPEG550-CH(2)CONH-GlyPheLeuGlyPheLeu-COO(-)), considerably enhanced cellular uptake in a concentration-dependent manner and was predominantly localized in the cytoplasm and nucleus upon incubation time. The uptake of rhenium cluster 2 was mediated by energy-dependent endocytosis, whereas rhenium cluster 3 was directly ingested into cells by cell-fusion-like mechanism. According to the cytotoxicity evaluation test, both rhenium clusters 2 and 3 did not exhibit acute cytotoxic effects up to 50 microM, at the practical concentration level of biological applications. It is, therefore, expected that the rhenium cluster complexes can be promising potential candidates as diagnostic agents for medical treatment.

Biodistribution and internal dosimetry of the 188Re-labelled humanized monoclonal antibody anti-epidemal growth factor receptor, nimotuzumab, in the locoregional treatment of malignant gliomas.

OBJECTIVE: To evaluate the biodistribution, internal radiation dosimetry and safety of the 188Re-labelled humanized monoclonal antibody nimotuzumab in the locoregional treatment of malignant gliomas. METHODS: Single doses of 370 or 555 MBq of 188Re-labelled nimotuzumab were locoregionally administered to nine patients with recurrent high-grade gliomas, according to an approved dose-escalation study. SPECT, planar scintigraphy and magnetic resonance images were combined for dosimetric and pharmacokinetic studies. Blood and urine samples were collected to evaluate clinical laboratory parameters and for absorbed doses calculations. Biodistribution, internal dosimetry, human anti-mouse antibody response and toxicity were evaluated and reported. RESULTS: The 188Re-nimotuzumab showed a high retention in the surgically created resection cavity with a mean value of 85.5+/-10.3%ID 1 h post-injection. It produced mean absorbed doses in the tumour region of approximately 24.1+/-2.9 Gy in group I (patients receiving 370 MBq) and 31.1+/-6.4 Gy in group II (patients receiving 555 MBq); the normal organs receiving the highest absorbed doses were the kidneys, liver and urinary bladder. About 6.2+/-0.8%ID was excreted by the urinary pathway. The maximum tolerated dose was 370 MBq because two patients showed severe adverse effects after they received 555 MBq of 188Re-nimotuzumab. No patient developed human anti-mouse antibody response. CONCLUSIONS: A locoregional single dose of 188Re-labelled nimotuzumab of approximately 370 MBq could be used safely in the routine treatment of patients suffering with high-grade gliomas. The efficacy of this therapy needs to be evaluated in a phase II clinical trial.

Radiolabeled melanin-binding peptides are safe and effective in treatment of human pigmented melanoma in a mouse model of disease.

The incidence of melanoma is rising, and therapeutic options for metastatic melanoma are limited. We report the results of experimental melanoma therapy with 188-Rhenium-labeled melanin-binding decapeptide ((188)RE-HYNIC-4B4) and a comprehensive safety evaluation of this treatment. (188)RE-HYNIC- 4B4 bound only to nonviable eumelanotic MNT1 and pheomelanotic SK-28-MEL human melanoma cells in vitro, as determined by immunofluorescence, which is consistent with the inaccessibility of intracellular melanin in live cells, and suggests specificity for tumors with a significant amount of extracellular melanin. Administration of 1 mCi (188)RE-HYNIC-4B4 to MNT1 tumor-bearing mice significantly slowed tumor growth, with the therapeutic effect being a result of specific binding to tumor melanin, as irrelevant (188)RE-labeled decapeptide did not produce therapeutic gain. Repeated doses of (188)RE-HYNIC-4B4 had a more profound effect on tumor growth than a single dose. Treatment of tumors with 0.3-0.4 cm diameter was more effective than of larger ones (0.5-0.7 cm). There was no difference in uptake of (188)REHYNIC- 4B4 in melanized tissues of black C57BL6 mice and no histologically apparent damage to these tissues in comparison with white BALB/C mice. Treatment of C57BL6 mice with (188)RE-HYNIC-4B4 did not change their behavior, as established by SHIRPA protocol, and did not cause damage to neurons and glial cells. These results indicate that radiolabeled melanin-binding peptides are efficient and safe in treatment of melanoma and could be potentially useful against this tumor.

DA-7911, 188Rhenium-tin colloid, as a new therapeutic agent of rheumatoid arthritis.

Radiation synovectomy is one of the most useful methods for treating patients with refractory synovitis because of its convenience, long-term effects, repeatability and the avoidance of surgery. In this study, we investigated the toxicity, stability and biodistribution of a rhenium-188 (188Re)-tin colloid to evaluate its suitability as a synovectomy agent. Twenty four hours after injecting the 188Re-tin colloids (74 KBq/0.1 mL) into the tail vein of ICR mice, most of the 188Retin colloidal particles was found in the lungs. In addition, there were no particle size changes at either room temperature or at 37 degrees C after injecting the 188Re-tin colloids in human plasma and synovial fluid. In vitro stability tests showed that the 188Re-tin colloid remained in a colloidal form without a critical size variation over a 2-day period. We investigated the leakage of 188Retin colloids from the intraarticular injection site with gamma counting in New Zealand white rabbits. The 188Re-tin colloids (55.5 MBq/0.15 mL) were injected at the cavum articular and the mean retention percentage of the 188Re-tin colloid was 98.7% for 1 day at the injection site, which suggests that there was neither change in the particle size nor leakage at the injection sites. In the biodistribution study with the SD rats, the liver showed the highest radioactivity (0.0427% ID/organ) except for the injected knees (99.49%). In the SD rats, mild toxicities including the skin or a synovium inflammation were observed as a result of a radioactivity of 15 mCi/kg at the intraarticular injection site. However, there was no systemic toxicity. In the Ovalbumin (OVA)-induced arthritic rabbits, the 188Re-tin colloid improved the macroscopic, the histological score and reduced the knee joint diameter when compared to the arthritic control. In conclusion, a 188Re-tin-colloid is considered as a strong candidate for radiation synovectomy with a superior efficacy and safety.

188Re-labeled anti-CD66 monoclonal antibody in stem cell transplantation for patients with high-risk acute myeloid leukemia.

We have intensified the conditioning regimen prior to stem cell transplantation in 57 patients with high-risk AML and MDS by treating patients with a 188Re-labeled anti-CD66 monoclonal antibody. Dosimetry was performed prior to therapy and a favorable dosimetry was observed in all cases. Radioimmunotherapy with the labeled antibody provided a mean of 15.5 Gy of additional radiation to the marrow, the kidney was the normal organ receiving the highest dose of supplemental radiation (mean 7.4 Gy): Radioimmunotherapy was followed by standard full-dose conditioning with total body irradiation (12 Gy) (n = 30) or busulfan (n = 27) and high-dose cyclophosphamide +/- thiotepa. Patients subsequently received a T cell depleted allogeneic graft from a HLA-compatible family donor (n = 24), a matched unrelated donor (n = 23) or a haploidentical family donor (n = 6). In four patients, an unmanipulated autologous graft was used. Infusion-related toxicity due to the labeled antibody was minimal and no increase in treatment-related mortality due to the radioimmunoconjugate was observed. Day +30 and day +100 mortalities were 3 and 7%, respectively, and after a median follow-up of 26 months treatment-related mortality was 30%. Late renal toxicity was observed in 14% of patients. The disease-free survival rate for 44 patients in 1 or 2 CR or in very good PR (< 15% blasts in the marrow at transplant) is 64% with only 8% disease-free survival for those with > 15% blasts in the marrow at transplant.

On the safety of synoviorthesis in haemophilia.

One of the best procedures to prevent haem-arthrosis has been radioactive synovectomy (synoviorthesis). Since the first report of radioactive synovectomy in haemophilia of Ahlberg in 1971 [1], many centres adopted this procedure as the one of choice, through fibrosing the synovial membrane, prevent further haemarthrosis. Since 1976 we have performed 104 such radioactive synoviorthesis in 97 patients, age ranging from 6 to 40 years with a mean of 10 years. Sixty-five of these patients were under 12 years of age. The knees were injected in 61 cases, elbow in 26 cases, ankles in 14 cases and shoulders in three cases. The clinical results of this procedure show 80% of excellent results with no further bleeding. In case of failure, a new injection can be given in the same joint at a 6-month interval, or an injection for the same purpose in other joint. One of the criticisms against this method is the possible chromosomal damage induced by the radioactive material. In our centre, four studies have been carried out in order to see whether these changes, when they occur, are everlasting; all have demonstrated that chromosomal changes are reversible. The radioactive material used in the two first studies was Gold-189 (189Au). In 1978, 354 metaphases were studied with 61 ruptures, 17.23% (nonpremalign) and six structural changes, considered premalign (1.69%). Any number below 2% is considered not to be dangerous. A further study was done in 1982, in the same group of patients with a result of 21 ruptures (3.34%) and no structural changes. This demonstrated that the possible premalign changes disappeared with time. A third study was performed in a series of 13 patients that sustained radioactive synoviorthesis with Rhenium-186 (186Re) in November 1991. For comparison, we carried out a chromosomal study just before and 6 months after the radioactive material injection. The results confirmed that changes that could be linked to the radiation, appeared equally in nonirradiated patients, and those changes due to the radiation disappear with time, never reaching the dangerous zone of 2%. In the group treated with 186Re we studied an additional number of 130 metaphases with identical results and no structural changes. In a study on patients where 90Y was the radiocolloid, no premalign change was found before or after the synoviorthesis. It seems, in view of these results, that radioactive synovectomy is safe and gives great benefits to the haemophilic patients.

Evaluation of toxicity and efficacy of 186Re-hydroxyethylidene diphosphonate in patients with painful bone metastases of prostate or breast cancer.

UNLABELLED: Twenty-eight patients (12 men with prostate cancer, 16 women with breast cancer) were included in a phase II trial to evaluate the efficacy of 186Re-hydroxyethylidene diphosphonate (HEDP) on pain from bone metastasis and the toxicity of this agent. METHODS: After intravenous administration of 1295 MBq 186Re-HEDP, the efficacy was evaluated by means of a daily log. RESULTS: We observed an objective response in 67% of prostate cancer patients and in 36% of breast cancer patients. The mean duration of response was 45 d for prostate cancer patients and 24 d for breast cancer patients. No major adverse effects were observed. Marrow toxicity did not exceed grade 2 for white blood cells and grade 3 for platelets using National Cancer Institute criteria. CONCLUSION: 186Re-HEDP provides safe symptomatic relief of pain in prostate cancer patients. The benefit of this treatment is less clear in breast cancer patients. Further studies should be conducted to evaluate treatment by 186Re-HEDP at an earlier stage of the disease.

Rhenium-188 microspheres: a new radiation synovectomy agent.

Radiation synovectomy is efficacious in controlling the symptoms of rheumatoid arthritis. However, the procedure is not widely used because of concerns about leakage of radiopharmaceuticals from the treated joints. Leakage can be minimized by selecting particles of an appropriate size. In this study, we labelled microspheres with 188Re and analysed its biodistribution after intra-articular injection in rabbits with antigen-induced arthritis. Gamma camera imaging was performed to quantify the mean retention of 188Re in the knees. The mean retention of 188Re was 98.7, 94.6 and 93.6% at 1, 24 and 48 h, respectively. The biodistribution data revealed very low radioactivity in all organs at different times, which suggests the leakage of radiotracer from the knee was negligible. Our preliminary results indicate that 188Re microspheres are a potentially effective radiopharmaceutical for radiation synovectomy.

Ionic rhenocene derivatives with antitumor activity.

The antitumor activity of the three air-stable bis(cyclopentadienyl)rhenium derivatives [(C5H5)2-ReCl2]+Cl-,[(C5H5)2ReCl2]+[AsF6]- , and [(C5H5)2-ReCl2]+[SbF6]- was tested against Ehrlich ascites tumor in female CF1 mice. All three compounds contain the group-7 transition metal rhenium in the +5 oxidation state as their central metal atom. They are ionic, salt-like complexes that are composed of the cationic [(C5H5)2ReCl2]+ moiety and one of the negatively charged counterions Cl-, AsF6-, or SbF6-. Both the chloro and the hexafluoroarsenate complexes induced a maximal cure rate of 100% when given either in a dose range of 120-160 mg/kg (rhenocene trichloride) or at a single dose of 180 mg/kg (hexafluoroarsenate derivative). The hexafluoroantimonate complex effected a maximal cure rate of only 50% at 60 mg/kg. For the two former compounds, the values for the therapeutic index (TI) amounted to 1.7 and 2.1, respectively. No impairment of the general condition or pathologic symptoms in the viscera could be detected by observation of the animals during the days following treatment with therapeutic doses or by autopsy of the surviving animals on the key date (day 90). The rhenocene derivatives investigated in the present study represent a new class of antitumor metallocene compounds as well as the first rhenium(V) complexes exerting cytostatic activity.