Dexrazoxane provided moderate protection in a catecholamine model of severe cardiotoxicity.

Positive effects of dexrazoxane (DEX) in anthracycline cardiotoxicity have been mostly assumed to be associated with its iron-chelating properties. However, this explanation has been recently questioned. Iron plays also an important role in the catecholamine cardiotoxicity. Hence in this study, the influence of DEX on a catecholamine model of acute myocardial infarction (100 mg/kg of isoprenaline by subcutaneous injection) was assessed: (i) the effects of an intravenous dose of 20.4 mg/kg were analyzed after 24 h, (ii) the effects were monitored continuously during the first two hours after drug(s) administration to examine the mechanism(s) of cardioprotection. Additional in vitro experiments on iron chelation/reduction and influence on the Fenton chemistry were performed both with isoprenaline/DEX separately and in their combination. DEX partly decreased the mortality, reduced myocardial calcium overload, histological impairment, and peripheral haemodynamic disturbances 24 h after isoprenaline administration. Continuous 2 h experiments showed that DEX did not influence isoprenaline induced atrioventricular blocks and had little effect on the measured haemodynamic parameters. Its protective effects are probably mediated by inhibition of late myocardial impairment and ventricular fibrillation likely due to inhibition of myocardial calcium overload. Complementary in vitro experiments suggested that iron chelation properties of DEX apparently did not play the major role.

Dexrazoxane for the prevention of cardiac toxicity and treatment of extravasation injury from the anthracycline antibiotics.

The cumulative cardiac toxicity of the anthracycline antibiotics and their propensity to produce severe tissue injury following extravasation from a peripheral vein during intravenous administration remain significant problems in clinical oncologic practice. Understanding of the free radical metabolism of these drugs and their interactions with iron proteins led to the development of dexrazoxane, an analogue of EDTA with intrinsic antineoplastic activity as well as strong iron binding properties, as both a prospective cardioprotective therapy for patients receiving anthracyclines and as an effective treatment for anthracycline extravasations. In this review, the molecular mechanisms by which the anthracyclines generate reactive oxygen species and interact with intracellular iron are examined to understand the cardioprotective mechanism of action of dexrazoxane and its ability to protect the subcutaneous tissues from anthracycline-induced tissue necrosis.

The use of dexrazoxane for the prevention of anthracycline extravasation injury.

BACKGROUND: The use of the anthracycline anticancer drugs doxorubicin, daunorubicin, epirubicin and idarubicin sometimes results in accidental extravasation injury and can be a serious complication of their use. OBJECTIVE: The object of this review was to evaluate the preclinical and clinical literature on the use of dexrazoxane in preventing anthracycline-induced extravasation injury. METHODS: A review of the literature was carried out using PubMed. RESULTS/CONCLUSIONS: Dexrazoxane, which is clinically used to reduce doxorubicin-induced cardiotoxicity, has been shown in two clinical studies and in several case reports to be highly efficacious in preventing anthracycline-induced extravasation injury. Dexrazoxane is a prodrug analog of the metal chelator EDTA that likely acts by removing iron from the iron-anthracycline complex, thus preventing formation of damaging reactive oxygen species.

Medicinal chemistry of probimane and MST-16: comparison of anticancer effects between bisdioxopiperazines.

Bisdioxopiperazines, including ICRF-154 and razoxane (ICRF-159, Raz), are a family of anticancer agents developed in the UK, specifically targeting neoplastic metastases. Two other bisdioxopiperazine derivatives, probimane (Pro) and MST-16, were synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. In order to determine the similarities and differences between these agents in medical chemistry, we evaluated the anti-tumor and anti-metastatic effects of Pro and MST-16 in vitro and in vivo against a number of human tumor cell lines and one of murine origin (Lewis lung carcinoma, LLC), and one human tumor xenograft (LAX-83) in nude mice. Our results show that Pro was cytotoxic to human tumor cell lines in vitro (IC50 < 50 microM for 48 h), approximately 3 to 20-fold more than MST-16. Pro and MST-16 manifested more prolonged cytotoxicity than some other first-line anticancer drugs including 5-fluorouacil, vincristine and doxorubicin, and maintain their cytotoxic effects for 4 days in vitro. In animal experiments, Pro and Raz were active against primary tumor growth (35-50 %) and significantly inhibited pulmonary metastasis of LLC (inhibition > 90 %) at dosage below LD(5). Both Raz and Pro were effective in administration schedules of 1, 5 and 9 days. Both Raz (25-32 %) and Pro (55-60 %) caused statistically significant inhibition of the growth of LAX 83 (a human lung adeno-carcinoma xenograft) in nude mice. In this model, Pro was more effective against LAX83 than Raz at equitoxic dosages. These findings suggest that Pro is active against more categories of tumors both in vivo and in vitro, which in some circumstances may make it superior to the currently-used anticancer bisdioxopiperazines, including razoxane and MST-16.

Thrombopoietin protects against in vitro and in vivo cardiotoxicity induced by doxorubicin.

BACKGROUND: Doxorubicin (DOX) is an important antineoplastic agent. However, the associated cardiotoxicity, possibly mediated by the production of reactive oxygen species, has remained a significant and dose-limiting clinical problem. Our hypothesis is that the hematopoietic/megakaryocytopoietic growth factor thrombopoietin (TPO) protects against DOX-induced cardiotoxicity and might involve antiapoptotic mechanism exerted on cardiomyocytes. METHODS AND RESULTS: In vitro investigations on H9C2 cell line and spontaneously beating cells of primary, neonatal rat ventricle, as well as an in vivo study in a mouse model of DOX-induced acute cardiomyopathy, were performed. Our results showed that pretreatment with TPO significantly increased viability of DOX-injured H9C2 cells and beating rates of neonatal myocytes, with effects similar to those of dexrazoxane, a clinically approved cardiac protective agent. TPO ameliorated DOX-induced apoptosis of H9C2 cells as demonstrated by assays of annexin V, active caspase-3, and mitochondrial membrane potential. In the mouse model, administration of TPO (12.5 microg/kg IP for 3 alternate days) significantly reduced DOX-induced (20 mg/kg) cardiotoxicity, including low blood cell count, cardiomyocyte lesions (apoptosis, vacuolization, and myofibrillar loss), and animal mortality. Using Doppler echocardiography, we observed increased heart rate, fractional shortening, and cardiac output in animals pretreated with TPO compared with those receiving DOX alone. CONCLUSIONS: These data have provided the first evidence that TPO is a protective agent against DOX-induced cardiac injury. We propose to further explore an integrated program, incorporating TPO with other protocols, for treatment of DOX-induced cardiotoxicity and other forms of cardiomyopathy.

Cardiac toxicity related to cancer treatment.

Cardiac toxicity is a dose-limiting toxicity that may occur during cancer treatment or several years after therapy ends. Cardiac toxicity may be caused by chemotherapy, biotherapy, and radiation therapy and may result in cardiomyopathy, congestive heart failure, dysrhythmias, and myocardial ischemia. The risk for developing cardiac toxicity varies based on type of treatment, patient age, presence of preexisting or concurrent heart disease, and concomitant treatment. Patients at high risk require careful evaluation and monitoring during and in the years following therapy to detect cardiac changes. Fortunately, cardioprotective agents and newer radiation therapy techniques decrease the risk for treatment-related cardiac toxicity. Oncology nurses can become more informed in the assessment of cardiac toxicity and can arm themselves with knowledge about early identification of symptoms as well as specific agents and treatments that increase risk for cardiac toxicity.

The cardioprotective effect of the iron chelator dexrazoxane (ICRF-187) on anthracycline-mediated cardiotoxicity.

The cardiotoxic effect of anthracyclines limits their use in the treatment of a variety of cancers. The reason for the high susceptibility of cardiac muscle to anthracyclines remains unclear, but it appears to be due, at least in part, to the interaction of these drugs with intracellular iron (Fe). The suggestion that Fe plays an important role in anthracycline cardiotoxicity has been strengthened by observation that the chelator, dexrazoxane (ICRF-187), has a potent cardioprotective effect. In the present review, the role of Fe in the cardiotoxicity of anthracyclines is discussed together with the possible role of Fe chelation therapy as a cardioprotective strategy that may also result in enhanced antitumour activity.

[Angiosarcoma of the right atrium: local control via low radiation doses and razoxane. A case report]. / Angiosarkom des rechten Vorhofs: lokale Kontrolle durch niedrige Strahlendosen und Razoxan. Ein Fallbericht.

BACKGROUND: Angiosarcomas of the heart are rare neoplasms bearing an unfavorable prognosis. In recent series, the median survival is about 5 months. The response to radiation therapy is uncertain. CASE REPORT: A 65-year-old copper smith with an angiosarcoma of the right atrium and metastases of the liver received a partial resection of the primary tumor in January 1992. This was followed by a polychemotherapy including ifosfamide, epirubicin and dacarbacin (DTIC). In April 1992, after 5 cycles of this treatment a large regrowth of the primary and multiple pulmonary metastases were observed. After a 4-day pretreatment with the radiosensitizer razoxane, the large tumor of the right heart was irradiated with 25 MV photons of a linear accelerator. Single doses of 200 cGy were given via parallel opposed fields. The total radiation dose at the tumor was 30 Gy. Concomitantly, razoxane was given at a dose of 125 mg twice daily during the radiation days until the end of the radiotherapy. The treatment was well tolerated and the patient went into a subtotal remission. Chest X-rays from September 1992 revealed a progression of the metastases in the lung and the liver, the recurrent tumor of the right atrium remained in a subtotal remission. The patient was retreated with ifosfamide, epirubicin and DTIC. No substantial remission of the metastases occurred and the patient died at the end of January 1993. At autopsy, the recurrent primary and the lung metastases within the region of the former radiation field remained locally controlled. CONCLUSION: Reviewing the literature and considering this case, irradiation seems to be a valid treatment option for the local control of cardiac angiosarcomas. The combination of radiotherapy with razoxane eventually allows a considerable reduction of the radiation dose.

Phase I trials of dexrazoxane and other potential applications for the agent.

The clinical development of dexrazoxane (DEX; ICRF-187; Zinecard, Pharmacia and Upjohn, Kalamazoo, MI) was originally begun using it as an antineoplastic agent. It had a unique mechanism of action and activity in a variety of in vitro and in vivo models. Phase I trials with the agent began in January 1979. The phase I trials indicated that DEX could be safely administered, with leukopenia and thrombocytopenia being the dose-limiting toxicities, on a number of different schedules of administration. Some hints of antitumor activity were also noted. In the phase I studies it was also noted, based on the chelating abilities of DEX, that the compound caused marked increases in urine clearance of iron and zinc in patients receiving the agent. That information, plus the information being generated in preclinical studies that DEX could protect against the cardiotoxicity induced by anthracyclines (through a decrease in free radical formation), led to the use of DEX as a cardioprotective agent (as thoroughly discussed in this supplement). However, in addition to working as a cardioprotective agent, DEX has other potential applications that are outlined below and include (1) treatment of patients with acquired immunodeficiency syndrome-related Kaposi's sarcoma, based on its activity as an angiogenesis inhibitor; (2) enhancement of the effects of cisplatin, based on its ability to increase the antiproliferative effects of cisplatin on human ovarian cancer cells; (3) use for treatment of iron overload states in patients who are allergic to deferoxamine; (4) treatment of patients with psoriasis; (5) protection from hyperoxic effects on the lungs; (6) protection from bleomycin-induced pulmonary fibrosis; (7) attenuation of acetaminophen-induced hepatotoxicity; (8) prevention of mucositis; and (9) other applications. Clearly, there should be additional investigations to maximize the usefulness of the very interesting DEX molecule.

Chemical, biological and clinical aspects of dexrazoxane and other bisdioxopiperazines.

The bisdioxopiperazine dexrazoxane (ICRF-187) has proven to be clinically very effective in reducing the cardiotoxicity of doxorubicin and other anthracyclines. Doxorubicin is thought to exert its toxicity through iron-based oxygen free radical-induced oxidative stress on the relatively unprotected cardiac muscle. Upon hydrolysis, dexrazoxane forms a compound similar to ethylenediaminetetraacetic acid (EDTA) which, like EDTA, is a strong chelator of iron. Dexrazoxane presumably exerts its cardioprotective effects by either binding free or loosely bound iron, or iron complexed to doxorubicin, thus preventing or reducing site-specific oxygen radical production that damages cellular components. The chemistry, biochemistry, and cell biology of dexrazoxane and other bisdioxopiperazines are discussed. The pre-clinical studies demonstrating the protective effects of dexrazoxane against toxicities caused by doxorubicin, other anthracyclines, bleomycin, alloxan, acetaminophen, and oxygen are also discussed. In vitro and in vivo studies of the cardioprotective and other effects of other bisdioxopiperazines are also covered. Also discussed are the anti-metastatic and radiosensitization effects of razoxane and dexrazoxane. The current clinical status of dexrazoxane in preventing anthracycline-induced toxicities in both adult and pediatric patients is reviewed.

Chelation therapy in cardiovascular disease: ethylenediaminetetraacetic acid, deferoxamine, and dexrazoxane.

This review was conducted to assess whether there is sufficient evidence for the clinical use of chelation therapy in cardiovascular disease based on original articles and abstracts published in the last 30 years, with emphasis placed on the most recent placebo-controlled studies. Articles postulating the mechanisms of chelation also were included. The majority of the literature focused on three chelators in particular, ethylenediaminetetraacetic acid (EDTA), deferoxamine, and dexrazoxane (ICRF-187). Historically, much has been written on the beneficial effects of EDTA. However, there are few controlled studies, and the mechanism of action of EDTA is poorly understood. Although studies of deferoxamine are more recent, most of the research is limited to animals and ex vivo models. Recently, dexrazoxane was approved, but only for parenteral use for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer. Given these limitations, it is concluded that more controlled studies are required to determine the efficacy of chelation therapy in cardiovascular disease before it can be used broadly in the clinical setting.

Monohydroxyethylrutoside, a dose-dependent cardioprotective agent, does not affect the antitumor activity of doxorubicin.

The cumulative dose-related cardiotoxicity of doxorubicin is believed to be caused by the production of oxygen- free radicals. 7-Monohydroxyethylrutoside (monoHER), a semisynthetic flavonoid and powerful antioxidant, was investigated with respect to the prevention of doxorubicin-induced cardiotoxicity in mice and to its influence on the antitumor activity of doxorubicin in vitro and in vivo. Non-tumor-bearing mice were equipped with a telemeter in the peritoneal cavity. They were given six weekly doses of 4 mg/kg doxorubicin i.v., alone or in combination with either 100 or 250 mg/kg monoHER i.p., 1 h prior to doxorubicin administration and for the following 4 days. Cardiotoxic effects were measured from electrocardiogram changes up to 2 weeks after treatment. Protection against cardiotoxicity was found to be dose dependent, with 53 and 75% protection, respectively, as calculated from the reduction in the increase in the ST interval. MonoHER and several other flavonoids with good antioxidant properties were tested for their antiproliferative effects in the absence or the presence of doxorubicin in A2780 and OVCAR-3 human ovarian cancer cells and MCF-7 human breast cancer cells in vitro. Some flavonoids were directly toxic at 50 and 100 microM, whereas others, including monoHER, did not influence the antiproliferative effects of doxorubicin at these concentrations. The influence of monoHER was further tested on the growth-inhibitory effect of 8 mg/kg doxorubicin i.v., given twice with an interval of 1 week in A2780 and OVCAR-3 cells that were grown as s.c. xenografts in nude mice. MonoHER, administered 1 h before doxorubicin in a dose schedule of 500 mg/kg i.p. 2 or 5 days per week, was not toxic and did not decrease the antitumor activity of doxorubicin. It can be concluded that monoHER showed a dose-dependent protection against chronic cardiotoxicity and did not influence the antitumor activity of doxorubicin in vitro or in vivo.

Dexrazoxane cardioprotection for patients receiving FAC chemotherapy: a pharmacoeconomic evaluation.

Anthracyclines are among the most effective and commonly-prescribed antitumor agents but have dose-limiting cumulative cardiotoxicity. We performed a pharmacoeconomic evaluation of the ability of dexrazoxane to prevent cardiac-related adverse events in patients with Stage IIIB or IV metastatic breast cancer who were treated with a median of 10 cycles of intravenous FAC (5-fluorouracil, doxorubicin and cyclophosphamide) at doses of 500/50/500 mg/m2 respectively. Dexrazoxane was given at 500 mg/m2 commencing at the seventh cycle of treatment. We determined the cost of each cardiac event prevented and the cost of each additional life-year saved by dexrazoxane use. The cost per cardiac event prevented was CDN $5745 and the cost per additional life-year saved was CDN $2856. With the increasing use of anthracyclines in Stages I and II breast cancer, these favorable clinical and economic results may broaden the range of therapeutic possibilities for anthracyclines in adjuvant and metastatic therapy of breast cancer.

[An evaluation of the cardioprotective action of the preparation ICRF-187 (Cardioxane) during the treatment of breast cancer with large doses of adriamycin]. / Otsenka kardioprotektivnogo deistviia preparata ICRF-187 (kardioksan) pri lechenii bol'nykh rakom molochnoi zhelezy bol'shimi dozami adriamitsina.

Twenty females with disseminated breast cancer received courses of polychemotherapy with 21-day intervals. The regimen comprised adriamycin (ADM), cyclophosphamide and 5-fluorouracil in the dose 50, 500 mg/m2, respectively. 30 minutes prior to the treatment the patients were given the cardioprotector cardioxan (1000 mg/m2). Cardiological control (ECG, EF according to echo-CG and radionuclide ventriculography, PP/EP M1/M2, T1/T2 according to echo-polycardiography and Doppler cardiography) was performed before the treatment and at ADM total dose 200-300 mg/m2 followed by measurements at each dose increase by 100 mg/m2. The findings showed no evidence of ADM-related cardiac damage up to ADM dose 900-1000 mg/m2 in the case of cardioxan protection, though there was a tendency to M1/M2 increase which needs further studies as it suggests worsening of left ventricular diastolic contractility.

The pharmacokinetics of high-dose epirubicin and of the cardioprotector ADR-529 given together with cyclophosphamide, 5-fluorouracil, and tamoxifen in metastatic breast-cancer patients.

A high-pressure liquid chromatographic method for determination of the bisdioxopiperazine derivative ADR-529 (ICRF-187), a compound proven effective in protection against anthracycline-induced cardiotoxicity, has been developed. The limit of quantitation was 5 ng/ml using a narrow-bore 5-microns silica column and UV detection. The method was used for determination of pharmacokinetic profiles of ADR-529 after a 3-weekly i.v. administration of different doses of ADR-529 (600-1000 mg/m2) together with different doses of epirubicin (E, 60-100 mg/m2), fixed-dose cyclophosphamide (C, 600 mg/m2), fixed-dose 5-fluorouracil (F, 600 mg/m2), and daily administration of tamoxifen (T, 30 mg; CEF-T) in the treatment of patients with metastatic breast cancer. Pharmacokinetic parameters for epirubicin were also determined. The aim of the study was to determine (1) whether the pharmacokinetics of ADR-529 as part of a combination with CEF-T changes with increasing doses of ADR-529 and increasing doses of epirubicin and (2) whether the pharmacokinetics of epirubicin in the same combinations is altered with the administration of increasing doses of ADR-529. A total of 82 patients were included. A crossover study including 16 of the patients showed no significant difference in epirubicin pharmacokinetic parameters when epirubicin was given with or without concomitant administration of ADR-529. Apart from minor changes in the distributional half-lives, the pharmacokinetic parameters of epirubicin were not altered with increasing doses of ADR-529, nor were the pharmacokinetic parameters of ADR-529 itself. Escalating doses of epirubicin did not significantly alter the pharmacokinetic parameters of ADR-529 with the exception of a 30% increase in the terminal half-life and a decrease in total body clearance when the epirubicin dose was raised from 60 to 100 mg/m2. We conclude that concomitant administration of ADR-529 does not alter the distribution and elimination of epirubicin in doses suitable for preventing the anthracycline-induced cardiotoxicity.

Protective effect of ICRF-187 against normal tissue injury induced by adriamycin in combination with whole body hyperthermia.

The use of [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)]propane (ICRF-187) as a protective agent against normal tissue toxicity caused by combined Adriamycin (ADR) and whole body hyperthermia (WBH; 2 h at 41.5 degrees C) was assessed in a rat model. The effect of ICRF-187 on the antitumor response induced by the combination of ADR and WBH was also investigated in order to assess alterations in the therapeutic index of this combined therapeutic modality treatment. ICRF-187 significantly reduced ADR-mediated body weight loss, renal toxicity, and cardiomyopathy under both normothermic and hyperthermic conditions as shown by morphological and functional assays. ADR-induced neuropathy (seen only in normothermic rats) was also ameliorated by ICRF-187. Although this study did not show a pronounced effect of ICRF-187 on ADR-induced acute myelosuppression, ADR-mediated chronic anemia, leukocytosis, and thrombocytosis were reduced by ICRF-187 in both normothermic and WBH-treated rats. The effect of ICRF-187 on antitumor response was evaluated with a tumor growth delay assay using an in vivo transplantable fibrosarcoma. ICRF-187 caused no significant change in tumor growth delay induced by either ADR alone or ADR combined with WBH. Indeed, the only complete tumor regression following treatment resulted from the combination of ICRF-187 plus ADR plus WBH. Thus, ICRF-187 significantly increases the therapeutic index of the combined modality treatment of ADR and WBH by selectively reducing normal tissue toxicity without interfering with antitumor efficacy.

Effects of ICRF-187 on the cardiac and renal toxicity of epirubicin in spontaneously hypertensive rats.

A study was made of the protective effect of ICRF-187 against the cardiotoxicity and nephrotoxicity produced by epirubicin in spontaneously hypertensive rats (SHR). A total of 20 SHR were divided into 4 groups of 5 animals; the first group received i.v. injections of 1.5 mg/kg epirubicin; the second was treated with i.p. injections of 50 mg/kg ICRF-187 30 min before receiving 1.5 mg/kg epirubicin; the two remaining groups received ICRF-187 and saline, respectively, and served as controls. The experiment was terminated after 12 weekly injections (total cumulative dose of epirubicin, 18 mg/kg). Morphologic studies showed that severe cardiomyopathy manifested by myofibrillar loss and dilatation of the sarcoplasmic reticulum and nephropathy characterized by tubular dilatation and atrophy, protein casts in the lumina of renal tubules, and glomerular vacuolization occurred in SHR given epirubicin alone. Animals receiving the combination of ICRF-187 and epirubicin showed a marked reduction in the severity of cardiomyopathy and a moderate reduction in nephropathy. These changes, and their modification by ICRF-187, were similar to those we have previously observed in SHR treated with total cumulative doses of 12 mg/kg doxorubicin. Such pathologic changes were absent in animals receiving ICRF-187 or saline alone. The findings of this study suggest that ICRF-187 can be used clinically to prevent the cardiotoxicity of epirubicin, particularly in situations in which this drug may have to be given either in large doses or to patients at high risk of developing anthracycline cardiotoxicity.

Reduction of chronic doxorubicin cardiotoxicity in beagle dogs by bis-morpholinomethyl derivative of razoxane (ICRF-159).

Addition of morpholinomethyl substituents to razoxane (ICRF-159) produced a compound (bis-4-morpholinomethyl-3,5-dioxopiperazinyl-1,2-propane (MM-159) considerably more water-soluble than razoxane. The increased solubility allowed MM-159 to be examined for protective activity against chronic doxorubicin (DXR) cardiotoxicity. Adult beagle dogs of either sex were given, i.v. at 3-week intervals, either DXR (1.75 mg/kg) alone or DXR 15 min after MM-159 (25 mg/kg). Control animals received MM-159 (25 mg/kg) or saline without DXR. The experiment was terminated 3 weeks after the ninth injection (total DXR dose, 15.75 mg/kg). Of the eight animals given DXR alone, five died after receiving seven to eight injections (12.25-14 mg/kg DXR) and the remaining three were killed after eight injections because they were in poor condition. Marked ascites was noted in four of these eight dogs. When frequency and extent of myocardial lesions (vacuolation and myofibrillar loss) were assessed on a scale from 0 to 4+, severe lesions (3+) were present in all eight dogs given DXR alone, but no abnormalities (lesion score 0) were found in the hearts of three of eight dogs given MM-159 and DXR and the five remaining animals in this group had minimal (1+; four dogs) or mild (2+; one dog) alterations. DXR reduced the erythrocyte count, hemoglobin, and hematocrit when administered alone, but not in combination with MM-159. Such protection against DXR hematologic effects was not noted previously when dogs were pretreated with ICRF-187, the d-isomer of razoxane, despite the fact that pretreatment with ICRF-187 was as effective as MM-159 in reducing chronic DXR cardiotoxicity. It remains to be determined whether there are other differences in biological activity between MM-159 and ICRF-187.

Razoxane y teleroentgen radiación en psoriasis resistentes al PUVA y al metotrexato / Razoxane and teleroentgentherapy in psoriasis resistent to PUVA and methotrexate

Se describe la experiencia clínica con el uso de Razoxone ICRF 159, una nueva droga antitumoral, en el tratamiento de 57 pacientes con formas severas de psoriasis. Esta medicación demostró ser efectiva sobre todo en las formas generalizadas eritrodérmicas y con compromisos articulares. Es bien tolerada y parece estar libre de hepatotoxicidad; sin embargo puede producir depresión medular, efecto que está directamente relacionado con la dosis. Se investigó su asociación con teleroentgenterapia por su propiedad radiopotenciadora

Razoxane y teleroentgen radiación en psoriasis resistentes al PUVA y al metotrexato / Razoxane and teleroentgentherapy in psoriasis resistent to PUVA and methotrexate

Se describe la experiencia clínica con el uso de Razoxone ICRF 159, una nueva droga antitumoral, en el tratamiento de 57 pacientes con formas severas de psoriasis. Esta medicación demostró ser efectiva sobre todo en las formas generalizadas eritrodérmicas y con compromisos articulares. Es bien tolerada y parece estar libre de hepatotoxicidad; sin embargo puede producir depresión medular, efecto que está directamente relacionado con la dosis. Se investigó su asociación con teleroentgenterapia por su propiedad radiopotenciadora (AU)