Pretreatment with ICRF-187 provides long-lasting protection against chronic daunorubicin cardiotoxicity in rabbits

Summary The long-term protective effect of ICRF-187 against chronic daunorubicin cardiotoxicity was examined. Rabbits were given 3.2 mg daunorubicin/kg, with or without pretreatment with 25 mg ICRF-187/kg, once every 3 weeks over an 18-week period (6 doses). The experiment was terminated 3 months after the last treatment. At this time, all seven rabbits given daunorubicin alone had evidence of myocardial alterations ranging from minimal (2 animals) to mild (5 animals). Pretreatment with ICRF-187 caused a significant reduction in both the incidence and the severity of cardiac lesions. Hearts from the majority (5 of 7) of animals given the combination of ICRF-187 and daunorubicin were normal; myocardial alterations were minimal in the remaining rabbits treated with ICRF-187. In previous studies ICRF-187 was found to cause a reduction in cardiotoxicity 1–3 weeks after the final anthracycline dose. The results of the present study demonstrate that pretreatment with ICRF-187 provides prolonged protection against the cardiomyopathy, as opposed to producing only a delay in the appearance of cardiac alterations.     

ICRF-187 permits longer treatment with doxorubicin in women with breast cancer.

PURPOSE: To test potential protection by ICRF-187 against cumulative doxorubicin-dose-related cardiac toxicity, we conducted a randomized clinical trial in 150 women with advanced breast cancer. PATIENTS AND METHODS: Patients received fluorouracil (5FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days intravenously (IV) (control regimen, 74 patients), or the same regimen preceded by ICRF-187 1,000 mg/m2 IV (experimental regimen, 76 patients). RESULTS: We previously reported that ICRF-187 in this dose and schedule provides cardiac protection and does not substantially alter the noncardiac toxicity or antitumor efficacy of the control regimen. In this updated analysis of the entire patient cohort, we provide additional support for these findings and demonstrate that patients in the ICRF-187 group received more cycles (median, 11) and higher cumulative doses (median, 500 mg/m2) of doxorubicin than patients in the control group (median, nine cycles, P less than .01; and 441 mg/m2, P less than .05). Twenty-six patients in the ICRF-187 group received doxorubicin doses of at least 700 mg/m2, and among them, 11 patients received 1,000 mg/m2 or more. Only three patients in the control group received doxorubicin doses of 700 mg/m2; the maximum dose administered to one patient in this group was 950 mg/m2. ICRF-187 cardiac protection was demonstrated by difference in incidence of clinical congestive heart failure (CHF; two patients in the ICRF-187 group v 20 in the control group; P less than .0001) and by differences in resting left ventricular ejection fraction (LVEF) determined by multigated radionuclide (MUGA) scan from baselines and that required patient removal from study (five patients in the ICRF-187 group had a decrease in LVEF to less than 0.45 or a decrease from the baseline LVEF of 0.20 or more v 32 in the control group; P less than .000001). Among the 30 patients who had an assessable endomyocardial biopsy at cumulative doxorubicin 450 mg/m2, none of 16 in the ICRF-187 group and six of 14 in the control group had a score of 2 (P less than .05). ICRF-187 cardiac protection was observed in patients with and without prior chest-wall radiation or other risk factors for developing doxorubicin cardiac toxicity. CONCLUSION: By protecting against cumulative doxorubicin-induced cardiac toxicity, ICRF-187 permits significantly greater doses of doxorubicin to be administered to patients with greater safety.     

Comparative study of doxorubicin, mitoxantrone, and epirubicin in combination with ICRF-187 (ADR-529) in a chronic cardiotoxicity animal model.

In this study doxorubicin, epirubicin, and mitoxantrone were compared for their cardiotoxic potential in a chronic mouse model in an effort to identify and compare their mechanism(s) of toxicity. In addition, the cardioprotective ability of ICRF-187 [(+/-)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] with each anticancer drug was evaluated in this model. The antioxidant capacity (superoxide dismutase, reduced glutathione, catalase, and glutathione peroxidase) was assessed following drug treatment. Five-week-old BALB/c mice received weekly i.p. injections of each drug or the drug and ICRF-187 over a 3-month period. ICRF-187 was administered 30 min prior to the anticancer drug. The hearts were examined by electron and light microscopy to assess subcellular changes, and the cardiac and hepatic antioxidant levels were measured concurrently. Chronic treatment with these drugs or each combined with ICRF-187 did not change the antioxidant levels relative to the control values. However, all three drugs caused cardiac damage during chronic exposure. Both epirubicin and mitoxantrone caused less severe damage than doxorubicin, and epirubicin was the least cardiotoxic of the three. ICRF-187 was cardioprotective for epirubicin and doxorubicin but not for mitoxantrone. These results suggest epirubicin acts by a mechanism similar to that of doxorubicin that is probably mediated by oxygen-free radicals, while mitoxantrone acts by a different mechanism to cause cardiotoxicity.     

Modification of doxorubicin-induced cardiotoxicity: effect of essential fatty acids and ICRF-187 (dexrazoxane)

The capacity of an oil, containing gamma-linolenic acid (GLA), to reduce the severity of doxorubicin-induced cardiotoxicity has been investigated in a rat model. Groups of 12-week-old, male, Sprague–Dawley rats were injected intravenously (i.v.) with single doses (3 mg/kg body weight) of doxorubicin (DOX). Daily for 1 week prior to DOX administration and for up to 20 weeks afterwards groups of rats received either an oil containing both GLA and linoleic acid (So-1100, Scotia Pharmaceuticals), at two dose levels, or an oil containing linoleic acid, but no GLA (So-1129) by oral gavage. Other groups of rats received water as a control. One of the groups of rats that received water also received i.v. ICRF-187 (60 mg/kg) 15 min prior to DOX. A group of animals acted as age-matched controls. The maximum reduction in body weight in the first 2 weeks after the administration of DOX. was used as a measure of acute toxicity. This was most severe in the group receiving a combination of DOX and ICRF-187 (5.6±0.43%). Animals receiving 2 ml of either So-1100 or So-1129 were the least affected (≈2.5%). Measurements of cardiac volume output made at various intervals after DOX administration indicated a ≈35% reduction in cardiac function in the control and So-1129 oil group after 20 weeks. The corresponding reduction in the groups receiving ICRF-187 and 2 ml of So-1100 was ≈16%. The group receiving daily doses of 1 ml So-1100 showed an intermediate response. The death of an animal with signs of congestive cardiac failure occurred in 40% of the animals in the DOX only control (water) group. There were no deaths in the groups of rats receiving either ICRF-187 or pre- and post-administration of 2 ml of So-1100. It was concluded that an oil containing GLA (So-1100) has similar cardioprotective properties against DOX-induced cardiotoxicity as ICRF-187, but with less general toxicity in this rat model.     

Comparison of the protective effects against chronic doxorubicin cardiotoxicity and the rates of iron (III) displacement reactions of ICRF-187 and other bisdiketopiperazines

Histologic and biochemical studies were carried out to compare the protective activity of various bisdiketopiperazines against the cardiac and renal toxicity induced by doxorubicin in spontaneously hypertensive rats (SHR), a well-established animal model of this disorder, with: (1) the rates of hydrolysis of these agents to form the iron-chelating derivatives (which are considered to cause a decrease in the formation of reactive oxygen intermediates) and (2) the ability of these derivatives to bind iron. SHR were given 12 weekly injections of doxorubicin, 1 mg/kg i.v. either alone or 30 min after the administration of ICRF-154, ICRF-187, ICRF-192, ICRF-197, ICRF-198, ICRF-239 and ADR-559. Semiquantitative grading of the severity of the resulting cardiac and renal lesions showed that ICRF-187, ICRF-154 and ADR-559 were the most protective, whereas ICRF-197 and ICRF-239 provided intermediate degrees of protection, and ICRF-192 and ICRF-198 were not protective. Quantitative measurements in vitro revealed only relatively small differences in the rates of opening of the two diketopiperazine rings of the various agents to form the corresponding iron-chelating diacid diamide derivatives, and in the ability of these various derivatives to remove iron from the iron–doxorubicin complex. Such differences showed no relationship with cardioprotective activity. Some bisdiketopiperazines (including ICRF-154 and ICRF-187) with cardioprotective activity also are inhibitors of DNA topoisomerase II; however, the significance of this relationship remains uncertain, since ADR-925, the open-ring derivative of ICRF-187, does not inhibit DNA topoisomerase II. Received: 8 May 1996 / Accepted: 14 January 1997     

The protective activity of ICRF-187 against doxorubicin-induced cardiotoxicity in the rat

Summary The protective activity of the bisdioxopiperazine ICRF-187 against the cardiotoxicity of doxorubicin was evaluated in the rat using both functional and histological assays. Animals that had received a single i. v. dose of doxorubicin (4 mg/kg) alone were compared with those that had been pretreated with a single i. v. injection of saline or ICRF-187 (40 or 60 mg/kg). All rats showed a transient reduction in body weight during the first 3 weeks after drug administration. The greatest reduction (16%) was observed in animals that had received a combination of ICRF-187 (40 or 60 mg/kg) and doxorubicin. Deaths related to cardiotoxicity were observed only in rats that had received doxorubicin alone and in those treated with saline; most of the deaths occurred at between 8 and 13 weeks after drug administration. Sequential assessments of heart function showed a persistent depression of cardiac output in animals that had received doxorubicin, with or without pretreatment with ICRF-187. The reduction in cardiac output observed in rats that had been pretreated with ICRF-187 (40 or 60 mg/kg) amounted to 15% and 30% after 12 and 20 weeks, respectively, indicating that cardioprotection was only partial. Nevertheless, this represented a marked improvement as compared with the 35% reduction in cardiac output measured at 12 weeks in animals that had received doxorubicin but without pretreatment with ICRF-187. Histological examination of animals that had died during the course of the study and had received doxorubicin after pretreatment with saline revealed severe myocardial lesions typical of doxorubicin-induced damage. In contrast, animals that had been pretreated with ICRF-187 and survived for up to 20 weeks after treatment showed a marked amelioration of these lesions. The present findings may be interpreted as a true cardioprotection or a delay in the onset of the cardiotoxicity of doxorubicin resulting from pretreatment with the bisdioxopiperazine ICRF-187. Although prior and ongoing clinical trials clearly indicate that ICRF-187 protects patients well against doxorubicin-induced heart damage, further investigations are required beforehigh doses of ICRF-187 can be used as a means of increasing the protective activity of this drug against doxorubicin-induced cardiotoxicity.This work was supported by the Cancer Research Campaign     

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

Summary Addition of morpholinomethyl substitutents 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 [14] 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.     

Effect of pretreatment with ICRF-187 on the total cumulative dose of doxorubicin tolerated by beagle dogs

Studies were made of the influence of ICRF-187 on the functional and morphological effects of very large cumulative doses of doxorubicin given over a prolonged period of time. Adult beagles of either sex (6.2-11.6 kg) were given doxorubicin (1.75 mg/kg i.v.) either alone or 15 min after ICRF-187 (25 mg/kg, i.v.) at 3-week intervals. Control dogs received ICRF-187 (25 mg/kg, i.v.) or 0.9% saline without doxorubicin. Of eight animals receiving doxorubicin alone, five died; two after a total dose of 12.25 mg/kg and three after 14 mg/kg; three others were in poor condition at the time of euthanasia after 14 mg/kg. Of eight animals receiving both ICRF-187 and doxorubicin, four died; two after 35 mg/kg, one after 43.75 mg/kg, and one after 52.5 mg/kg; two other dogs were euthanized after 43.75 mg/kg because of difficulties encountered in giving i.v. injections, and two dogs survived a total dose of 52.5 mg/kg. All control dogs survived. None of the treatment or control groups developed consistent echocardiographic changes or alterations in mean arterial pressure. By 300 days after onset of treatment, dogs given ICRF-187 and doxorubicin developed significant prolongation of the PQ interval; by 550 days, surviving dogs in this group developed ventricular premature contractions. Each animal receiving doxorubicin alone had severe myocardial lesions (lesion score 3+). Of the animals given ICRF-187 and doxorubicin, one that received 35 mg/kg doxorubicin had no lesions; of four given 43.75 mg/kg, three had no lesions and one had minimal lesions (lesion score 1+); of three given 52.5 mg/kg, one had minimal (lesion score 1+), and two had moderate (lesion score 2+) lesions. Control animals had no myocardial lesions. Thus, ICRF-187 provided significant protection when administered with doxorubicin over a period of 90 weeks, and made it possible to give doses of doxorubicin which otherwise would have been lethal.     

Comparison of the effectiveness of (+/-)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187) and N-acetylcysteine in preventing chronic doxorubicin cardiotoxicity in beagles

This investigation examined the potential of N-acetylcysteine (NAC) and ICRF-187, alone and in combination, to protect against chronic doxorubicin cardiotoxicity. Adult beagles of either sex (7.3 to 12.5 kg) were given doxorubicin (1.75 mg/kg i.v.) either alone or 30 min after either ICRF-187 (25 mg/kg i.p.), NAC (200 mg/kg i.p.), or ICRF-187 (25 mg/kg i.p.) and NAC (200 mg/kg i.p.) at 3-week intervals. Control dogs received ICRF-187 (25 mg/kg i.p.), NAC (200 mg/kg i.p.), ICRF-187 (25 mg/kg i.p.) and NAC (200 mg/kg i.p.), or 0.9% NaCl solution without doxorubicin. The experiment was terminated 3 weeks after the seventh injection (total doxorubicin dose, 12.25 mg/kg). Three animals pretreated with NAC and one pretreated with ICRF-187 before receiving doxorubicin died or were in poor condition and were killed before the end of the study. The frequency and extent of myocardial lesions (vacuolization and myofibrillar loss) were assessed on a scale of 0 to 4+. Such lesions were present in all six dogs given doxorubicin alone and were marked to severe (3+ to 4+) in five of these dogs and moderate (2+) in one. Lesions of comparable severity (2+ to 4+) were also apparent in the hearts of dogs given the combination of NAC and doxorubicin. In contrast, no abnormalities (lesion score 0) were found in the hearts of three of six dogs given doxorubicin and ICRF-187 and in four of six dogs given doxorubicin following the combination of ICRF-187 and NAC; the remaining animals in these two groups had minimal lesions. At the dosage regimen used in the present experiments, doxorubicin, NAC, or ICRF-187 alone or in combination did not cause alterations in lungs, liver, kidney, or small intestine. Decreases in WBC count, RBC count, and hemoglobin occurred in dogs given doxorubicin with or without the various pretreatments. Thus, pretreatment with ICRF-187 was effective and pretreatment with NAC was ineffective in reducing chronic doxorubicin cardiotoxicity.     

Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin.

BACKGROUND: Although doxorubicin is an anticancer agent with a wide spectrum of activity, therapy with this anthracycline must often be discontinued at a time of benefit to the patient because of the drug's cumulative cardiotoxicity. ICRF-187 (ADR-529, dexrazoxane) is a bisdioxopiperazine compound that protects against cardiac toxicity induced by doxorubicin. PURPOSE: Our objectives in this study were to determine the maximum tolerated dose of ADR-529 (which uses a different vehicle than ICRF-187) when given with a fixed doxorubicin dose and to determine whether ADR-529 alters doxorubicin pharmacokinetics. METHODS: Twenty-five patients were treated with doxorubicin (60 mg/m2) preceded by administration of ADR-529 in escalating dosages (i.e., 60, 300, 600, 750, and 900 mg/m2) to groups of three to nine patients. ADR-529 was administered over a 15-minute period beginning 30 minutes before doxorubicin treatment; the protocol was repeated every 3 weeks. Blood was sampled frequently for drug levels, which were determined by high-pressure liquid chromatography with fluorescence (doxorubicin) and electrochemical detection (ADR-529). RESULTS: Dose-limiting neutropenia occurred in four of six previously treated patients at an ADR-529 dose of 600 mg/m2; the dose ratio of ADR-529 to doxorubicin was 10:1. For three additional patients with better Eastern Cooperative Oncology Group performance status and a maximum of one prior chemotherapy regimen, 600 mg/m2 was tolerated, but grade 3 or 4 neutropenia occurred in four of six patients who received an ADR-529 dose of 900 mg/m2 and in three of four patients at a dose of 750 mg/m2. Doxorubicin's estimated terminal half-life was 39.5 +/- 18.3 (mean +/- SD) hours; the area under the curve for plasma concentration of drug x time (AUC) was 1.74 +/- 0.40 (micrograms/microL) x hour. Total-body clearance was 598 +/- 142 microL/m2 per minute (N = 20), and it did not vary with ADR-529 dose. Estimated distribution and elimination phase half-lives for plasma ADR-529 were 0.46 +/- 0.30 hours and 4.16 +/- 2.94 hours, respectively. Total-body clearance was 111 +/- 87 microL/m2 per minute (N = 18); AUC was linear (r2 = .92), and the clearance rate was constant (r2 = .18) from 60 to 900 mg/m2. CONCLUSIONS: Myelotoxicity was dose limiting for ADR-529 at 600-750 mg/m2 when given with a fixed dose of doxorubicin at 60 mg/m2 (dose ratios of ADR-529 to doxorubicin ranged from 10:1 to 12.5:1). When used in combination, ADR-529 did not perturb doxorubicin's distribution, metabolism, or excretion; therefore, other mechanisms of cardioprotection must be involved. IMPLICATIONS: We recommend that an ADR-529 dose of 600 mg/m2 be given with single-agent doxorubicin at a dose of 60 mg/m2 in future studies.     

Prevention of chronic doxorubicin cardiotoxicity in beagles by liposomal encapsulation

Antitumor drugs such as doxorubicin have been encapsulated into liposomes as a means of enhancing activity and reducing toxicity. The present study was initiated to determine whether chronically administered liposome-encapsulated doxorubicin would be less toxic than the free drug. Doxorubicin was prepared in positively charged cardiolipin liposomes, and 1.75 mg/kg was given i.v. to each of five beagles. A second group received the free drug at 1.75 mg/kg. Additional animals received i.v. injections of either doxorubicin-free liposomes or 0.9% NaCl solution. All substances were given at 3-week intervals, and the experiment ended 1 week after the seventh injection (total dose, 12.25 mg/kg). A temporary reduction in food consumption was noted during the first few days after the administration of either form of doxorubicin. The effect was more severe in the dogs given free doxorubicin, and body weight decreased significantly only in this group of animals. Three dogs given free doxorubicin died or were killed before the end of the study because they were in poor condition. Lesions consisting mainly of vacuolization and myofibrillar loss were noted in the hearts of all five dogs given free doxorubicin. The severity of the lesions ranged from 2 to 4 (average, 3.4). In contrast, no abnormalities were found in any of the hearts from dogs given the liposomal doxorubicin. The most obvious general toxic effect caused by administration of free doxorubicin was alopecia, which was entirely prevented when doxorubicin was encapsulated into liposomes. At the dosage regimen utilized, liposomal doxorubicin and free doxorubicin exerted comparable degrees of bone marrow suppression. Thus, liposomal encapsulation of doxorubicin decreased cardiac and other toxic effects elicited by free doxorubicin. Whether this advantage can be translated into effective antineoplastic activity will need further evaluation.     

Exercise preconditioning provides long-term protection against early chronic doxorubicin cardiotoxicity

Acute doxorubicin (DOX) cardiotoxicity can be attenuated by exercise preconditioning, but little is known of whether this cardioprotection continues beyond 10 days post-DOX administration. The purpose of this study was to determine the effects of exercise preconditioning on early chronic DOX-induced cardiotoxicity. Male rats were randomly assigned to sedentary, treadmill, or wheel running groups. Treadmill and wheel running animals participated in a progressive treadmill training protocol or voluntary wheel running, respectively, for 10 weeks. Following the intervention, animals were further randomized to receive either DOX (sedentary + DOX, treadmill + DOX, wheel running + DOX) or saline (sedentary + saline, treadmill + saline, wheel running + saline). All animals then remained sedentary for 4 weeks. A 22% reduction in fractional shortening was observed in left ventricles from previously sedentary animals receiving DOX when compared with sedentary + saline. This degree of decline was not observed in treadmill + DOX and wheel running + DOX. Sedentary + DOX possessed significantly depressed mitral and aortic valve blood flow velocities when compared with sedentary + saline, but these decrements were not observed in treadmill + DOX and wheel running + DOX. Ex vivo analysis revealed that left ventricular developed pressure and maximal rate of pressure development were significantly lower in sedentary + DOX when compared to sedentary + saline. Treadmill and wheel running prior to DOX treatment protected against these decrements. Exercise cardioprotection was associated with preserved myosin heavy chain but not sarcoendoplasmic reticulum Ca(2+) ATPase 2a expression. In conclusion, 10 weeks of prior exercise protected against early chronic DOX cardiotoxicity suggesting that training status may be a determining factor in the degree of late-onset cardiotoxicity experienced by cancer patients undergoing treatment with DOX.     

Protective effects of fructose-1,6-diphosphate on acute and chronic doxorubicin cardiotoxicity in rats

Summary The effects of fructose-1,6-diphosphate, an intermediate metabolite of glycolysis, on acute and chronic cardiotoxicity of doxorubicin were investigated in rats. In the acute study, urethane-anaesthetized Wistar female rats treated with 10 mg/kg i.v. doxorubicin developed a widening of the ST segment, an impairment of +dP/dt_max, and tachycardia. Pretreatment with 375 and 750 mg/kg i.p. fructose-1,6-diphosphate prevented the ST segment from widening, whereas only 750 mg/kg i.p. significantly attenuated the heart rate increase. Chronic cardiomyopathy was induced over a 6-week period by wekly doses of 3 mg/kg i. v. doxorubicin, being characterized in vivo by the progressive enlargement of the ST segment and the occurrence of histological alterations and in vitro by a marked impairment of the inotropic response elicited by adrenaline in isolated hearts from treated rats. Concurrent treatment with 150 and 300 mg/kg i. p. fructose-1,6-diphosphate thrice a week for 6 weeks did not lessen the chronic heart damage, whereas 600 mg/kg given i. p. significantly reduced the widening of the ST segment and the severity of histological damage in vivo, as well as significantly improving the contractile responses of hearts in vitro. These findings suggest that the administration of fructose-1,6-diphosphate plays a protective role in the acute and chronic cardiotoxicity of doxorubicin in the rat.Supported in part by grants from the National Research Council (CNR), Rome, Italy: (1) target project Medicina Preventiva e Riabilitativa, grant 87.00253.56; (2) target project Oncologia, grant 87.01184.44     

Reducing doxorubicin cardiotoxicity in the rat using deferred treatment with ADR-529

Summary The purpose of this study was to evaluate the optimal timing of ADR-529 administration to protect rats treated with doxorubicin (DXR) against drug-induced cardiotoxicity. Complete electrocardiographic monitoring (QRS complex, ST segment and T wave) and the histopathological analysis of cardiac tissue were used to assess the degree of heart damage produced in female rats treated with ten i.v. doses of 1 mg/kg DXR over a period of 15 weeks; body-weight increase and survival were also analyzed to evaluate the toxicity of treatments. Cardiac alterations induced by DXR were compared with those occurring in animals receiving 20 mg/kg i.v. ADR-529 at 30 min prior to DXR administration, starting at the first, third, or sixth DXR dose and given until the end of the study (15th week). Rats treated with DXR were severely cardiomyopathic, showing progressive and irreversible ECG alterations (QRS-complex and ST-segment widening and T-wave flattening) and marked degeneration of the myocardium (myocyte vacuolation, myofibrillar loss, and endomyocardial fibrosis). The most effective cardiac protection was provided by the administration of ADR-529 beginning with the first or third DXR dose. Delaying treatment with ADR-529 until the sixth DXR dose resulted in a significant reduction in its therapeutic action on heart damage. A significant difference in body-weight increase and survival was observed between the treatment groups: ADR-529 injected prior to the first DXR dose significantly protected animals from DXR toxicity, but this schedule was significantly more toxic than the administration of ADR-529 beginning with the third or sixth DXR dose. Taking into account the degree of cardiac protection and the toxicity of combination treatments, the results of the present study demonstrate the superiority of ADR-529 given prior to the third DXR dose over the other schedules tested. This finding suggests that significant protection against DXR-induced chronic cardiotoxicity in the rat can be obtained using deferred treatment with ADR-529.Presented in part at the 81st Annual Meeting of the American Association for Cancer Research, Washington, D. C., May 23–26, 1990ADR-529 is the proprietary name (Farmitalia Carlo-Erba, Milano, Italy) for ICRF-187     

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.     

Early and delayed clinical cardiotoxicity of doxorubicin

Five hundred thirty-four evaluable patients with breast cancer were treated with a combination of 5-fluorouracil, doxorubicin, and cyclophosphamide. The total planned dose of doxorubicin was 300 mg/m2 in patients with Stage II or III disease, and 450 mg/m2 in patients with isolated recurrences. The median time interval from start of adjuvant therapy to time of analysis was 68 months. Two percent had congestive heart failure associated with doxorubicin. Fifteen patients showed myocardial dysfunction attributed to either additional treatment with potentially cardiotoxic drugs for recurrent disease or other causes. The incidence of congestive heart failure was 1% in patients treated with up to 300 mg/m2, and 4% in patients who received 450 mg/m2 of doxorubicin. The median time interval from the end of doxorubicin to development of congestive heart failure was 1 month (range, 0-33 months). None of the 326 patients who have been followed 3 or more years (162 followed 5 or more years) since completion of doxorubicin therapy have developed congestive heart failure which was considered to be related from that therapy.