2-Methoxyestradiol reverses doxorubicin resistance in human breast tumor xenograft

PURPOSE: 2-Methoxyestradiol (2ME), an endogenous estradiol metabolite, was developed as a novel agent based on its antitumor activity and lack of toxicity. This study was designed to investigate the modulatory effect of 2ME on the antitumor effect of doxorubicin (Dox) in resistant breast tumor xenograft. Resistant MCF-7/Dox cells were implanted subcutaneously in nude mice METHODS: Treatment with Dox 5 mg/kg, 2ME 30 mg/kg and their combination continued twice a week for 2 weeks. RESULTS: Following 28 days from starting the treatment with Dox alone, the change in tumor volume from first day of treatment was 455.6 +/- 16.2%. Combined Dox and 2ME treatment significantly reduced tumor volume to 20.8 +/- 43%. Also, combined therapy resulted in enhanced tumor apoptotic and reduced proliferative activities relative to Dox alone. The apoptotic indices were 0.13 +/- 0.03 and 0.75 +/- 0.06 in Dox alone and Dox + 2ME groups, respectively. For Dox alone group, expression of the proliferative markers PCNA and Ki(67) were 0.78 +/- 0.06 and 0.63 +/- 0.18, respectively. They were significantly reduced to 0.28 +/- 0.1 and 0.12 +/- 0.1 for their corresponding combined Dox and 2ME group. Interaction analysis clearly indicated that 2ME synergies antitumor, apoptotic and anti-proliferative activity of Dox. Examining body weight, hepatic and cardiac histopathology of the different treatment groups revealed no significant signs of toxicity. CONCLUSION: These findings suggest that 2ME reverses Dox resistance, with benign side effects profile.     

国产长春瑞滨联合阿霉素治疗转移性乳腺癌的临床观察

目的：观察国产长春瑞滨（盖诺）联合阿霉素方案治疗转移性乳腺癌的临床疗效。方法：运用国产长春瑞滨（25mg/m^2 iv dl,5)加阿霉素（40mg/m^2iv dl)治疗转移性乳腺癌28例，结果：取得CR4例，PR13例，总有效率（CR＋PR）达60．7％；主要毒副反应为白细胞减少，发生率为92．8％，其中Ⅲ-Ⅳ度骨髓抑制占64．2％，结论：国产长春瑞滨加阿霉素方案对转移性乳腺癌疗效明确，血骨髓抑制明显。     

Alpha-tocopheryl succinate enhances doxorubicin-induced apoptosis in human gastric cancer cells via promotion of doxorubicin influx and suppression of doxorubicin efflux

Doxorubicin (DOXO), a chemotherapy drug, is widely used in clinic for treating a variety of cancers. However, the treatment eventfully fails due to drug resistance and toxicity. Therefore, a combination strategy is needed to increase efficacy and reduce toxicity of DOXO. alpha-tocopheryl succinate (α-TOS) exhibits anticancer actions in vitro and in vivo. Here, we reported that combination of DOXO+α-TOS cooperatively acted to induce apoptosis in SGC-7901 cells. α-TOS enhanced cellular level of DOXO via promotion of DOXO influx and suppression of DOXO efflux. DOXO induced MDR1 mRNA and protein expression and α-TOS inhibited this event, indicating that α-TOS suppressed DOXO efflux via inhibition of MDR1. Furthermore, combination of DOXO+α-TOS induced increased levels of Fas and Bax protein expression and cleavage of caspase-8 and caspase-9, suggesting that combination treatment induced Fas/caspase-8 and Bax mediated mitochondria dependent apoptosis. Taken together, our results demonstrated that α-TOS enhanced DOXO anticancer efficiency via promotion of DOXO influx and suppression of MDR-1 mediated DOXO efflux.     

沉默YAP逆转肺癌PC9细胞多柔比星耐药性及其机制研究

背景与目的：耐药性是导致肺癌患者化疗失败的主要原因。探讨YAP对人肺癌PC9细胞多柔比星耐药的逆转作用及其机制。方法：利用体外筛选方法从多柔比星敏感性肺癌细胞系PC9获得耐药细胞克隆,并检测YAP的表达水平;利用shRNA沉默细胞中YAP的表达,应用MTS法检测肿瘤细胞药物敏感性,流式细胞术检测细胞周期、凋亡及对Rh-123的吸收能力,蛋白[质]印迹法(Western blot)和实时定量聚合酶链式反应(quantitative real-time polymerase chain reaction,QRT-PCR)技术检测ABCB1、ABCC1、p53、Runx2、ITGB2和ErbB4的表达水平及丝氨酸/苏氨酸蛋白激酶(serine/threonine kinase,AKT)的磷酸化水平变化。结果：经体外诱导获得多柔比星耐药细胞克隆PC9/Adr,且YAP蛋白在其中高表达,利用shRNA得到不同YAP沉默程度的PC9/Adr。YAP沉默后,细胞生长速度降低,细胞对多柔比星的敏感性显著增加,细胞周期被阻滞在G0/G1期,多柔比星诱导的细胞凋亡增多,细胞吸收Rh-123也增多,并与YAP的沉默程度呈正相关。Western blot和QRT-PCR结果显示,YAP沉默后,ABCB1、ABCC1、Runx2、ITGB2和ErbB4蛋白表达下调,而p53的表达上调,AKT的磷酸化水平则下降。结论：YAP过表达与PC9/Adr的耐药性相关,沉默YAP可恢复PC9/Adr对多柔比星的敏感性。这一作用与调节耐药相关基因的表达、促进细胞凋亡有关。     

A dose-escalating pilot study of sterically stabilized, pegylated liposomal doxorubicin (Lipo-Dox) in patients with metastatic breast cancer

Doxorubicin is considered among the most active single agents used against advanced breast cancer. Recent advances in the design of liposomes as carriers of cytotoxic drugs have resulted in a new formulation of doxorubicin with improved pharmacokinetic and tumor-localizing properties. The objectives of this dose-escalating pilot study were to evaluate the efficacy and safety of the sterically stabilized, pegylated liposomal doxorubicin (Lipo-Dox) for the treatment of metastatic breast cancer. Lipo-Dox was given at the dosage of 45 mg/m² over 1 hr of intravenous infusion every 4 weeks initially and could be escalated up to a maximum of 60 mg/m². Response was assessable in 17 of 19 intent-to-treat patients. An objective response was achieved in 41.2% (95% confidence interval: 17.8%-64.6%) of patients (5.9% complete response and 35.3% partial response), and 23.5% had stable disease. Median time to disease progression was 163 days. Major treatment-related toxicities included neutropenia, stomatitis, and skin toxicity in this dose-escalation program. Impressively, no grade 4 toxicities have ever been observed. The only grade 3 nonhematological toxicity ever to occur was reversible skin toxicity, presented as palmar-plantar erythrodysthesia. No severe nausea/vomiting, wig-necessary alopecia, or significant cardiac function change were encountered. In conclusion, Lipo-Dox is shown by this first reported pilot study to be an active agent for treatment of advanced breast cancer with a safety profile that differs markedly from free doxorubicin. The dosage of 45-60 mg/m² every 4 weeks was well tolerated. Because myelosuppression and other nonhematological toxicities associated with Lipo-Dox were generally mild and acceptable, further assessment of this drug particularly in combination with other chemotherapeutic drugs in the management of early or advanced breast cancer is suggested.     

多柔比星的耐药机制

多柔比星广泛应用于乳腺癌等肿瘤的化疗中,但因耐药使其应用受到一定限制。多柔比星耐药的产生机制可能涉及转运蛋白、凋亡蛋白、DNA修复功能、酶等因素。逆转多柔比星耐药的研究也在持续进行,为临床上克服多柔比星耐药提供了有效方案。但具体机制仍有待进一步阐释,并期待提出更合理的策略以提高疗效。     

Cremophor reduces paclitaxel penetration into bladder wall during intravesical treatment

Purpose: We have previously shown that paclitaxel, when dissolved in water and instilled into the bladder, readily penetrates the urothelium. The FDA-approved formulation uses Cremophor and ethanol to dissolve paclitaxel. In the present study, the effects of this solvent system on the urine, bladder tissue, and plasma pharmacokinetics of intravesical paclitaxel were evaluated. Methods: Plasma, urine, and tissue pharmacokinetics were determined in five dogs treated for 120 min with paclitaxel (500 μg per 20 ml of 0.22% w/v Cremophor and 0.21% v/v ethanol) by intravesical instillation. Equilibrium dialysis was used to determine the free fraction of paclitaxel and the presence of Cremophor micelles was verified using a fluorescent probe method. Results: The average bladder tissue concentration was >1600-fold higher than the plasma concentration. Comparison of the results for paclitaxel dissolved in Cremophor/ethanol with our previous results of paclitaxel dissolved in water (500 μg per 20 ml) indicates that Cremophor/ethanol decreased the paclitaxel partition across the urothelium and reduced the average bladder tissue concentration by 75%, but did not alter the rate of paclitaxel penetration across the bladder wall, the urine pharmacokinetics or the plasma pharmacokinetics of paclitaxel. For Cremophor, the urine concentrations during the 120-min treatment ranged from 0.12% to 0.22%, and the concentration in bladder tissue from 0.00004% to 0.0009%. The threshold Cremophor concentration for micelle formation was 0.008%. We found that ethanol at concentrations up to 1% and Cremophor at concentrations below 0.01% did not alter the free fraction of paclitaxel, whereas Cremophor at higher concentrations, i.e. 0.065% and 0.25%, significantly reduced the free fraction by two- to six-fold, respectively. These results indicate that during intravesical instillation of the FDA-approved paclitaxel formulation, the concentration of Cremophor in urine was sufficient to form micelles, resulting in sequestration of paclitaxel into micelles, reduction in the free fraction of paclitaxel and consequently a reduction in paclitaxel penetration across the urothelium. In contrast, the Cremophor concentrations in bladder tissue were inadequate to form micelles and thus did not alter the drug penetration through the bladder tissue. Conclusions: We conclude that intravesical paclitaxel treatment using the FDA-approved formulation provides a significant bladder tissue targeting advantage, although the advantage is lower than when paclitaxel is dissolved in water. Received: 1 October 1998 / Accepted: 12 January 1999     

A phase-III trial of doxorubicin and docetaxel versus doxorubicin and paclitaxel in metastatic breast cancer: results of the ERASME 3 study

PURPOSE: In first-line metastatic breast cancer, both paclitaxel (P)-doxorubicin (A) and docetaxel (D)-doxorubicin (A) combinations have shown superiority over treatments without taxane. The aim of this study was to compare the two combinations. PATIENTS AND METHODS: Chemotherapy-naive (except for adjuvant therapy) metastatic breast cancer patients were randomly assigned to intravenous AD (arm D) or AP (arm P) every 3 weeks for a maximum of four cycles, then four cycles of single agent docetaxel (arm D) or paclitaxel (arm P). Primary endpoint was overall quality of life (QoL) measured by EORTC QLQ-C30 after four courses of doxorubicin-taxane combination. Secondary endpoints were toxicity, overall survival (OS), progression-free survival (PFS), and QoL sub-scores. RESULTS: Between March 2000 and April 2004, 210 patients were randomized: 103 to arm P and 107 to arm D. Patient characteristics were well balanced between arms. After four courses, QoL score differences between groups or compared to baseline scores were not significant. Response rate was 39.6% for AD and 41.8% for AP. After a median follow-up of 50.2 months, median PFS and median OS were 8.7 and 21.4 months in arm D and 8.0 and 27.3 months in arm P (p = 0.977 and 0.081, respectively). Hematological toxicity was significantly more frequent in arm D than in arm P (p < 10(-6)), as well as grades 3-4 asthenia (p = 0.03). Neuropathy occurred more frequently in arm P (p = 0.03). CONCLUSION: In this study, paclitaxel or docetaxel combined with doxorubicin were not significantly different in terms of QoL scores and efficacy, but had different toxicity profiles.     

Pegylated liposome-encapsulated doxorubicin and cisplatin in the treatment of head and neck xenograft tumours

Purpose: To evaluate the in vitro and in vivo activity of unencapsulated doxorubicin (DOX) and cisplatin (CDDP) and their pegylated liposome encapsulated counterparts (PLED and PLEC) in a subcutaneous model of human squamous cell cancer of the head and neck. Methods: In vitro cytotoxicity was determined by means of the sulphorhodamine B assay and in vivo activity was assessed in terms of tumour growth delay following single intravenous doses of the various agents. Treatment-related toxicity was evaluated by means of serial weight measurement. Results: The IC₅₀ values for DOX (12.1-fold) and CDDP (21.5-fold) were lower than for their liposome-encapsulated counterparts. When the two unencapsulated agents were compared, the IC₅₀ value for DOX was 16-fold lower than that for CDDP. In the in vivo studies, liposomes containing DTPA (PLEDTPA) exerted no effect on KB xenograft tumours when compared to untreated controls (P > 0.1). PLED was significantly more effective than DOX at doses of 2 mg/kg, 4 mg/kg and 8 mg/kg (P < 0.001 for all comparisons). At the 8 mg/kg dose, 7/13 animals treated with PLED were free of disease at 60 days, compared to 0/12 treated with DOX. PLEC displayed superior activity in comparison to CDDP at the 4 mg/kg dose level (P < 0.001), although at doses of 2 mg/kg and 10 mg/kg this comparison only reached borderline statistical significance (0.1 > P > 0.05). The highest dose level of 20 mg/kg was fatal to all animals in the CDDP group but well-tolerated by the animals in the PLEC group. On the basis of serial weight measurements, both PLED and PLEC were shown to be tolerated better than DOX and CDDP. Conclusion: Both PLED and PLEC were shown to exert significant activity against head and neck xenograft tumours, with PLED showing particular efficacy. Received: 2 November 1999 / Accepted: 14 February 2000     

ANTISENSE RNA OF SURVIVIN ENHANCES THE SENSITIVITY OF PANCREATIC CANCER CELL LINE PANC-1TO DOXORUBICIN

The reduced expression of surviving gene by antisense Oligonucleotide may repress tumor cell growth, promote the sensitivity of tumor cells to chemotherapy and induce tumor cell apoptosis. In this study a surviving antisense eukaryotic vector pcDNA3-SV Vas prepared in previous study was delivered into PANC-1 by electroperforation to test the effects of surviving antisense RNA on doxorubicin- induced apoptosis in pancreatic cancer cell line PANC-1 in hope to find a new way for pancreas ca…     

Accelerator mass spectrometry allows for cellular quantification of doxorubicin at femtomolar concentrations

Accelerator mass spectrometry (AMS) is a highly sensitive analytical methodology used to quantify the content of radioisotopes, such as ¹⁴C, in a sample. The primary goals of this work were to demonstrate the utility of AMS in determining total cellular [¹⁴C]anthracycline concentrations following administration of doxorubicin (DOX) and to develop a sensitive assay that is superior to high performance liquid chromatography (HPLC) for the quantification of [¹⁴C]anthracycline at the tumor level. In order to validate the sensitivity of AMS versus HPLC with fluorescence detection, we performed three studies comparing the cellular accumulation of DOX: one in vitro cell line study, and two in vivo xenograft mouse studies. Using AMS, we quantified cellular [¹⁴C]anthracycline content up to 4 h following in vitro exposure at concentrations ranging from 0.2 pg/ml (345 fM) to 2 μg/ml (3.45 μM) [¹⁴C]DOX. The results of this study show that, compared to standard fluorescence-based HPLC, the AMS method was over five orders of magnitude more sensitive. Two in vivo studies compared the sensitivity of AMS to HPLC using a nude mouse xenograft model in which breast cancer cells were implanted subcutaneously. After sufficiently large tumors formed, [¹⁴C]DOX was administered intravenously at two dose levels. Additionally, we tested the AMS method in a nude mouse xenograft model of multidrug resistance (MDR) in which each mouse was implanted with both wild type and MDR+ cells on opposite flanks. The results of the second and third studies showed that [¹⁴C]anthracycline concentrations were significantly higher in the wild type tumors compared to the MDR+ tumors, consistent with the MDR model. Although this method does not discriminate between parent drug and metabolites, the extreme sensitivity of AMS should facilitate similar studies in humans to establish target site drug delivery and to potentially determine the optimal treatment dose and regimen.     

Effectiveness of Intravesical Doxorubicin Immediately Following Resection of Primary Non–muscle-invasive Bladder Cancer: A Propensity Score-matched Analysis

BackgroundThe purpose of this study was to investigate whether adding single immediate postoperative intravesical instillation of doxorubicin (SID) to transurethral resection of bladder tumor (TURBT) significantly reduced the risk of recurrence in patients with non–muscle-invasive bladder cancer (NMIBC).Materials and MethodsWe retrospectively analyzed the records of 720 patients diagnosed with primary NMIBC between 2002 through 2018 at the Kameda Medical Center. The primary outcome measure was time to recurrence. Time to progression was also compared. The cohort of SID and the cohort of TURBT alone were matched one-to-one by propensity scores. Matching was done by patient age, gender, and factors of the European Organization of Research and Treatment of Cancer recurrence risk table. The associations of adding SID and clinical outcomes were assessed with uni- and multivariate competing-risk regression models.ResultsAfter matching, a total of 364 patients, including 182 receiving SID and 182 receiving TURBT alone, were analyzed. No statistically significant differences existed among the measured baseline characteristics in propensity score-matched cohorts. In the multivariate analysis, there was a significantly longer time to recurrence in patients receiving SID (subdistribution hazard ratio, 0.68; 95% confidence interval, 0.49-0.95; P = .024) in propensity score-matched cohorts. There was no significant difference in time to progression (subdistribution hazard ratio, 0.61; 95% confidence interval, 0.11-3.49; P = .58) in univariate analysis.ConclusionsOur results demonstrated that SID significantly reduced the recurrence risk of primary NMIBC. Doxorubicin could be an inexpensive alternative to other evidenced-based chemotherapeutic agents for single immediate intravesical chemotherapy.     

The inactivation of doxorubicin by long ultraviolet light

Purpose: Irradiation of doxorubicin (DOX) dissolved in RPMI medium 1640 by long ultraviolet (UVA) light results in a rapid decline in the cytotoxic activity of the drug. The present study was designed to sort out which component(s) of this medium are associated with the UVA inactivation of DOX. Methods: The effects of UVA irradiation of DOX in solutions of various compositions were evaluated by measuring the changes in the drug growth inhibitory activity in P388 cells and in the DOX absorbance spectrum. Results: Riboflavin seemed to be the major photosensitizing component in the medium and the effect was enhanced by the presence of histidine, methionine, tryptophan and tyrosine but not by other amino acids. The changes in DOX resulting from UVA irradiation in the presence of riboflavin, were not blocked by 1,4-diazabicyclo [2.2.2]octane (5 mM ), superoxide dismutase (300 units/ml ), catalase (150 units/ml) or sodium benzoate (50 mM). The effects of UVA light on doxorubicin could be prevented by excess ascorbic acid. Conclusions: The effects of UVA on DOX are mediated by riboflavin. The photoexcited riboflavin apparently interacts directly with DOX rather than by first forming reactive oxygen species. The results suggest that the photoinactivation of DOX may involve an oxidation step. The mechanism by which certain amino acids facilitate the photoinactivation of DOX is not known. It is suggested that patient intake of riboflavin and exposure to the sun and fluorescent light could affect the outcome of anthracycline treatment. Received: 4 September 1996 / Accepted: 21 February 1997     

Photodynamic enhancement of doxorubicin cytotoxicity

Argon ion laser irradiation at 514.1 nm and 488 nm dramatically increased doxorubicin cytotoxicity in an L929 cell clonogenic survival assay. The cytotoxicity was dependent on both the drug concentration and the total light energy delivered such that at 5 g doxorubicin/ml and 800 J/cm², cytotoxicity was enhanced by a factor of>10⁴ relative to that achieved with drug alone. Irradiation times in excess of 2 min and power densities in excess of 100 J/cm² were required to produce the effect. Beyond this 2-min limit, cytotoxicity was not related to the duration of exposure if the total energy delivered was held constant. The ability of catalase and superoxide dismutase to abolish completely the increase in cytotoxicity produced by laser irradiation suggests that the cytotoxic mechanism may depend on the generation of active oxygen species by the photodynamically excited drug.     

The role of doxorubicin and epirubicin in the treatment of patients with metastatic hormone-refractory prostate cancer

Advanced hormone-refractory prostate cancer (HRPC) is characterized by prevalently osteoblastic bone metastases which are what mostly affect these patients’ quality of life and make the assessment of response to treatment particularly difficult by commonly used criteria. HRPC cannot be cured by any available therapeutic option, and chemotherapy has to be still considered as a palliative treatment. The anthracyclines doxorubicin (Dox) and epirubicin (Epi), alone or in combination with other agents, have been extensively used in the treatment of HRPC, but controversial results have been reported. The majority of reviewed studies reported a pain reduction in >50% of patients receiving Dox or Epi, suggesting a substantial palliative effect by their use in metastatic HRPC. The weekly schedule of anthracyclines seemed to achieve similar results to the 3-weekly schedule but with a better toxicity profile. Although the toxic adverse effects were usually manageable when anthracyclines were combined with other agents, toxicity was severe by a number of aggressive regimens. Docetaxel is today approved for the treatment of HRPC, and must be considered the standard platform on which new agents may be combined. Given that HRPC includes a heterogeneous group of patients with variable rates of tumour growth, the combination of docetaxel with active agents such as anthracyclines may deserve further clinical investigation.     

Role of DNA hypomethylation in the development of the resistance to doxorubicin in human MCF-7 breast adenocarcinoma cells

The resistance of cancer cells to chemotherapeutic agents is a major clinical problem and an important cause of treatment failure in cancer. Mechanisms that have developed to guard cancer cells against anti-cancer drugs are major barriers to successful anti-cancer therapy. Therefore, the identification of novel mechanisms of cellular resistance holds the promise of leading to better treatments for cancer patients. In the present study, we used human MCF-7 breast adenocarcinoma cell line and its doxorubicin-resistant variant MCF-7/R to determine the role of alterations of DNA methylation of chemoresitance-related genes, such as multidrug resistance 1 (MDR1), glutathione-S-transferase (GSTpi), O(6)-methylguanine DNA methyltransferase (MGMT), and urokinase (Upa), in the development of drug resistance. The promoter regions of MDR1, GSTpi, MGMT, and Upa genes were highly methylated in MCF-7 cell line but not in its MCF-7/R drug resistant variant. The hypomethylated status of MDR1 gene was associated with overexpression of P-glycoprotein. We hypothesize that acquirement of doxorubicin resistance of MCF-7 cells is associated with DNA hypomethylation of the promoter regions of the MDR1, GSTpi, MGMT, and Upa genes.     

Concurrent doxorubicin and radiotherapy for anaplastic thyroid cancer: A critical re-evaluation including uniform pathologic review

Background and purpose

Anaplastic thyroid carcinoma (ATC) is a rare, aggressive malignancy. The potential for pathologic misclassification complicates interpretation of published data. One standard treatment option for locoregionally advanced disease is weekly low-dose doxorubicin with concurrent radiation therapy, and was previously developed at our institution. We evaluated our more recent experience with this approach, which included pathologic confirmation of all cases.

Materials and methods

A retrospective review was performed on patients identified through the Memorial Sloan-Kettering Cancer Center (MSKCC) Cancer Database. Inclusion criteria: pathologically confirmed ATC; locoregional disease encompassable within a radiation portal; treatment with curative intent at MSKCC with planned weekly doxorubicin (10 mg/m²) and concurrent radiation. Principle outcomes assessed were locoregional progression-free survival (LR-PFS) and overall survival (OS).

Results

Thirty-seven patients were included. Median radiotherapy dose was 57.6 Gy, and was ?50 Gy in 29 (78%), administered through hyperfractionated or once-daily schedules. One-year outcomes were LR-PFS, 45%; OS, 28%.

Conclusion

The prognosis of patients with ATC remains grim and our current results appear inferior to those reported previously by our institution. More accurate histologic diagnoses and patient selection in the present series compared to the prior one may be responsible in part. Better therapy is desperately needed for this aggressive disease.     

Pharmacokinetics and metabolism of doxorubicin after short-term infusions in lymphoma patients

Purpose/Methods: Twenty-four patients (17 males and 7 females with a mean age of 54 years) with malignant lymphoma participated in a study of doxorubicin pharmacokinetics after 50 mg/m² as 10-min infusions. In addition to plasma samples, serial leukocyte samples and – in one subject – serial biopsy specimens from lymphoma infiltrates were obtained. The samples were analysed by reversed-phase high-performance liquid chromatography. Results: In contrast to several previous studies, the data suggested that 7-deoxydoxorubicinolone, and not doxorubicinone, is a metabolite of doxorubicin in humans. Doxorubicin, but no metabolites, was present in significant and fairly constant concentrations in circulating leukocytes. These levels may reflect the drug levels in lymphoma infiltrates. The data further suggest that metabolism to 7-deoxydoxorubicinone is subject to large interindividual variation, possibly due to a genetic polymorphism, and that significant levels of a metabolic product which may be a doxorubicin glucuronide can be recovered from plasma of patients treated with doxorubicin. Received: 30 November 1998 / Accepted: 16 March 1999     

Ifosfamide and doxorubicin in the treatment of advanced leiomyosarcoma

Leiomyosarcomas (LMS) are rare tumors with poor prognosis owing to the high rate of recurrent and metastatic disease. The combination of doxorubicin (Adriamycin) plus ifosfamide and mesna (AIM) results in moderate response rates of 10%-30%. The aim of this study was to assess the efficacy of the AIM regimen along with multimodality treatment including surgery and radiotherapy in patients with LMS. The clinicopathologic characteristics and outcomes of 51 patients with recurrent or metastatic LMS diagnosed between 2000 and 2014 who received the AIM regimen were analyzed retrospectively. Treatment consisted of ifosfamide 2500 mg/m² on days 1-3 (with mesna 2500 mg/m² days 1-3, 4-hour i.v. infusion), and doxorubicin 60 mg/m² on day 1 (2-hour i.v. infusion), which was repeated every 21 days. The mean age of the patients at diagnosis was 48.9 ± 11.2 years. A total of 42 patients were females (82.4%). The primary tumor site was the uterus in 30 (58.8%) patients. The most common metastatic sites were lung and liver. The median follow-up was 27.9 months (min: 4.3 max: 164.8). The median progression-free survival was 6.7 months (95% CI: 4.1-9.2). The median overall survival (OS) was 24.6 months (95% CI: 16.2-33.0). The overall response rate was 12% (6/51 pts). Response rates were higher in patients with uterine LMS (17%) compared with those with nonuterine LMS (5%); however, the OS times were similar. Surgical intervention for local or distant recurrence was associated with improved median OS (41 vs 16.6 months, P < 0.001). Myelosuppression was the major toxicity of this combination. In our study, the AIM regimen was effective in patients with LMS. Resection of local or distant recurrence was found to improve survival in our study.