Hydroxyapatite beads containing Doxorubicin hydrochloride (dox) and buthionine sulfoximine (bso) - a new anticancer drug design for local treatment with multiple-drugs

Doxorubicin hydrochloride (DOX) and buthionine sulfoximine (BSO) were adsorbed on to a drug-carrier, hydroxyapatite (HAP), to form a DOX and BSO-HAP complex. The time-course of the release of these drugs from the complex into phosphate-buffered saline (PBS) was measured photometrically at 37-degrees-C in vitro. After 3 h of incubation, almost all the BSO in the DOX and BSO-HAP complex was released into the PBS, whereas 48.7% of the DOX was released during this period. DOX was released continuously over 10 h of incubation, the rate of release being 7.3%h of the total amount released. Both DOX and BSO were eluted from the DOX and BSO-HAP complex over the first 3 h of incubation. From the 4 h of incubation, only DOX was released, indicating a slow-release property of the complex. The DOX and BSO-HAP complex developed in this study may in future have an in vivo application. It is possible that intracellular glutathione could be depleted first by the rapidly released BSO and that DNA strand breaks could then be intensified by the slowly released DOX. Therefore, this complex has potential as a new drug delivery system (DDS) in cancer chemotherapy.     

Phase II study of pegylated liposomal doxorubicin (Caelyx) and docetaxel as first-line treatment in metastatic breast cancer.

BACKGROUND: The aim of this study was to determine the activity and safety of pegylated liposomal doxorubicin (PLD; Caelyx) and docetaxel combination as first-line treatment in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-four patients with a median age of 63 years were treated with PLD 30 mg/m(2) (day 1) and docetaxel 75 mg/m(2) (day 2) every 3 weeks for six cycles. Recombinant human Granulocyte Colony-Stimulating Factor (rhG-CSF) could be used in patients with grade > or =3 neutropenia after the first cycle. RESULTS: Forty-two of 44 patients were assessable for response. The response rate (RR) was 64.3% (95% confidence interval 49.8% to 78.8%). Six patients (14.3%) achieved complete response (complete disappearance of all measurable and assessable disease lasting at least 4 weeks, no new lesions, no disease-related symptoms), partial response was observed in 21 patients (50%) > or =50% decrease of measureable disease lasting at least 4 weeks, no progression of assessable disease, no new lesions, no disease-related symptoms), eight patients had stable disease and seven patients progressive disease. Median disease-free and overall survival were not reached, but were in excess of 17 months (range 6-17 months). Twenty of the patients had received previous adjuvant chemotherapy (10 with epirubicin-containing regimen with a median cumulative dose of 400 mg/m(2)). Grade > or =3 neutropenia occurred in 18.4% and neutropenic fever in 9% of patients. Palmar-plantar erythrodysesthesia was observed in four patients. Dose reduction was necessary in seven patients. Two patients discontinued treatment: one due to prolonged grade 3-4 neutropenia and one due to neurotoxicity. No treatment-related deaths occurred. CONCLUSIONS: The combination of PLD and docetaxel achieved high RRs with acceptable toxicity as first-line treatment in MBC.     

A new in vitro screening system for anticancer drugs for the treatment of non-small cell lung cancer

We have evaluated a semiautomated radiometric assay (BACTEC 460 system) for screening of activity of anticancer drugs against human non-small cell lung cancer cell lines. Cells from seven cell lines were exposed to standard antineoplastic agents at four different concentrations using a 1-h incubation. Alpha 2-interferon was tested using a continuous incubation. In vitro drug activity was analyzed as a function of the clinically achievable serum concentration. Our results indicate that two cell lines (CALU-3, SK-MES-1) exhibit in vitro drug sensitivity patterns closest to those observed in clinical studies. These two cell lines might therefore be most useful for screening new anticancer compounds for activity against non-small cell lung cancer. The radiometric assay is a semiautomated system which has advantages over other, more time-consuming screening systems.     

A fractal dimension analysis: a new method for evaluating the response of anticancer therapy

BACKGROUND: The therapeutic effects of various anticancer therapies on malignant tumors are evaluated as objective response (OR) by comparing the tumor size before and after the therapy However, it is difficult to evaluate the OR because malignant tumors frequently have very irregular or stellate shapes. In the present study we investigated a new method for evaluating the response of esophageal cancer to radio-chemotherapy using the fractal dimension (FD). PATIENTS AND METHODS: The changes in tumor size or shape during therapy were recorded in 6 patients with esophageal cancer by esophageal fluoroscopy. The OR was evaluated by WHO standard criteria by calculating the tumor regression rate (TRR), while the FD was calculated by a standard compass-counting method. RESULTS: All 6 patients complained of dysphagia before therapy, but the food passage improved after therapy in all patients. The TRR after therapy ranged between -90% and 43.4%, and the OR was evaluated as no change (NC) in 5 patients and progressive disease (PD) in one patient. On the other hand, the RD gradually decreased in all 6 patients during the therapy. Furthermore, 5 patients underwent esophagectomy and the histological effect was evaluated as grade-2 response in two patients and grade-1 response in three patients. The decreases in the FD were 0.069 and 0.079 in grade-2 responses and 0.022-0.034 in grade-1 responses. By contrast, 4 NCs included 2 grade-2 responses and 2 grade-1 responses, and PD was evaluated as grade-1 response. These results suggested that the standard criteria for an OR could not accurately evaluate the therapeutic effect in some cases, and the changes in FD correlated with the improvement in the symptoms and histological effect more precisely than the TRR or the OR. CONCLUSION: The FD represented the therapeutic effect of radio-chemotherapy well for esophageal cancer, and may be widely applied for evaluating the therapeutic effect of cancer therapy.     

A feasibility study of doxorubicin/cisplatin (AP) for postoperative chemotherapy in patients with advanced endometrial cancer

OBJECTIVE: We evaluated the feasibility of doxorubicin/cisplatin (AP) for postoperative chemotherapy in patients with advanced endometrial cancer. METHODS: Patients with newly diagnosed advanced endometrial cancer received AP (doxorubicin 60 mg/m(2), cisplatin 50 mg/m(2)) every 3 weeks. Treatment was continued until disease progression or completion of 6 courses. Toxicities were evaluated every cycle according to NCI-CTCAE Ver.3.0. RESULTS: Fifteen patients were enrolled from April 2004 through December 2005. All patients successfully completed therapy. There were two patients who needed dose reduction and nine patients with prolongation of treatment interval. Patients with over Grade 3/4 toxicity were observed to have leucopenia (47%), neutropenia (67%), anemia (26%), and vomiting (13%). No grade 3/4 cardiac and renal failure were observed. CONCLUSIONS: The doxorubicin/cisplatin (AP) regimen is tolerated and can be safely given without severe toxicity.     

Arterial oil chemoembolization: a new method of treatment for pancreatic cancer

A novel method of intra-arterial oily chemoembolization of pancreatic tumor has been developed. It slowed down regional blood flow in tumor dramatically due to injection of gemcitabin-in-oil. As a result, a prolonged contact of tumor with the highly-concentrated chemotherapeutic drug along the microcirculatory bed was assured. Enhanced antitumor effect, unaccompanied by any increase in systemic toxicity, was obtained by intensifying gemcitabin perfusion in the tissue. Tumor vessels had to be contrast-enhanced during the selective angiography of great vessels feeding the pancreas. Diagnostic angiography was performed in 63 patients with locally advanced tumors (T4NxMo) in 1999-2002. A total of 98 intra-arterial oily chemoembolizations (1-11 per patient) were carried out in 32 (51%). One or two-year survival rates in these patients after hemzar were 50 and 15%, respectively. Arterial oily chemoembolization is a safe and potentially effective method for the treatment of pancreatic cancer.     

Randomized parallel study of doxorubicin plus paclitaxel and doxorubicin plus cyclophosphamide as neoadjuvant treatment of patients with breast cancer.

PURPOSE: This randomized, noncomparative, parallel-group study was designed to evaluate the pathologic complete response (pCR) rate of combined doxorubicin plus paclitaxel (AP) and doxorubicin plus cyclophosphamide (AC) as neoadjuvant chemotherapy in patients with previously untreated breast cancer who were unsuitable for conservative surgery. PATIENTS AND METHODS: A total of 200 patients with T2-3, N0-1, M0 disease were randomly assigned in a 2:1 ratio to receive preoperative chemotherapy with either doxorubicin 60 mg/m(2) plus paclitaxel 200 mg/m(2) as a 3-hour infusion (AP) or doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) (AC) every 3 weeks for 4 courses followed by surgery. RESULTS: A pCR (eradication of invasive carcinoma in tumor and in axillary lymph nodes) was found in 16% and 10% of patients in the AP and AC arms, respectively, by study center pathologists, and in 8% and 6% of patients, respectively, by independent pathologists. Patients with pCRs tended to have unifocal disease, tumors with negative hormonal receptor status, and less differentiation (Scarff, Bloom, and Richardson scale grade 3). Breast-conserving surgery was performed in 58% and 45% of patients in the AP and AC arms, respectively. An objective clinical response was achieved in 89% of patients in the AP arm and 70% in the AC arm. At a median follow-up of 31 months, disease-free survival (DFS) was higher in patients who reached pCR versus those without pCR (91% v 70%). CONCLUSION: The encouraging pathologic and clinical responses of patients with breast cancer after neoadjuvant chemotherapy with doxorubicin plus paclitaxel warrant additional investigation of paclitaxel in the neoadjuvant setting of breast cancer management.     

A phase II study of DWA2114R, a new platinum complex for breast cancer]

A multi-institutional phase II study of DWA2114R was conducted in breast cancer. DWA2114R at doses of 800-1,000 mg/m2 was administered by 1-hour intravenous infusion every 3-4 weeks on minimal two cycles. Fifty-two patients entered the study; 34 were eligible, 7 ineligible. Eleven patients were dropped from evaluation due to incomplete observations. There were 1CR, 6PR, 1MR, 12 NC, and 14 PD with an overall response rate of 20.6%. A median duration of responses was 11 weeks. Leukopenia and nausea/vomiting were frequently observed but well tolerated and recovery was quick. It is concluded that DWA2114R is a useful drug in the treatment of breast cancer.     

Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer.

BACKGROUND: This study was designed to demonstrate that efficacy [progression-free survival (PFS)] of CAELYX [pegylated liposomal doxorubicin HCl (PLD)] is non-inferior to doxorubicin with significantly less cardiotoxicity in first-line treatment of women with metastatic breast cancer (MBC). PATIENTS AND METHODS: Women (n=509) with MBC and normal cardiac function were randomized to receive either PLD 50 mg/m2 (every 4 weeks) or doxorubicin 60 mg/m2 (every 3 weeks). Cardiac event rates were based on reductions in left ventricular ejection fraction as a function of cumulative anthracycline dose. RESULTS: PLD and doxorubicin were comparable with respect to PFS [6.9 versus 7.8 months, respectively; hazard ratio (HR)=1.00; 95% confidence interval (CI) 0.82-1.22]. Subgroup results were consistent. Overall risk of cardiotoxicity was significantly higher with doxorubicin than PLD (HR=3.16; 95%CI 1.58-6.31; P<0.001). Overall survival was similar (21 and 22 months for PLD and doxorubicin, respectively; HR=0.94; 95%CI 0.74-1.19). Alopecia (overall, 66% versus 20%; pronounced, 54% versus 7%), nausea (53% versus 37%), vomiting (31% versus 19%) and neutropenia (10% versus 4%) were more often associated with doxorubicin than PLD. Palmar-plantar erythrodysesthesia (48% versus 2%), stomatitis (22% versus 15%) and mucositis (23% versus 13%) were more often associated with PLD than doxorubicin. CONCLUSIONS: In first-line therapy for MBC, PLD provides comparable efficacy to doxorubicin, with significantly reduced cardiotoxicity, myelosuppression, vomiting and alopecia.     

A phase I study of liposomal doxorubicin (Doxil) with topotecan

New therapies are needed for patients with advanced ovarian cancer who relapse after initial treatment with platinum and/or paclitaxel-based regimens. This study sought to determine the toxicities of combined liposomal doxorubicin (Doxil) and topotecan, and to determine a regimen for future phase II testing in ovarian cancer. Nine patients with advanced malignancies were treated with topotecan 1.0 mg/m2/day X 5 days followed by liposomal doxorubicin at a starting dose of 30 mg/m2 on day 5. Cycles were repeated every 28 days. A total of 13 cycles of therapy were administered. Grade IV neutropenia and grade IV thrombocytopenia developed in both of the two patients treated at the first dose level. Subsequent patients received only 20 mg/m2 liposomal doxorubicin. At that dose level, three patients experienced dose-limiting toxicity (one grade IV neutropenia, two grade IV neutropenia and thrombocytopenia). No responses were observed. These data indicate that the described regimen of liposomal doxorubicin and topotecan is not feasible because of excessive hematologic toxicity. Escalation to doses of liposomal doxorubicin or topotecan that have previously demonstrated antitumor activity was not possible. Future strategies to minimize such toxicity may include limiting eligibility to patients with minimal prior therapy, reducing the number of days of topotecan administration, or use of oral topotecan.     

Phase II study of single-agent pegylated liposomal doxorubicin HCl (PLD) in metastatic breast cancer after first-line treatment failure

OBJECTIVES: Aim of this study was to evaluate the clinical benefit and the toxicity of pegylated liposomal doxorubicin. PATIENTS AND METHODS: Patients with metastatic breast cancer (n = 30) who failed a prior chemotherapy regimen for metastatic disease received 45 mg/m2 pegylated liposomal doxorubicin (PLD) every 4 weeks following prophylactic administration of metoclopramide (10 mg) and dexamethasone (8 mg). RESULTS: 29 of 30 patients were assessed for clinical benefit and time to progression. All patients were assessed for toxicity and analysis of overall survival. 9 patients (31%) had a partial response, and 16 patients (55%) responded with stable disease, resulting in a clinical benefit rate of 86% (n = 25). Median time to progression was 4 months (95% CI: 2.8-5.2), median duration of response was 7 months (95% CI: 4.7-8.2), and median survival was 12 months (95% CI: 6.7-17.2). Skin toxicity was the most common adverse event (30%, all < or = grade 2). Other toxicities were remarkably low in occurrence. CONCLUSION: PLD is a well-tolerated, second-line monotherapy with a high rate of clinical benefit.     

The significance of a combination of hepatic artery pump reservoir and new immunotherapy for cancer (NITC) in the treatment of colorectal liver metastasis

Infusion of anti-cancer agents through a hepatic artery pump reservoir has been reported as a relatively useful means of treating multiple liver metastases but its mechanism of action remains to be clarified. We thought that immune responses might be involved in the mechanism of action of this therapy and attempted to test this assumption in patients with colorectal liver metastases. When the patients were divided into two groups by survival period (the 24-week or longer survival group and the less than 24-week survival group), the 24-week or longer survival group had significantly higher Th1 cytokine levels (p<0.001-0.05) and significantly lower VEGF levels (p<0.01) than the less than 24-week survival group. The survival rate tended to be higher in patients for whom intra-arterial infusion therapy was combined with NITC. These results suggest that the combined therapy induces some kind of immune reaction closely related to tumor size reduction and prolonged patient survival. It seems necessary to compare immune activity during intra-arterial infusion therapy alone with activity during intra-arterial infusion treatment in combination with a new immunotherapy.     

组蛋白伴侣FACT复合物抑制剂CBL0137—卵巢癌治疗新方向

卵巢癌作为三大妇科恶性肿瘤之一，即使研究了很多治疗方法，其生存率也并不理想。虽然大部分患者可以在标准治疗中得到缓解，但最终都会出现复发和耐药。对于复发性卵巢癌患者来说，关键目标在于寻找更加前沿的治疗策略，以提高治愈率。CBL0137作为组蛋白伴侣分子FACT复合物的小分子抑制剂，可以直接调控FACT促染色质转录活性，下调NF-κB，激活p53，从而抑制了肿瘤的生长，并且在胰腺癌、肾癌、小细胞肺癌和神经胶质细胞瘤中证实了其抗肿瘤作用。本篇综述，总结了目前卵巢癌药物治疗方法，阐述了CBL0137在多种癌症中表现出的抗肿瘤活性以及过程中涉及的多个靶点的抗肿瘤机制，总结了在卵巢癌中相应靶点的表达情况及最新研究进展。最后对CBL0137在卵巢癌治疗中的潜力进行了总结和展望。     

Gemcitabine plus doxorubicin as first-line treatment in advanced or metastatic breast cancer (MBC), a phase II study

Introduction: Doxorubicin and Gemcitabine have promising antineoplastic activity and manageable toxicity as a single agent in the treatment of patients (pts) with advanced breast cancer. Aim of the Study: This study evaluated the efficacy and toxicity of the combination of gemcitabine plus doxorubicin as first-line treatment of advanced or MBC patients. Patients and Methods: Patients with advanced or MBC received gemcitabine 1250mg/m2 IV on days 1 and 8 plus doxorubicin 60mg/m2 IV on day 1 every 21 days for a maximum of 6 cycles. Results: Thirty-five patients were included, and all are evaluable for safety and efficacy. Median age was 47 years (range, 33 to 60 years). Fourteen patients (40%) were post-and 21 (60%) were premenopausal. Prior treatment included mastectomy (23pts); adjuvant nonanthracycline containing combination chemotherapy (18pts); adjuvant hormonal therapy (3pts) and 2 pts did not receive any adjuvant therapy. Twelve patients had metastatic disease at presentation. Seventeen pts were chemonaive. Hormonal receptors were positive in 6, negative in 21, and unknown in 8 pts. Site of metastasis included one site in 15 pts, two sites in 14, and three sites in 6 pts. Complete remission was observed in 6/35 (17.1%) and partial remission in 14/35 (40%) pts, for an overall response rate of 57.1%. Stable disease was observed in 8 (22.9%) and progressive disease in 7 (20%) pts. The median time to tumor progression was 7 months (range, 5-23 months; 95% CI, 6-8 months) and the median survival time was 16 months (range, 6-43 months; 95% CI, 13-19 months). The overall survival at 1 and 2 years was 74.2% and 34.2%; respectively; with 4/35 (11.4%) patients alive at 40 months. A total of 186 cycles of treatment were administered (range2-6 cycles, median 6 cycles). The doses of both doxorubicin and gemcitabine were modified after interim analysis of toxicity following the first 22 cycles administered to the first 10 patients [Mucositis grade 3-4 occurred in 6/10 (60%), grade 3-4 neutropenia in 3/10 (30%), and febrile neutropenia grade 3 in 2/10 (20%) patients] to doxorubicin 50mg/m2 on day 1 and gemcitabine to 1000 mg/m2 on days 1 and 8 in the remaining cycles. After doses reduction, the toxicity was generally tolerable. CONCLUSION: The combination of gemcitabine plus doxorubicin after doses modification can be safely administered every 21 days with promising response as first-line therapy for MBC. The response rate, time to disease progression and overall survival rates of this regimen are comparable to other standard therapies for MBC, as well as other gemcitabine combinations.     

Biweekly peglated liposomal doxorubicin/oxaliplatin for ovarian cancer resistant to taxane-platinum treatment: A Phase II study

Aim: The aim of this Phase II study was to evaluate the activity and safety of biweekly pegylated liposomal doxorubicin (PLD) and oxaliplatin (L-OHP) in patients with platinum-taxane resistant ovarian cancer. Materials and Methods : Treatment consisted of PLD (20 mg/m 2 ) on Day 1; and L-OHP (50 mg/m 2 ) administered on Days 1 and 2, every two weeks. Response to therapy was assessed using the Response Evaluation Criteria in Solid Tumors RECIST ; toxicity was evaluated by the National Cancer Institute Common Toxicity Criteria. Results: Forty patients pretreated with platinum/taxane chemotherapy, with a median age of 61 years, were recruited for the study. Thirty-eight patients were available for response evaluation: three complete responses and nine partial responses were registered; resulting in an overall response rate of 31.5%. Twenty-eight patients gained clinical benefit (73.7%) from this chemotherapy regimen. Median time to progression (TTP) and overall survival (OS) were 5.5 and 10 months respectively. The hematological and non-hematological toxicity profile was favorable. No Grade 4 toxicity was observed. Major toxicities included Grade 3 neutropenia (13.2%), Grade 2 palmar-plantar erythrodysesthesia (7.9%), and Grade 1-2 neuropathy in 15.8% of patients. Conclusion: Biweekly PLD and L-OHP combination has high activity, with less than anticipated adverse toxicity, for treatment of platinum-resistant ovarian cancer. A comparison of the doublet PLD/L-OHP with single-agent treatment is warranted.