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PubMed2003

Pharmacokinetics of doxorubicin administered i.v. as Myocet (TLC D-99; liposome-encapsulated doxorubicin citrate) compared with conventional doxorubicin when given in combination with cyclophosphamide in patients with metastatic breast cancer.

Myocet (TLC D-99) is a liposomal formulation of the anti-neoplastic drug doxorubicin with an improved therapeutic index compared with conventional doxorubicin. The objective of this study was to assess the plasma disposition of doxorubicin when administered i.v. as TLC D-99 and to compare this to conventional drug. Metabolite (doxorubicinol) plasma levels were also quantitated in both treatment groups. Plasma was collected during the first course of treatment from 10 patients receiving TLC D-99 60 mg/m and 10 receiving conventional doxorubicin 60 mg/m2, each with cyclophosphamide 600 mg/m2. Samples were assayed for total doxorubicin (all doxorubicin regardless of whether it is encapsulated or not), encapsulated doxorubicin (TLC D-99 group only) and doxorubicinol using high-performance liquid chromatography. Plasma concentrations of total doxorubicin were higher in patients receiving TLC D-99 than in patients receiving conventional doxorubicin. The clearance of total doxorubicin after administration of TLC D-99 was lower (approximately 9-fold) and the volume of distribution at steady state was less (25-fold) than that of doxorubicin after conventional drug. Doxorubicinol was detected in the plasma of all patients in both treatment groups. The mean AUC(0-infinity) of doxorubicinol for patients receiving TLC D-99 (1.5+/-0.4 M x h) was not statistically different than that in patients receiving conventional doxorubicin (1.8+/-0.4 M x h), although the appearance of the peak doxorubicinol concentration occurred later and was lower in patients receiving TLC D-99. There was a correlation between the plasma AUC(0-infinity) of total doxorubicin and the degree of myelosuppression in patients receiving conventional doxorubicin, but this correlation was not found in patients receiving TLC D-99.

Adult↗

PubMed1993

Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas.

PURPOSE: This three-armed phase III study in adults with advanced soft tissue sarcomas was planned as a comparison of objective regression rates, toxicity, and survival of patients receiving doxorubicin alone, ifosfamide plus doxorubicin, and mitomycin plus doxorubicin plus cisplatin. PATIENTS AND METHODS: Between December 1987 and July 1990, 279 patients with histologically confirmed sarcomas were enrolled to receive treatment A (doxorubicin 80 mg/m2), treatment B (ifosfamide 7.5 g/m2 plus doxorubicin 60 mg/m2), or treatment C (mitomycin 8 mg/m2 plus doxorubicin 40 mg/m2 plus cisplatin 60 mg/m2). RESULTS: Of 262 assessable patients, 74 (29%) achieved objective tumor regression. Objective regression occurred in 20% of the 90 patients who received doxorubicin alone (complete remission [CR] rate, 2%), in 34% of the 88 who received ifosfamide plus doxorubicin (CR rate, 3%), and in 32% of the 84 who received mitomycin plus doxorubicin plus cisplatin (CR rate, 7%). With grade 3 or greater myelosuppression in 53% of group A, 80% of group B, and 55% of group C, regimen B was significantly more myelosuppressive than either regimen A or C (P = .01) with two, three, and one treatment-related deaths, respectively. Synovial sarcomas were responsive to ifosfamide plus doxorubicin, especially among patients younger than 40 years of age. CONCLUSION: Ifosfamide plus doxorubicin produced a significantly higher regression rate (P = .03) than did doxorubicin alone; however, this was achieved at a level of myelosuppression significantly more intense than that produced by the single agent or by the three-drug combination. Mitomycin, doxorubicin, and cisplatin also appeared to be more active than the single agent; however, at a myelosuppression level similar to that of doxorubicin alone, this trend (P = .07) did not attain the usual level for significance. No significant survival differences were observed.

Adult↗

PubMed2006

Improved anti-tumor response rate with decreased cardiotoxicity of non-pegylated liposomal doxorubicin compared with conventional doxorubicin in first-line treatment of metastatic breast cancer in patients who had received prior adjuvant doxorubicin: results of a retrospective analysis.

Our objectives were to ascertain the safety (cardiotoxicity) and efficacy of non-pegylated liposomal doxorubicin [Myocet (M)] compared with conventional doxorubicin (A) in patients with metastatic breast cancer (MBC) who had received adjuvant anthracycline treatment and were at high risk of developing iatrogenic cardiomyopathy. This retrospective analysis is based on data pooled from two prospective phase III comparative randomized clinical trials comparing Myocet versus conventional doxorubicin in combination with cyclophosphamide and as single agents, respectively, for the treatment of MBC. The outcome measures reviewed in this analysis were overall response, time to treatment failure, time to disease progression, overall survival and cardiotoxicity. The analysis was carried out by strata according to patients' previous exposure to adjuvant anthracyclines. Kaplan-Meier, log-rank chi-test, Cox proportional-hazards and Cochran-Mantel-Haenszel statistics were used for the analysis. Sixty-eight patients were included in this analysis: 29 and 39 patients from Studies 1 and 2, respectively, had received adjuvant anthracycline treatment. Study 1, with n=297, compared M 60 mg/m (M60) plus cyclophosphamide (C) 600 mg/m (C600) versus A 60 mg/m (A60) plus C600 as first-line treatment for MBC. Twenty-nine patients had received prior adjuvant doxorubicin, of whom, after randomization, 14 received M60+C600 and 15 received A60+C600 for the treatment of MBC. Study 2, with n=224, compared M 75 mg/m (M75) with A 75 mg/m (A75) as first-line treatment for MBC disease. Thirty-nine patients had received prior adjuvant doxorubicin, of whom, after randomization, 18 received M75 and 21 received A75 for their MBC. Hence, 32 patients received M-containing regimens and 36 received A-containing regimens for the treatment of MBC. Median age in both groups was 54 years. The groups were well balanced in terms of demographic characteristics. Overall response rates were 31% and 11% for M-treated patients and A-treated patients, respectively (Cochran-Mantel-Haenszel P=0.04, odds ratio=4.0). Median time to progression was 4.5 versus 3.4 months [log-rank P=0.66, hazard ratio (HR)=1.14], median time to treatment failure was 4.2 versus 2.1 months (log-rank P=0.01, HR=2.06) and median survival time was 16 versus 15 months (log-rank P=0.71, HR=1.12). Cardiac events occurred in 22% of M-treated patients [one congestive heart failure (CHF)] versus 39% of A-treated patients (three CHFs) (log-rank, P=0.001). Median lifetime dose at onset of cardiotoxicity was 780 mg/m for M versus 580 mg/m for A (log-rank P=0.001, HR=4.8). This retrospective analysis shows that treatment based on non-pegylated liposomal doxorubicin (Myocet) significantly reduced the risk of cardiotoxicity in patients with MBC who had received prior adjuvant doxorubicin. Furthermore, anti-tumor activity and time to treatment failure were significantly improved compared with patients who received treatment based on conventional doxorubicin for their MBC. This analysis revisits the therapeutic option of including doxorubicin in the treatment of MBC patients who have had prior adjuvant anthracycline exposure.

Adult↗

PubMedDate not supplied

Comparison of three approaches to doxorubicin therapy: free doxorubicin, liposomal doxorubicin, and beta-glucuronidase-activated prodrug (HMR 1826).

BACKGROUND: Three approaches to doxorubicin therapy are directly compared: free doxorubicin, liposomal doxorubicin and beta-glucuronidase-activated prodrug (HMR 1826). MATERIALS AND METHODS: The optimal dose of HMR 1826 was determined to be 200 mg/kg once a week and subsequent studies were carried out comparing HMR 1826 at 200 mg/kg 1x/wk, liposomal doxorubicin (Doxil) at 9 mg/kg 1x/wk and free doxorubicin at 7 mg/kg 1x/wk in seven different human tumor xenograft models. RESULTS: All three forms of doxorubicin inhibited tumor growth with similar efficacy in each of the tumor models with the exception of MDA-MB-231 tumor xenografts, which were resistant to free doxorubicin but sensitive to Doxil and HMR 1826. Overall less weight loss was observed with HMR 1826 treatment. CONCLUSIONS: The efficacy of HMR 1826 is equal to or better than that of doxorubicin and Doxil at a safe dose and schedule, indicating that the beta-glucuronidase activated prodrug approach is safe and effective.

Animals↗

PubMed2003

Combined action of doxorubicin and gestagens on doxorubicin-sensitive and doxorubicin-resistant MCF-7 cells.

The combined cytostatic effect of doxorubicin and gestagens progesterone, medroxyprogesterone acetate, mecigestone, and butagest on doxorubicin-resistant and doxorubicin-sensitive human breast cancer MCF-7 cells was studied by the MTT assay. On the 6th day of incubation progesterone, medroxyprogesterone acetate, mecigestone, and butagest in high concentrations (10(-5) M) potentiated the cytostatic action of doxorubicin in sensitive and resistant cells by 30-50%. Potentiation of the cytostatic effect produced by doxorubicin in sensitive cells is related to intrinsic cytotoxic activity of gestagens. In resistant cells these changes are associated with potentiation of the effect of doxorubicin.

Antibiotics, Antineoplastic↗

PubMed2003

HPLC-MS/MS determination of a peptide conjugate prodrug of doxorubicin, and its active metabolites, leucine-doxorubicin and doxorubicin, in dog and rat plasma.

A HPLC-MS/MS Electrospray (ESI) method was developed and validated to quantify a peptide conjugate prodrug of doxorubicin (Dox-Con) and its active metabolites leucine-doxorubicin (Leu-Dox) and doxorubicin (Dox) in dog and rat plasma. The analytes were extracted from plasma by solid-phase extraction on a Bond Elut C8 cartridge and eluted with chloroform-methanol (2:1). Eluates were evaporated and reconstituted in acetonitrile-5 microM sodium trifluoroacetate in 0.1% aqueous formic acid (20:80) and injected onto a Waters Oasis HLB column. Analytes were eluted from the column with a solvent gradient into the mass analyzer. The ions were quantified in the selected reaction-monitoring mode (SRM), using positive ions, on a triple quadrupole mass spectrometer. The lower limits of quantification for Dox-Con, Leu-Dox, and Dox in plasma, were approximately 5, 1 (dog)/6 (rat), and 0.5 ng/ml, respectively. Intra- and inter-assay accuracy (% of nominal concentration) and precision (%CV) for all analytes were within 15 and 16%, respectively.

Animals↗

PubMed1989

Weekly doxorubicin versus doxorubicin every 3 weeks in cyclophosphamide, doxorubicin, and cisplatin chemotherapy for non-small cell lung cancer.

A prospective randomized study was done to determine the effect of different doxorubicin (Adriamycin [ADR], Adria Laboratories, Columbus, OH) administration (schedules every week versus every 3 weeks) on the productivity of a cyclophosphamide, ADR, cisplatin (CAP) chemotherapy regimen for patients with non-small cell lung cancer (NSCLC). Electrocardiograms, multigated cardiac scans, echocardiograms, and endomyocardial biopsies were done serially for cardiac monitoring. Of 102 patients, 47 ahd inoperable limited disease (LD), 47 had extensive disease (ED), and eight had no evidence of disease. In the last group chemotherapy was given adjuvantly. Fifty-one patients were entered into each treatment arm. The groups were formed according to extent of disease and were comparable in terms of patient characteristics. In these groups, the overall response rates using both schedules in LD patients were similar: in patients without chest irradiation previously, there was a response of 35% with ADR weekly, and 31% with ADR triweekly; in LD patients with chest irradiation previously, the response was 20% with ADR weekly, and 25% with ADR triweekly; and in ED patients, 16% with ADR weekly, and 11% with ADR triweekly. There was no significant difference in survival between the two treatment groups. However, results for all responders suggested a longer duration of response with weekly than with triweekly ADR (complete plus partial response: 35.8 versus 11.4 weeks, P = 0.06; minor response: 34 versus 11.5 weeks, P = 0.003, respectively). Results also suggested that weekly ADR was less cardiotoxic than triweekly ADR: 29% of patients in the former group had no changes or only minor changes in endomyocardial biopsy results, whereas all patients in the latter group had at least grade 0.5 changes at a similar dosage. The median doses of weekly ADR were higher at the same endomyocardial biopsy-defined toxicity levels. No correlation was found between toxic effects defined by endomyocardial biopsy results and those defined by noninvasive monitoring techniques, although the number of patients assessed was small. Weekly ADR produced less granulocytopenia and a lower incidence of fever (6% versus 16%, P less than 0.001) than did triweekly ADR. Alopecia, nausea, vomiting, and diarrhea were significantly less for weekly ADR than triweekly Adr (P less than 0.0005, less than 0.0005, and less than 0.005, respectively). These data suggest that weekly ADR can achieve the same therapeutic results as the standard triweekly regimen with less cardiotoxicity, myelotoxicity, alopecia, diarrhea, nausea, and vomiting in patients with NSCLC.

Adenocarcinoma↗

PubMed1986

Serum and tissue concentrations of doxorubicin after IV administration of doxorubicin or doxorubicin-DNA complex to patients with gastrointestinal cancer.

Blood and tissue concentrations of doxorubicin (DOX) were assayed after an intraoperative IV test dose of either free DOX 10 mg or its DNA complex 10 mg to patients with gastrointestinal cancer. After administration of the free drug, blood DOX levels decreased in an at least biphasic way, while DOX-DNA gave higher blood concentrations, which decreased slowly with no clear inflexion point on the concentration-time curve within the first hour. Tissue concentrations of DOX did not differ significantly after the two forms of the drug, liver being the tissue with the highest levels, followed by lymph node metastases, tumor tissue, muscle, and normal intestinal mucosa. If skeletal muscle can be used as a substitute for myocardium, lower cardiotoxicity of DOX-DNA than of DOX is not likely to be due to a difference in tissue uptake and retention between the two forms of DOX.

DNA↗

PubMed1988

Differential effect of the calmodulin inhibitor trifluoperazine in modulating cellular accumulation, retention and cytotoxicity of doxorubicin in progressively doxorubicin-resistant L1210 mouse leukemia cells. Lack of correlation between cellular doxorubicin levels and expression of resistance.

Calmodulin inhibitors are effective in enhancing cytotoxic effects of doxorubicin (DOX) in DOX-resistant cells, possibly by enhancing cellular levels of drug. In the present study, L1210 mouse leukemia cells adapted to grow in vitro, in the presence of 0.025 to 0.25 microgram/ml DOX, and identified as L1210/DOX0.025, L1210/DOX0.05, L1210/DOX0.1, and L1210/DOX0.25 were approximately 5-, 10-, 20-, and 40-fold DOX resistant, respectively, compared to parent-sensitive cells (L1210/S). Using a soft agar colony assay and 3-hr drug exposure, the IC50 concentration of DOX in the progressively DOX-resistant (5- to 40-fold) L1210 cells ranged from 0.25 to 2.0 micrograms/ml and from 0.08 to 0.25 microgram/ml in the absence and presence of a non-cytotoxic concentration of 5 microM trifluoperazine (TFP) respectively. Further, based on the observed in vitro cytotoxic response, the IC50 concentration of DOX in the presence of 5 microM TFP was 2.5-, 4-, 6.7- and 8-fold lower than DOX without 5 microM TFP in the L1210/DOX0.025, L1210/DOX0.05, L1210/DOX0.1, and L1210/DOX0.25 resistant sublines respectively. In contrast, the IC50 of DOX in L1210/S cells was approximately 0.05 microgram/ml with or without 5 microM TFP. Cellular accumulation of DOX was 15-50% lower in the progressively resistant L1210 sublines compared to similarly treated L1210/S cells. However, in the presence of 5 microM TFP, cellular accumulation of DOX in the L1210/DOX0.05 and L1210/DOX0.1 but not L1210/DOX0.25 was comparable to the L1210/S cells. Cellular retention of DOX in the absence or presence of 5 microM TFP was comparable in similarly treated L1210/S, L1210/DOX0.05 and L1210/DOX0.1 cells, and a 2-fold reduction in the retention of DOX in the absence versus the presence of 5 microM TFP was apparent only in L1210/DOX0.25 cells. At the IC50 of DOX in the presence of 5 microM TFP, although cellular accumulation of DOX was concentration dependent over the range of 1-20 microM TFP, enhancement in cytotoxicity of DOX was dose dependent at 1-5 microM TFP but not 5-20 microM TFP. In cells treated for 3 hr at the IC50 concentration of DOX alone or DOX plus 5 microM TFP, cellular accumulation of DOX was 7- to 14-fold and 2.5- to 3.5-fold higher, respectively, in resistant than in sensitive cells. Additionally, following treatment for 3 hr at the IC50 dose of DOX in the absence or presence of 5 microM TFP, drug retention at 3 hr was 4- to 6-fold and 1.5-fold higher, respectively, in the resistant versus sensitive cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1986

Comparative pharmacokinetics of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes.

The comparative pharmacokinetics of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes was evaluated in rats at a dose of 6 mg/kg i.v. Doxorubicin was entrapped in cardiolipin liposomes by using 11.2 mumol of drug, 5.6 mumol of cardiolipin, 28.5 mumol of phosphatidylcholine, 19.5 mumol of cholesterol, and 11.1 mumol of stearylamine. The peak plasma concentration with free doxorubicin at 5 min was 1.7 micrograms/ml which was reduced to 0.3 micrograms/ml by 1 h. With cardiolipin liposomes, the peak plasma concentration of doxorubicin achieved at 5 min was 20.9 micrograms/ml. The plasma levels of doxorubicin decreased gradually and by 1 h the drug concentration in plasma was 10 micrograms/ml. The plasma levels of free doxorubicin and doxorubicin entrapped in liposomes were fitted to a 3-compartment computer model. The terminal half-life with free doxorubicin in plasma was 17.3 h whereas it was 69.3 h with drug entrapped in liposomes. The area under the plasma concentration curve with liposomal doxorubicin was 81.4 micrograms X h X ml-1 compared to 1.95 micrograms X h X ml-1 observed with free doxorubicin. The steady state volume of distribution with free doxorubicin was about 23-fold higher than liposomal doxorubicin. The terminal half-life with free doxorubicin in cardiac tissue was 17.9 h compared to 12.6 h with drug encapsulated in liposomes. The terminal half-lives in liver and spleen following administration of liposomal doxorubicin were 15- and 2.3-fold higher, respectively, compared to free drug; furthermore, the concentration X time values of liposomal doxorubicin in liver were 26-fold higher and in spleen 6-fold higher than the free drug. Free doxorubicin and doxorubicin entrapped in liposomes demonstrated 17 and 20% excretion in bile of the injected dose, respectively, in rats. The present studies demonstrate that liposomal encapsulation of doxorubicin significantly alters its pharmacokinetics in plasma and tissues compared to free drug.

Animals↗

PubMed1993

Doxorubicin and doxorubicinol pharmacokinetics and tissue concentrations following bolus injection and continuous infusion of doxorubicin in the rabbit.

Cumulative dose-related, chronic cardiotoxicity is a serious clinical complication of anthracycline therapy. Clinical and animal studies have demonstrated that continuous infusion, compared to bolus injection of doxorubicin, decreases the risk of cardiotoxicity. Continuous infusion of doxorubicin may result in decreased cardiac tissue concentrations of anthracyclines, including the primary metabolite doxorubicinol, which may also be an important contributor to cardiotoxicity. In this study, doxorubicin and doxorubicinol plasma pharmacokinetics and tissue concentrations were compared in New Zealand white rabbits following intravenous administration of doxorubicin (5 mg.kg-1) by bolus and continuous infusion. Blood samples were obtained over a 72-h period after doxorubicin administration to determine plasma doxorubicin and doxorubicinol concentrations. Rabbits were killed 7 days after the completion of doxorubicin administration and tissue concentrations of doxorubicin and doxorubicinol in heart, kidney, liver, and skeletal muscle were measured. In further experiments, rabbits were killed 1 h after bolus injection of doxorubicin and at the completion of a 24-h doxorubicin infusion (anticipated times of maximum heart anthracycline concentrations) to compare cardiac concentrations of doxorubicin and doxorubicinol following both methods of administration. Peak plasma concentrations of doxorubicin (1739 +/- 265 vs 100 +/- 10 ng.ml-1) and doxorubicinol (78 +/- 3 vs 16 +/- 3 ng.ml-1) were significantly higher following bolus than infusion dosing. In addition, elimination half-life of doxorubicinol was increased following infusion. However, other plasma pharmacokinetic parameters for doxorubicin and doxorubicinol, including AUC infinity, were similar following both methods of doxorubicin administration. Peak left ventricular tissue concentrations of doxorubicin (16.92 +/- 0.9 vs 3.59 +/- 0.72 micrograms.g-1 tissue; P < 0.001) and doxorubicinol (0.24 +/- 0.02 vs 0.09 +/- 0.01 micrograms.g-1 tissue; P < 0.01) following bolus injection of doxorubicin were significantly higher than those following infusion administration. Tissue concentrations of parent drug and metabolite in bolus and infusion groups were similar 7 days after dosing. The results suggest that cardioprotection following doxorubicin infusion may be related to attenuation of the peak plasma or cardiac concentrations of doxorubicin and/or doxorubicinol.

Animals↗

PubMed1996

Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer.

PURPOSE: To determine whether a schedule-dependent interaction occurs when paclitaxel and doxorubicin are administered sequentially. PATIENTS AND METHODS: Ten patients with metastatic breast cancer received paclitaxel 125 mg/m2 over 24 hours either immediately before or after doxorubicin 48 mg/m2 over 48 hours as the initial chemotherapy treatment. Two such courses were given, and the sequence of administration was reversed after course 1. In cohort 1, paclitaxel preceded doxorubicin for course 1. In cohort 2, doxorubicin preceded paclitaxel for course 1. Doxorubicin levels were measured serially during the infusion and for 24 hours following it. Patients were assessed clinically for the occurrence of stomatitis and infection and granulocyte counts were measured twice weekly. RESULTS: Eight patients had complete pharmacokinetic sampling for both courses. The mean end-of-infusion plasma doxorubicin concentrations (Cmax) were 70% higher in the paclitaxel-doxorubicin sequence compared with the reverse sequence (45 +/- 8 ng/mL v 26 +/- 5 ng/ mL). The mean doxorubicin clearance was 32% lower in the paclitaxel-doxorubicin sequence (34.3 +/- 10.3 L/h v 51.6 +/- 16.1 L/h, P < .01). Clinically, hematologic and mucosal toxic effects were worse in the paclitaxel-doxorubicin sequence. The median absolute granulocyte count was 0.2/microL in the paclitaxel-doxorubicin sequence and 1.3/microL in the doxorubicin-paclitaxel sequence. Seven of 10 patients who received the paclitaxel-doxorubicin sequence had grade 2 (n = 4) or 3 (n = 3) stomatitis, while only one of 10 patients who received the doxorubicin-paclitaxel sequence had grade 2 stomatitis and none had grade 3. CONCLUSION: When paclitaxel by 24-hour infusion precedes doxorubicin by 48-hour infusion, doxorubicin clearance is reduced by nearly one third, which results in grade 2 and 3 stomatitis. To prevent this effect when paclitaxel (by 24-hour infusion) and doxorubicin are administered sequentially, doxorubicin should be given first. The mechanisms for this effect are under investigation.

Adult↗

PubMed2001

Differences in the intracellular distribution of acid-sensitive doxorubicin-protein conjugates in comparison to free and liposomal formulated doxorubicin as shown by confocal microscopy.

PURPOSE: To investigate differences in the cellular uptake and intracellular distribution of protein-bound doxorubicin in comparison to free doxorubicin and a liposomal formulation (CAELYX) METHODS: LXFL 529 lung carcinoma cells were incubated with an acid-sensitive transferrin and albumin conjugate of doxorubicin, a stable albumin doxorubicin conjugate, and free and liposomal doxorubicin for up to 24 h. The uptake of doxorubicin was detected with confocal laser scanning microscopy (CLSM). To investigate the intracellular localization of the anticancer drug, lysosomes, Golgi apparatus, and mitochondria were also stained by various organelle-specific fluorescent markers. In vitro efficacy of the doxorubicin derivatives was examined with the BrdU incorporation assay. RESULTS: The acid-sensitive albumin and transferrin doxorubicin conjugates showed enhanced cytotoxicity in comparison to liposomal doxorubicin, whereas the stable albumin-doxorubicin conjugate showed only marginal activity. Of all compounds tested, doxorubicin showed the highest cytotoxicity. CLSM studies with specific markers for lysosomes, mitochondria, and the Golgi apparatus demonstrated that protein-bound doxorubicin or liberated doxorubicin was accumulated in the mitochondria and Golgi compartments, but not in the lysosomes after 24 h. Free doxorubicin showed a time-dependent intracellular shift from the nucleus to the mitochondria and Golgi apparatus. Fluorescence resulting from incubation with CAELYX was primarily detected in the nucleus. CONCLUSIONS: Our results indicate that other organelles in addition to the cell nucleus are important sites of accumulation and interaction for protein-bound doxorubicin or intracellularly released doxorubicin as well as for free doxorubicin.

Antineoplastic Agents↗

PubMed1985

Similar changes in cardiac morphology and DNA synthesis induced by doxorubicin and 4'-epi-doxorubicin.

Doxorubicin is an antineoplastic agent whose clinical administration is limited by dose-dependent irreversible cardiomyopathy. Doxorubicin inhibits the rate of DNA synthesis in cultured rat myocardial cells after 1 h incubation with 16 microM, as is demonstrated by a decreased incorporation of [methyl-3H]thymidine. An analogue of doxorubicin, 4'-epi-doxorubicin, also inhibits the rate of DNA synthesis within 1 h after treatment with 16 microM, to the same extent as doxorubicin-treatment of myocardial cells. Furthermore, similarity between doxorubicin and 4'-epi-doxorubicin in their effect on the myocardial thymidylate pool was also demonstrated by a significantly decreased incorporation of total [methyl-3H]thymidine. The effect of doxorubicin on the rate of DNA synthesis in cultured rat skeletal muscle cells treated for 1 h with 16 microM was quantitatively the same as in myocardial cells. Light microscopy of doxorubicin- and 4'-epi-doxorubicin-treated myocardial cells and doxorubicin-treated skeletal muscle cells showed distinct nucleolar fragmentation and revealed no differences between the two drugs in their effect on either myocardial or skeletal muscle cells. Electron microscopy of myocardial cells following doxorubicin treatment showed increased nuclear pleomorphism and invaginations, along with a striking and distinctive clumping of nuclear chromatin. Furthermore, an apparent high density of the mitochondria due to an increased matrix volume and a concomitant decrease in the intermembrane compartment were observed. The results of this study indicate that doxorubicin-induced inhibition of cardiac DNA synthesis in cultured myocardial cells is nonpredictive of cardiotoxicity. The mechanism is at least bimodal, and the apparent minor toxicity of 4'-epi-doxorubicin compared with that of doxorubicin in clinical trials cannot be distinguished by a difference in the inhibition of DNA synthesis in the rat heart.

Animals↗

PubMed2004

The hepatic pharmacokinetics of doxorubicin and liposomal doxorubicin.

To determine the role of the hepatic sinusoidal endothelium in the hepatic disposition of liposomal doxorubicin, we compared the hepatic pharmacokinetics of doxorubicin hydrochloride and the pegylated, liposomal formulation of doxorubicin (Caelyx). The multiple indicator-dilution technique and electron microscopy were used to study the disposition of doxorubicin and liposomal doxorubicin in the rat liver. Doxorubicin had a volume of distribution 1.56 +/- 0.45 times greater than that of the extracellular marker, sucrose, whereas liposomal doxorubicin had a volume of distribution 0.56 +/- 0.30 times smaller than that of sucrose (P < 0.001). The recovery of doxorubicin was less than that of liposomal doxorubicin (70 +/- 24% versus 94 +/- 17%, P < 0.05). The disposition of liposomal doxorubicin was found to be flow-limited, whereas a permeability-limited sequestration model fitted doxorubicin. The transfer of doxorubicin across the hepatocyte membrane was symmetrical (permeability - surface area product for influx 0.02 +/- 0.01 ml s/g versus 0.03 +/- 0.02 ml s/g for efflux) and consistent with diffusion. Electron microscopy confirmed that liposomes were restricted entirely to the sinusoidal lumen and none were seen in the extracellular space of Disse. Liposomal doxorubicin is restricted to the sinusoidal lumen, presumably secondary to steric exclusion by fenestrations in the sinusoidal endothelium. This provides the mechanism for the longer half-life and reduced hepatic extraction of liposomal doxorubicin compared with doxorubicin. The sinusoidal endothelium and fenestrations within the sinusoidal endothelium have an important role in hepatic pharmacology and are important considerations when designing liposomal preparations.

Animals↗

PubMed1985

A randomized study of doxorubicin versus doxorubicin plus cisplatin in endocrine-unresponsive metastatic prostatic carcinoma.

Thirty-seven patients with hormonally refractory prostatic carcinoma entered a randomized trial comparing doxorubicin and doxorubicin plus cisplatin. All patients had failed prior hormonal treatment. Mean Karnofsky performance status (76% doxorubicin versus 75% combination), percent of patients with prior palliative irradiation (40% doxorubicin versus 35% combination), and hemoglobin levels of less than or equal to 12 g/dl (30% doxorubicin versus 24% combination) were roughly equivalent in the two treatment groups. More patients treated with doxorubicin than the combination treatment had an elevated acid phosphatase level at study entry (90% versus 65%). Measurable bidimensional tumors were present in 13 patients in 16 sites in the doxorubicin arm and in 10 patients in 11 sites in the combination arm. Partial responses were seen in 1 of 13 patients in the doxorubicin arm and 2 (20%) of 10 patients in the combination arm. Improvement in Karnofsky performance status of 20% or greater was rarely observed with either treatment (7% doxorubicin versus 8% combination). Acid phosphatase levels normalized or improved by 50% in 39% of patients who received doxorubicin and 27% of patients who received the combination. The overall response rate by National Prostatic Cancer Project Criteria was 53% for doxorubicin and 59% for doxorubicin plus cisplatin. Myelotoxicity and gastrointestinal toxicity were severe, particularly in the combination arm, and required discontinuation of treatment in some patients who responded to treatment. Moderate renal dysfunction (creatinine value 2.0-3.0 mg/dl) occurred only in the combination arm at an incidence of 23%. Time to progression and survival were similar for the two treatment groups. In this small group of 37 patients, the combination of cisplatin and doxorubicin showed no improvement over doxorubicin alone in response, response duration, or survival, and was difficult to administer in this patient population.

Adenocarcinoma↗

PubMed2002

Intravenous administration to rabbits of non-stealth and stealth doxorubicin-loaded solid lipid nanoparticles at increasing concentrations of stealth agent: pharmacokinetics and distribution of doxorubicin in brain and other tissues.

The pharmacokinetics and tissue distribution of doxorubicin incorporated in non-stealth solid lipid nanoparticles (SLN) and in stealth solid lipid nanoparticles (SSLN) (three formulations at increasing concentrations of stearic acid-PEG 2000 as stealth agent) after intravenous administration to conscious rabbits have been studied. The control was the commercial doxorubicin solution. The experiments lasted 6 h and blood samples were collected at fixed times after the injections. In all samples, the concentration of doxorubicin and doxorubicinol were determined. Doxorubicin AUC increased as a function of the amount of stealth agent present in the SLN. Doxorubicin was still present in the blood 6 h after the injection of SLN or SSLN, while no doxorubicin was detectable after the i.v. injection of doxorubicin solution. Tissue distribution of doxorubicin was determined 30 min, 2 and 6 h after the administration of the five formulations. Doxorubicin was present in the brain only after the SLN administration. The increase in the stealth agent affected the doxorubicin transported into the brain; 6 h after injection, doxorubicin was detectable in the brain only with the SSLN at the highest amount of stealth agent. In the other rabbit tissues (liver, lungs, spleeen, heart and kidneys) the amount of doxorubicin present was always lower after the injection of any of the four types of SLN than after the commercial solution. In particular, all SLN formulations significantly decreased heart and liver concentrations of doxorubicin.

Animals↗

PubMed2005

Proanthocyanidin from grape seeds enhances doxorubicin-induced antitumor effect and reverses drug resistance in doxorubicin-resistant K562/DOX cells.

With the aim of enhancing the efficacy of chemotherapeutic agents, we investigated the antitumor actions and reversal effect on drug resistance of proanthocyanidin plus doxorubicin. The results showed that proanthocyanidin 12.5-200 mg/L significantly inhibited proliferation of K562, K562/DOX, SPC-A-1, and Lewis cells in vitro in a time- and concentration-dependent manner, as determined by microculture tetrazolium assay. A combination of proanthocyani din 12.5, or 25 mg/L and doxorubicin treatment synergistically inhibited cell proliferation with decreased IC50 values. Proanthocyanidin reverses drug resistance in doxorubicin-resistant K562/DOX cells, and IC50 values were decreased by 9.19 (3.64-23.19), 2.56 (1.48-.44), and 0.94 (0.81-1.09) mg/L, respectively, after 24 h treatment with doxorubicin 0.1-9.0 mg/L alone or in combination with proanthocyanidin 12.5 or 25 mg/L; the proanthocyanidin reversal fold was 3.6 and 9.8, respectively. Under confocal laser scanning microscope, the combination of proanthocyanidin 25 or 50 mg/L with doxorubicin 3 mg/L significantly increased the accumulation of intracellular doxorubicin, Ca2+, and Mg2+, and reduced the pH value and mitochondrial membrane potential in K562/DOX cells as compared with doxorubicin alone (p < 0.01). Additionally, the apoptosis rate was increased by 11.3% +/- 3.3%, 14.2% +/- 5.4%, and 23.8% +/- 2.8%, respectively, for doxorubicin 3 mg/L alone or with proanthocyanidin 12.5 or 25 mg/L, as compared with controls (3.0% +/- 1.4%), as demonstrated by flow cytometry. In vivo experiments demonstrated that i.p. administration of proanthocyanidin 10 mg/kg with doxorubicin 2 mg/kg had an inhibitory effect on the growth of transplantation tumor sarcoma 180 and hepatoma 22 in mice as compared with doxorubicin alone (p < 0.05). These results suggest that proanthocyanidin enhances doxorubicin-induced antitumor effect and reverses drug resistance, and its mechanism is attributed partially to the promotion of doxorubicin-induced apoptosis through an elevation of intracellular doxorubicin, and Ca2+, Mg2+ concentration, and a reduction of pH value and mitochondrial membrane potential.

Animals↗