Dose Of Adriamycin Research Articles

Effect of Terminalia arjuna extract on adriamycin‐induced DNA damage

The effect of a bark extract of Terminalia arjuna (TAE) was studied on the alteration of adriamycin (ADR)-induced micronuclei formation in cultured human peripheral blood lymphocytes. Exposure of lymphocytes to ADR resulted in a dose-dependent increase in the micronuclei formation indicating DNA damage. Pretreatment of lymphocytes with TAE before ADR treatment resulted in a significant decline in micronuclei formation. Increasing doses of ADR caused a dose-dependent increase in the frequency of lymphocytes bearing one, two and multiple micronuclei. Prior exposure of lymphocytes to 15 microg/mL of TAE significantly reduced the frequency of lymphocytes bearing one, two and multiple micronuclei when compared with ADR-treated control. TAE-inhibited the induction of (*)OH (hydroxyl), O2(*-) (superoxide), DPPH (1,1-diphenyl-2-picrylhydrazyl), ABTS(*+) (2,2-azino-bis-3-ethyl benzothiazoline-6-sulphonic acid) radicals in a dose-dependent manner. These results demonstrate that TAE protects DNA against ADR-induced damage.

IL-1-like production in adriamycin-induced nephrotic syndrome in the rat

Rats receiving a single dose of adriamycin (7.5 mg/kg) develop heavy proteinuria and morphological abnormalities similar to those observed in minimal change nephrotic syndrome in humans. A concomitance between enhanced I-a display by resident glomerular macrophages, IL-1-like cytokine secreted by whole isolated rat glomeruli and proteinuria was observed in adriamycin-injected rats during the experimental protocol. In addition, in vitro studies have shown that after stimulation with adriamycin or lipopolysaccharide (LPS) this cytokine is mainly produced by resident glomerular macrophages in culture. Although the precise mechanism of proteinuria in this model needs to be further studied, our results indicate that IL-1-like cytokine could be an important mediator implicated in the structural and functional disturbances occurring at the glomerular capillary wall level in adriamycin nephrosis.

Adriamycin produces a reproducible teratogenic model of gastrointestinal atresia in the mouse

Gastrointestinal atresia is a major cause of bowel obstruction in the newborn. Experimental models and clinical observations have demonstrated the heterogeneous nature of its pathogenesis. A proportion is due to late intra-uterine vascular insults and some are genetic in nature. Epidemiological studies have found gastrointestinal atresia to occur with other birth defects, in particular VACTERL anomalies, suggesting that a subset of cases may result from an early disturbance to intestinal morphogenesis. Adriamycin is teratogenic in rats, producing gastrointestinal atresia and VACTERL anomalies. The mouse is the foremost mammal studied by developmental biologists, offering an expanding wealth of knowledge and scientific research techniques. The aim of this study was to create an Adriamycin mouse model for investigating the development of gastrointestinal atresia. CBA/Ca mice were accurately time-mated (n = 30). Four different doses of Adriamycin (0-saline control, 4, 5 and 6 mg/kg) at three different timings of injections were compared (12 groups). Dams received two intraperitoneal injections, 24 h apart, commencing on day 7, 7.5 or 8. Foetuses were harvested on day 18. Gastrointestinal atresia and VACTERL anomalies were examined using a dissecting microscope. Adriamycin produced type IIIa gastrointestinal atresia in six treatment groups. The effect of Adriamycin depended on the timing and dose of the injections. VACTERL anomalies were only found in four treatment groups, proposing overlapping critical embryological windows for these malformations. Gastrointestinal atresia can be induced by the teratogen Adriamycin, occurring with and without VACTERL anomalies. This produces a reproducible mouse model in which the molecular pathogenesis of gastrointestinal atresia may be studied.

Chemotherapie des nicht-endemischen Burkitt-Lymphoms

14 patients (12 men, 2 women, mean age 26.3 [15-47] years) with histologically confirmed Burkitt's lymphoma were subjected between 1984 and 1989 to chemotherapy originally developed for treating lymphomas in children. Treatment consisted of medium doses of methotrexate, cyclophosphamide, teniposide, cytarabine, adriamycin and prednisone, intrathecal administration of methotrexate and if necessary prophylactic or therapeutic irradiation of the cranium. Most of the patients (64%) were in advanced stages of the disease. The rate of complete remissions was 100%. Four patients (29%) had a recurrence. Side effects were leukopenia (WHO grade III and IV) in 71%, grade III anaemia in 43% and grade III-IV thrombopenia in 29% of the patients. Considerable mucositides in 5 of the 14 patients (36%), and in one case a tumour lysis syndrome with transient renal insufficiency were other therapy-induced side effects. These results suggest that this treatment course can be successful also in non-endemic Burkitt's lymphoma in adolescents and adults.

Immunohistochemical study of proteins linked to apoptosis in rat fetal kidney cells following prepregnancy adriamycin administration in the mother

Adriamycin is an antibiotic of the anthracycline group. In a previous study, we showed that administration of a single dose of adriamycin (i.p. injection, 5mg/kg body weight) 4 weeks before pregnancy in female Wistar rats induced histological changes in the fetal renal cells typical of apoptosis and also over-expression of heat shock proteins (HSP70). Using a similar experimental model, we have now examined renal cells in fetuses (gestation day 20) to investigate the pathways of the transduction signal of apoptosis in these cells that is induced by prepregnancy maternal administration of adriamycin. Immunolocalization of several proteins - p53, Bax, Apaf-1 and caspase 9 - which take part in the mitochondrial pathway of apoptosis and caspase 12, which takes part in the endoplasmic reticulum pathway of apoptosis, was determined. The results showed that adriamycin administered to the mother rat before pregnancy subsequently induced changes in fetal kidneys involving both the mitochondrial pathway of apoptosis, with increased labeling of the proteins p53, Bax, Apaf-1 and caspase 9, and the endoplasmic reticulum pathway of apoptosis, with increased labeling of caspase 12. Immunolabeling of these proteins was quantified using an image analysis program.

381: Echocardiography on neonates exposed to anthracycline therapy in utero for maternal cancer

UTERO FOR MATERNAL CANCER ELYCE CARDONICK, ANIQA USMANI, SADIA GHAFFAR, DENNIS WOOD, MARC LEVINE, Robert Wood Johnson University, OBGYN, Camden, New Jersey, Cooper University Hospital, OBGYN, Camden, New Jersey, Thomas Jefferson University, Philadelphia, Pennsylvania, Robert Wood Johnson University, pediatric cardiology, camden, New Jersey OBJECTIVE: To evaluate the cardiac function of neonates exposed to anthracyclines in utero. STUDY DESIGN: This was an observational study. Pregnant women diagnosed with cancer who underwent anthracycline based chemotherapy and delivered a liveborn infant after 24 weeks, were offered enrollment. Patients provided written consent to obtain doses and dates of chemotherapy treatment. Due to the known cardiotoxicity of anthracyclines in pediatric and adult populations, echocardiograms were offered to all newborns exposed as fetuses. Women chose to perform this echocardiogram locally or at the institution of the primary investigator. RESULTS: This is the largest report of echocardiograms performed in neonates exposed to chemotherapy in utero. Twenty one neonates participated. Women were treatment for Hodgkin’s Disease with ABVD (Adriamycin/BleomycinVincristine/Dacarbazine) for Hodgkin=s Disease (n 3), CHOP (Cyclophosphamide/ Adriamycin/Vincristine/Prednisone) for NonHodgkin=s Lymphoma (n 1), and Adriamycin/Cytoxan for breast cancer (n 17). There were no cases of exposure to epirubicin or idarubicin. Mean dosage of Adriamycin was 54.3mg/m2 / 10. Baseline fetal cardiac evaluation was normal prior to starting chemotherapy.Neonatal echocardiograms were performed at a mean age of 13 / 27months, with children ranging in age from 3 days of life to 9.75 years. LV dimensions, RV wall, IVS and LV posterior wall thickness measurements were within normal limits for age and BSA. Mean shortening fraction was 41 / 10%. (normal 33 / 3%). In all 21, AV and semilunar valves were normal. Great arteries were normal in 20/21, with one case of a small pulmonary artery fistula. Patent foramen ovale was noted in 6 cases, all in children less than 2.5 months of age. No additional structural or any functional heart defects were diagnosed in any of these children. CONCLUSION: Cardiac function appears to be preserved in neonates exposed to adriamycin chemotherapy in utero. Any toxicity effects on fetal myocytes were not evident in postnatal echocardiograms.

The Efficacy and Toxicity of the RAD Regimen (Revlimid®, Adriamycin®, Dexamethasone) in Relapsed and Refractory Multiple Myeloma - A Phase I/II Trial of “Deutsche Studiengruppe Multiples Myelom”.

Background: Lenalidomide (Revlimid®; Len) has important efficacy in relapsed/refractory multiple myeloma (MM), with or without dexamethasone (Dex). Addition of Adriamycin® might further enhance antimyeloma activity of Len and Dex in patients (pts) with relapsed/refractory MM. We report data from a multicentre dose-finding phase I/II trial involving the RAD regimen (Revlimid®, Adriamycin®, Dex).Methods: A modified Fibonacci design was chosen to enroll MM pts with measurable disease and <3 prior treatment lines. Pts were required to have adequate hematopoietic and organ function; prior Len treatment was an exclusion criterion. RAD was administered for 6 28-day cycles along with either aspirin® 100 mg/day or low-molecular-weight heparin for prophylaxis of venous thromboembolism (VTE). Phase I was a dose-escalating study with increasing doses of either Len (10–25 mg/day) or Adriamycin (4–9 mg/m2/day). Using pegfilgrastim support (G; 6 mg, day (d) 6), the maximum tolerated dose was not reached, even at the 5th dose level (DL; 5+G: Len 25 mg d1–21; Adriamycin 9 mg/m2 as a 24h infusion d1–4; and Dex 40 mg d1–4 and 17–20 of each 28-day cycle). This dose was next used in phase II.Results: 69 pts with a median age of 65 (range, 46–77) years were included in the study and received at least 3 cycles. Prior anti-myeloma treatments included prior autologous stem cell transplantation (72%), prior allogeneic SCT (12%), bortezomib (57%), and thalidomide (20%). Grades 3/4 neutropenia and thrombocytopenia occurred in 44% and 32% of pts, respectively. Incidence of VTE was 7.5%. No neuropathy was diagnosed de novo. Three patients prematurely discontinued the trial due to catheter-related septicemia, thrombosis of basilar artery, and prolonged pneumonia. Fifty pts evaluable for response assessment were divided into 2 groups: 20 pts from phase I, who received doses up to DL 5+G and 30 pts on DL 5+G from both phase I and II. Using the European Group for Blood and Marrow Transplantation criteria, overall response rate (ORR) for DL 1–4 was 60% including 5 pts (25%) with near complete response (nCR). ORR for 30 pts on DL 5+G was 87%, including 7 pts (23%) with immunofixation-negative CR and an additional 18 pts (60%) with nCR. Median overall time to progression was 40 (4 to 75+) weeks with a very short median time to response of 4 (3–28) weeks. Several pts were evaluable for cytogenetic analysis performed by FISH: 17/37 (46%) had 13 q deletion (del[13q]). Partial response (PR) or better was seen in 12/17 pts (71%) with del(13q). Chromosomal translocation (4;14) was present in 4/25 (16%) evaluable pts with 1 having progressive disease (PD) and 3 PR. Del(17p) involving the tumor suppressor gene p53 and being associated with a particular adverse prognosis was found in 6/31 pts (19%): PR was noted in 2 pts, while 2 pts each had stable disease and PD.Conclusion: RAD incorporating 25 mg of Len for 21 of 28 days demonstrated potential utility as a new combination regimen for heavily pre-treated myeloma pts. Toxicity was moderate and predictable. The efficacy of this regimen is considerable as a CR plus nCR rate of 83% was observed with DL 5+G. In addition, high responses were observed even in patients displaying high-risk cytogenetic abnormalities.

Dose Dense and Dose Intense ABVD (dd-di ABVD) in Advanced and Intermediate-Stage Hodgkin's Lymphoma (HL).

ABVD is still considered the standard therapy for HL being a good balance of efficacy and tolerability. Here we report the 3-yr results of a phase 2 study which explore the possibility to ameliorate the performance of this (g)old schedule. Modifications of the standard ABVD and strategy concepts :1.Each patient received a total of 6 cycles2.For advanced stage, Adriamycin (ADM) was escalated from 50 to 70 mg/m2 in the cycles 1,2,3,4.3.Intermediate stage patients (pts) were treated without the dose escalation of ADM.4.The cumulative doses of ADM were 380 (advanced-) and 300 mg/m2 (intermediate-stage).5.The inter-cycle period was shortened from 28 to 21 days for all 6 cycles; the 4 drugs were delivered at d 1 and 11 of each cycle.6.Primary G-CSF was given from d4 to d8, and from d14 to d18 of each cycle.7.The therapy program was driven by interim-FDG-PET. Normalisation of PET at the end of 2nd cycles was indicator of early complete response (CR), while the persistence of PET+ lesion(s) at the end of the 4th cycle was indicator of failure and consequently the treatment was shift to a salvage therapy8.Consolidation Radiotherapy was reserved only for bone lesions.From June 2004 to May 2006 fifty-eight pts were enrolled (Tab 1). On 20th August 2007 all patients have performed the interim-PET and 54/58 pts completed the treatment. Administered RDIs ranged between 1.10 to 1.44 (median 1.34) for DD-DI ABVD, and 1.18 to 1.34 (median 1.24) for DD ABVD. Hematologic toxicity was moderate and self-limiting with grade 3 or 4 neutropenia and anemia occuring in less than 20% of courses. Non-hematologic toxicity was generally mild to moderate. A limited number of G3-G4 reversible events determined the need for intervention (RBC's trasfusions) or hospitalisation (pulmonary infections, GI and respiratory tracts, and neurological effects).The majority of pts presented a mild to moderate palmar-plantar erythrodysesthesia. Early cardiac toxicity was very mild. 55/ 58 obtained the early CR (95%) and 54/ 54 the CR (100%); a 60-yr old man died of pneumonia a month after the end of the last cycle still being in CR while one-site relapse occurred in a 27-yr old girl at ten month from the end of therapy. All the other pts are alive and disease-free. (tab 2 and fig 1). DD-DI ABVD and DD ABVD are feasible, well tolerated and highly active in advanced and intermediate HL: at 3 years from the beginning of the study these schedules confirm to be a promising strategy for optimal long-term results.tab 1Presentation featuresN%GHSGNCItotal58100%N%N%advanced3662%5188%intermediate2238%712%male2136%age>45-yr610%bulky2136%stage IV1729%B symptoms3764%extranodal2035%ESR >50 mm3052%LDH ratio>12543%IPS>32035%N sites>34272%Tab 2Response and Survival DataNearly CRCRTRMRelapse3-yr EFS3-yr OS58 (100%)55 (95%)54/54 (100%)1 (2%)1 (2%)98%98%GHSGadvanced3635 (97%)33/33 (100%)100%97%intermediate2220 (91%)21/21 (100%)95%100%NCIadvanced5149 (96%)48/48 (100%)98%98%intermediate76 (86%)6/6 (100%)100%100%median f-up 17 mos [Display omitted]

Phyllanthus maderaspatensis, a dietary supplement for the amelioration of adriamycin-induced toxicity and oxidative stress in mice

The effect of ethanol extract of Phyllanthus maderaspatensis (PME), a popular south Indian dietary supplement, was studied for its chemoprotective property on adriamycin (ADR)-induced toxicity and oxidative stress in mice. Adriamycin toxicity was evaluated biochemically by measuring the serum concentration of lactate dehydrogenase (LDH) and creatinine phosphokinase (CPK). Genotoxicity was evaluated by measuring the frequency of micronucleated polychromatic erythrocytes (MNPCEs) in bone marrow cells. Oxidative stress in the heart tissue was estimated by measuring the glutathione (GSH) levels in the homogenate. The treatment of mice with different doses of PME (400 mg/kg and 600 mg/kg body weight, p.o.,) for 7 days before the administration of a single i.p. dose of ADR (15 mg/kg) exhibited significant protection in a dose-dependent manner. The results clearly indicate that PME has a protective effect against ADR-induced toxicity, as revealed by the decrease in the concentrations of LDH, CPK, and the frequency of MNPCEs. The increased levels of GSH are indicative of the antioxidant property of PME.

Adriamycin produces a reproducible teratogenic model of vertebral, anal, cardiovascular, tracheal, esophageal, renal, and limb anomalies in the mouse

Background/Purpose The Adriamycin rat model is an established model for vertebral, anal, cardiac, tracheal, esophageal, renal, and limb (VACTERL) anomalies and gastrointestinal atresias. Mice are the foremost mammal studied by developmental biologists, providing greater availability of molecular probes, antibodies, and transferable knowledge with transgenic studies. Only tracheoesophageal malformations have been previously described in the Adriamycin mouse model. The aim of this study was to carry out a dose-response analysis of the teratogenicity of Adriamycin in the mouse to determine the effect of the dose and timing of exposure in producing tracheoesophageal malformations and show if it causes other VACTERL anomalies. Methods CBA/Ca mice were accurately time mated (n = 30). Four different doses (0 [saline], 4, 5, and 6 mg/kg) of Adriamycin (EBEWE Pharma Ges.m.b.H. Nfg.KG, A-4866 Unterach, Austria) at 3 different timings of injections were compared. Dams received 2 intraperitoneal injections, 24 hours apart, commencing on day 7, 7.5, or 8. Fetuses were harvested on day 18. Anomalies were examined using a dissecting microscope and serial transverse sections. Results Administering Adriamycin at 6 mg/kg on days 7 and 8 had the most teratogenic effect, with 80% of fetuses having 3 or more VACTERL anomalies: anorectal malformation, 100%; tracheoesophageal malformation, 50%; right-sided aortic arch, 58.3%; bladder agenesis/bilateral hydronephrosis, 100%. Conclusion This study establishes a mouse model that should provide insights into the cellular and molecular mechanisms underlying VACTERL anomalies.

Pre-administration of docetaxel protects against adriamycin-induced cardiotoxicity

We have revealed in a pre-clinical study that the combination of adriamycin (ADR) and docetaxel (DOC) in which ADR was administered 12 h after DOC injection not only significantly reduced leukopenia and toxic death but also significantly increased the antitumor effect compared with the dosing schedule without an interval between each injection used commonly in clinical practice. The purpose of this study was to clarify in mice whether the toxic death caused by ADR was reduced by administering ADR after DOC injection when the doses and dosing-interval of ADR and DOC were changed. ADR alone or a combination of ADR and DOC (ADR/DOC group in which both drugs were administered simultaneously or DOC-ADR group in which ADR was administered after DOC injection) was administered every 7 days in mice. When dosing intervals (0-24 h) were changed, there were no differences in survival rate among the 6, 12, and 24-h interval groups, although these groups showed significantly higher survival rate compared with the ADR/DOC group. When the dose of ADR (2.5-15 mg/kg) was changed, the survival rate was higher in all the DOC-ADR groups than the ADR alone groups. When the dose of DOC (3.125-12.5 mg/kg) was changed, DOC caused a dose-dependent reduction in toxic death. Although there was no striking difference in adverse effects between the ADR alone and DOC-ADR groups, the DOC-ADR group showed markedly attenuated increases in CPK-MB activity compared with the ADR alone group. We conclude that pre-administration of DOC may protect against ADR-induced toxic death and cardiotoxicity.

Accuracy of Staging as a Predictor for Recurrence After Liver Transplantation for Hepatocellular Carcinoma

We read with interest the paper from Shah et al. regarding “Accuracy of staging as a predictor for recurrence after liver transplantation for hepatocellular carcinoma” published in Transplantation (1). We at the Liver Transplant Unit in Newcastle-upon-Tyne, United Kingdom, have carried out a similar analysis of patients transplanted for hepatocellular carcinoma (HCC) and end-stage liver disease between January 2000 and December 2005 in our unit. During the above period, 15 patients with HCC underwent liver transplantation. Thirteen patients were within the Milan criteria on preoperative imaging. Two patients had tumors that were outside the Milan criteria but considered to be within the extended UCSF criteria. All patients had imaging repeated at three monthly intervals while on the transplant waiting list. Ten patients received Adriamycin based neoadjuvant therapy (transarterial chemoembolization in nine, systemic chemotherapy in one) while on the waiting list. All patients received a single dose of Adriamycin intraoperatively during the anhepatic phase and systemic chemotherapy posttransplantation. At a median follow-up of 57 months, three patients had developed tumor recurrence after 8, 18, and 32 months respectively. Detailed analysis of the explanted livers revealed that preoperative imaging had understaged tumors in eight patients. Six patients were understaged in terms of number of lesions (more than three), one patient in terms of both size and number of lesions, and one patient had previously unidentified major vascular invasion. The accuracy of cross-sectional imaging in our study was hence 46.7%. One patient with recurrence had been transplanted for a tumor that was within the Milan criteria both on imaging and explant examination. All three patients with recurrence had Edmonton grade 3/4 tumors with microvascular invasion. We agree with Shah et al. that current imaging technology has several limitations in staging HCC in the context of cirrhosis. Better markers of disease progression are needed to refine patient selection and growth rate of the largest nodule as described by the authors appears to be a step in this direction. There is, however, an urgent need for the identification of more reliable tumor markers (genomic- or proteomic-based) that are predictive of high pathological grade and vascular invasiveness because these factors have been shown to correspond with disease recurrence and poor prognosis. Until such markers are available, cross-sectional imaging will remain but an imperfect guide to staging HCC for transplantation. Mettu S. Reddy Derek M. Manas Regional Liver Unit Freeman Hospital Newcastle-upon-Tyne, United Kingdom

In vitro effects of adriamycin: a dose–response study

The in vivo effects of adriamycin (ADR) on the mouse and rat embryos are well described in the literature. However, there is a lack of knowledge about the in vitro effects of ADR. The aim of this study was to investigate the effects of ADR on the developing mouse embryo and to identify a dose of ADR, which could be used for further studies of ADR effects in vitro. CD1 mouse embryos were collected at day 8.5 post conception. They were cultured in the presence of different doses of ADR (0, 125, 250, 375 and 500 microM). After 24 h, the culture was stopped and the embryos (n = 77) were scored morphologically using the Brown-Fabro scoring system and the mean score for each organ was calculated. Dose-response plots were generated and the effective dose 50 (ED50) for each organ was identified from the plots. The effects of ADR on the developing embryo were found to be dose related and there is a dose-response relationship in most of the plots. The dose-response plots were found to be parallel for some organs. A dose of 250 microM ADR was identified as the appropriate dose for further in vitro studies. The effects of ADR on the embryos were dose related and there is a dose-response relationship in most of the developing systems. The presence of parallel dose-response plots for some regions is suggestive of similar mechanism of action of ADR on these regions. A dose of 250 microM of ADR was identified for the first time in the literature and could be used for further studies of the effects of ADR on the mouse foregut in vitro.

The Role of Telomerase Activity and Telomere Length in Cellular Sensitivity to DNA Damaging Agents.

Dyskeratosis congenita (DC) is a premature aging syndrome characterized by progressive bone marrow failure, abnormal skin pigmentation and nail dystrophy. We have described an autosomal dominant form of DC (AD DC) in a large three-generation kindred that is due to a mutation in the gene encoding human telomerase RNA (hTR). While telomere shortening is a normal consequence of the aging process, DC patients display extremely short telomeres in many somatic cell types, including hematopoietic cells, and they often suffer from bone marrow failure. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative therapy for marrow failure in DC. However, HSCT in DC is generally poorly tolerated and associated with significant morbidity, perhaps as a consequence of increased sensitivity of dividing cells to cytotoxic agents during myeloablative therapy. To test this hypothesis, we characterized lymphocytes from various AD DC patients and age matched controls that had been placed in long term culture following in vitro exposure to irradiation (137Cs) and varying doses of Taxol, Adriamycin, and Etoposide. Cell proliferation and viability were quantified by direct visual counting on a hemocytometer, and flow cytometry was employed to assess apoptosis and cell surface expression of senescent markers. In addition to DC lymphocytes having a decreased proliferative capacity and higher basal apoptotic levels, an increased sensitivity to irradiation, Taxol, Adriamycin, and Etoposide was noted. These results suggest that telomere shortening may be an important factor in determining cellular tolerance to cytotoxic therapy and support the concept of reduced intensity HSCT regimens in both aged individuals and DC patients. Further studies have been initiated to determine whether reconstitution of telomere length in DC cells alters response to cytotoxic agents.

Radiation dose and long term risk of cardiac pathology following radiotherapy and anthracyclin for a childhood cancer

Purpose To determine the cardiac status in children 15 years (yrs) or more after a solid tumour treatment. Patients and Methods Of the 447 patients, 229 were fully studied and 218 were not. The following cardiac evaluation was proposed to all the 447 consecutive patients: (1) cardiac Doppler US by one of two expert cardiologists; (2) cardiac rhythm and conduction abnormalities including 24-h holter ECG; (3) 131I-mIBG myocardial scintigraphy; (4) serum brain natriuretic peptide levels at rest; (5) an exercise test with VO 2max measurement. The radiation dose delivered to 7 points in the heart was estimated for all patients who had received radiotherapy. Results Cardiac disorder was diagnosed in 89 evaluated patients (39%) including 24 heart failures and 65 other asymptomatic cardiac diseases. When adjusting on potential confounders, cardiac disorder and cardiac failure risks were respectively linear (ERR at 1 Gy: 26%) and linear-quadratic (ERR at 1 Gy: 19%) functions of the average radiation dose received to the heart. No interaction between cumulative dose of adriamycin and average radiation dose was evidenced for cardiac disorders, but the ERR/Gy of cardiac failure was higher for patients receiving less than 350 mg/m 2 of Adriamycin. Conclusion Long term heart pathologies are probably one of the major iatrogenic risks encored by patients who survived a childhood cancer. This study strongly emphasizes the need to limit the heart irradiation during radiotherapy, particularly, for patients who also received or were susceptible to later received adriamycin.

Tei index in adult patients submitted to adriamycin chemotherapy: failure to predict early systolic dysfunction

This study prospectively assessed whether Tei index is predictive of early systolic dysfunction in adults undergoing adriamycin treatment. Left ventricular ejection fraction (LVEF) was obtained by radionuclide ventriculography at baseline and after treatment. Tei index was evaluated by echocardiography at baseline, at an intermediary cycle and at the end of chemotherapy. Fifty-five predominantly female patients (91%) with breast cancer (80%) and without known cardiac disease were evaluated. After treatment (adriamycin dose of 304 +/- 47 mg/m(2)), systolic dysfunction (final LVEF < 50%) occurred in eight patients (14%). Baseline, intermediate or variation of Tei index were not accurate to predict early systolic dysfunction ("c" statistics < or = 0.60). Baseline Tei index > 0.39, for example, had a sensitivity of 75%, specificity of 55%, positive predictive value of 22% and negative predictive value of 93%. Tei index does not appear to be a useful tool for detection of early adriamycin cardiotoxicity in adults.

Adriamycin promotes macrophage dysfunction in mice

Impaired wound healing contributes to the morbidity and mortality associated with adriamycin chemotherapy. Macrophages are essential for tissue repair and loss of macrophage function leads to impaired wound healing. We recently showed that adriamycin is a potent inducer of thiol oxidation and cell injury in cultured macrophages (FASEB J. 19:1866–1868; 2005). Here we tested the hypothesis that adriamycin also promotes oxidative stress and macrophage dysfunction in vivo. We treated FVB mice twice a week either with low doses of adriamycin (4 mg/kg) or with the same volume of saline by tail vein injection for a total of 8 injections. Wound healing was significantly delayed in adriamycin-treated mice. The number of resident peritoneal macrophages was decreased by 30% and macrophage recruitment in response to thiogycolate stimulation was decreased by 46% in mice treated with adriamycin. LPS-induced TNFα and IL-1β secretion from macrophages of adriamycin-treated mice was decreased by 28.7 and 29.5%, respectively, compared to macrophages isolated from saline-injected mice. Peritoneal macrophages isolated from adriamycin-treated mice also showed increased formation of reactive oxygen species and enhanced protein-S-glutathionylation. In summary, our results show that low cumulative doses of adriamycin are sufficient both to promote sustained thiol oxidative stress and macrophage dysfunction in vivo and to delay tissue repair, suggesting that macrophage dysfunction contributes to impaired wound healing associated with adriamycin chemotherapy.

Protective effect of lycopene on adriamycin-induced cardiotoxicity and nephrotoxicity

The aim of this study was to investigate the possible protective role of lycopene on adriamycin (ADR)-induced heart and kidney toxicity using biochemical and histopathological approaches. Rats were randomly divided into four groups. The first group received no medication and was regarded as the control group; the second group was injected with a single dose of ADR; the third group was treated with lycopene for 10 days before ADR injection and the last group was treated with lycopene for 2 days before and for 3 days after the administration of a single dose of ADR. ADR (10 mg/kg) was intraperitoneally (i.p.) injected as a single dose and lycopene (4 mg/kg) was administered in corn oil by gavage. The levels of malondialdehyde (MDA) and reduced glutathione (GSH) in both the heart and kidneys were higher in the group treated with ADR alone than in the control group, and were lower in the groups administered with lycopene than in the ADR alone group. Although the activity of catalase (CAT) in the heart was higher in the ADR alone group than in the control group, it was lower in the kidneys. In particular, treatment with lycopene post-injection normalized both cardiac and kidney CAT activities. In heart and kidney tissues, glutathione peroxidase (GSH-Px) activities were not significantly different between all groups. Significant increases in the levels of plasma creatinine and urea were observed in the ADR group when compared to the control group, and these increases were normalized by lycopene treatment. Cardiac and renal histopathological changes were observed in the ADR group as compared to the control group. In contrast, these histopathological changes appeared nearly normal in the groups treated with lycopene pre- and post-injection. In conclusion, this study clearly indicated that ADR treatment markedly impaired cardiac and renal function and that treatment with lycopene might prevent this toxicity in rats.

THE CLASSIC: Amputation and Adriamycin in Primary Osteosarcoma

THE CLASSIC: Amputation and Adriamycin in Primary Osteosarcoma

Modulation by Melatonin of the Cardiotoxic and Antitumor Activities of Adriamycin

In this study, we investigated the effects of melatonin on adriamycin-induced cardiotoxicity both in vivo in rats and in vitro, and on the antitumor activities of adriamycin on MDA-231 and NCI breast cancer cells. Rats that received a single intraperitoneal injection of 25 mg/kg adriamycin showed a mortality rate of 86%, which was reduced to 20% by melatonin treatment (10 mg/kg, SC for 6 days). Melatonin attenuated adriamycin-induced body-weight loss, hemodynamic dysfunction, and the morphologic and biochemical alterations caused by adriamycin. Melatonin also reduced adriamycin-induced nuclear DNA fragmentation, as assessed by the comet assay. In addition, the antitumor activity of adriamycin could be maintained using lower doses of this drug in combination with melatonin. Melatonin treatment in the concentration range of 0.1-2.5 mM inhibited the growth of human breast cancer cells. In terms of oncolytic activity, the combination of adriamycin and melatonin improved the antitumor activity of adriamycin, as indicated by an increase in the number of long-term survivors as well as decreases in body-weight losses resulting from adriamycin treatment. These results indicate that melatonin not only protects against adriamycin-induced cardiotoxicity but also enhances its antitumor activity. This combination of melatonin and adriamycin represents a potentially useful regimen for the treatment of human neoplasms because it allows the use of lower doses of adriamycin, thereby avoiding the toxic side effects associated with this drug.