Chemobrain in rats: Behavioral, morphological, oxidative and inflammatory effects of doxorubicin administration

PURPOSE We conducted a phase I/II trial of concurrently administered 72-hour infusional paclitaxel and doxorubicin in combination with granulocyte colony-stimulating factor (G-CSF) in patients with previously untreated metastatic breast cancer and bidimensionally measurable disease. PATIENTS AND METHODS We defined the maximum-tolerated dose (MTD) of concurrent paclitaxel and doxorubicin administration and then studied potential pharmacokinetic interactions between the two drugs. Forty-two patients who had not received prior chemotherapy for metastatic breast cancer received 296 total cycles of paclitaxel and doxorubicin with G-CSF. RESULTS The MTD was determined to be paclitaxel 180 mg/m2 and doxorubicin 60 mg/m2 each by 72-hour infusion with G-CSF. Diarrhea was the dose-limiting toxicity (DLT) of this combination, with three of three patients developing abdominal computed tomographic (CT) scan evidence of typhlitis (cecal thickening) at the dose level above the MTD. All patients developed grade 4 neutropenia (absolute neutrophil count [ANC] < 500 microL), generally less than 5 days in duration. This combination was generally safely administered at dose levels at or below the MTD. The overall response rate was 72% (28 of 39 patients; 95% confidence interval [CI], 55% to 85%), with 8% complete responses (CRs) (three of 39; 95% CI, 2% to 21%) and a median response duration of 9 months. The median overall survival time for all patients is 23 months, with a median follow-up duration of 28 months. Pharmacokinetic studies showed that administration of paclitaxel and doxorubicin together by 72-hour infusion did not affect the steady-state concentrations of either drug. CONCLUSION Concurrent 72-hour infusional paclitaxel and doxorubicin can be administered safely, but is associated with significant toxicity. The overall response rate of this combination in untreated metastatic breast cancer patients is similar to that achieved with other doxorubicin-based combination regimens. The modest complete response rate achieved suggests that this schedule of paclitaxel and doxorubicin administration does not produce significant additive or synergistic cytotoxicity against breast cancer.

Download Full-text

Influence of Fullerenol C60(OH)24 on Doxorubicin Induced Cardiotoxicity in Rats

Materials Science Forum ◽

10.4028/www.scientific.net/msf.518.525 ◽

2006 ◽

Vol 518 ◽

pp. 525-530 ◽

Cited By ~ 17

Author(s):

V. Djordjević-Milić ◽

A. Djordjević ◽

S. Dobrić ◽

Rade Injac ◽

D. Vučković ◽

...

Keyword(s):

Structural Damage ◽

Heart Function ◽

Treated Group ◽

Heart Tissue ◽

Cardiovascular Reflexes ◽

Control Group ◽

Heart Damage ◽

Cardioprotective Effects ◽

Doxorubicin Administration

Earlier investigation of fullerenol, C60(OH)24, features, in vitro, showed that fullerenol have strong antioxidative potential. In this work, we examined the influence of fullerenol as a potential antioxidative protector on doxorubicin induced cardiotoxicity in rats. Experiments were performed on adult Wistar rats, both gender. Animals were divided into six groups, each containing eight individuals. Doxorubicin was administrated i.v. (tail vein) in single dose of 8mg/kg. Fullerenol C60(OH)24 in treated animals was administrated i.p. (in doses 50, 100, 200 mg/kg) for 30 min. before application of doxorubicin. Control group (intact animals) was given saline (1 mL/kg). One group was treated only with fullerenol (100 mg/kg i.p.). Cardiotoxicity of doxorubicin as well as cardioprotective effects of fullerenol were evaluated following the heart function monitored by ECG recording during adrenalin i.v. infusion, and pathomorphological examination of the heart tissue. These evaluations were performed on the day 2 and 7 after doxorubicin administration. Both functional and pathomorphological investigations revealed no heart damage two days after given treatments. However, on the day 7 after doxorubicin injection, changes in cardiovascular reflexes to adrenalin as well as structural damage were manifest. The time for appearance of adrenalin-induced reflex bradicardia in ECG record was significantly longer in doxorubicin treated group in comparison with the control one. Also, pathomorphological examination of the heart tissue showed vacuolization of cardiomyocites. In fullerenol pretreated groups these described changes were ameliorated and corresponded to the control values. These results suggest that fullerenol might be potential cardioprotector in doxorubicin treated individuals.

Download Full-text