Cryptophycins: a novel class of potent antimitotic antitumor depsipeptides

The antitumor cryptophycins are synthetic derivatives of the desipeptide cryptophycins isolated from the cyanobacterium Nostoc sp. Cryptophycin 52 that is currently in clinical trial in solid tumors, is prepared by total synthesis of four key fragments that are coupled to form the final product. The mechanism of anticancer activity of the cryptophycins has been associated with their destabilization of microtubules and with their induction of bcl-2 phosphorylation leading to apoptosis. The cryptophycins maintain activity against ovarian and breast carcinoma cells that overexpress the multidrug resistance efflux pump P-glycoprotein. Cryptophycin 52 has demonstrated a broad range of antitumor activity against both murine and human tumors. In the human MX-1 breast carcinoma xenograft cryptophycin 55 produced greater-than- additive tumor response in combination with 5-fluorouracil. In human non-small cell lung carcinoma and human small cell carcinoma xenografts, administration of the cryptophycins along with gemcitabine, cisplatin or carboplatin resulted in antitumor activity greater than either agent alone. The cryptophycins appear to be additive with fractionated radiation therapy in the human H460 non-small cell lung carcinoma. In the human HCT116 colon carcinoma, the cryptophycins resulted in a greater than additive tumor response when administered sequentially with 5-fluorouracil or irinotecan. Treatment of animals bearing intraperitoneal human OVCAR-2 ovarian carcinoma with cryptophycin 52 resulted in survival times that were greater than those achieved with docetaxel or paclitaxel. Cryptophycin 52 is currently in early clinical testing.     

Antiangiogenic and antitumor effects of a protein kinase C beta inhibitor in human hepatocellular and gastric cancer xenografts

Hepatocellular carcinoma and gastric cancer are the most prevalent tumors worldwide. Hep3B hepatocellular carcinoma and HS746T gastric cancer were used as models for these diseases in culture and in vivo. The PKC beta inhibitor 317615.2HCl was not very cytotoxic toward HS746T or Hep3B cells in culture and was, in the main, additive in cytotoxicity with cisplatin, 5-fluorouracil and gemcitabine when cell in monolayer were exposed to these agents in combination with 317615.2HCl. Treatment of nude mice bearing HS746T or Hep3B xenografts with 317615.2HCl orally twice daily resulted in a small decreased in CD31-stainable intratumoral vessels in the HS746T tumors and 60% decrease in CD31-stainable vessels in the Hep3B tumors. Somewhat larger decreases were observed in the vessel stained with CD105. As a single agent 317615.2HCl produced tumor growth delays between 6.5 and 15 days in the HS746T xenograft and between 5 and 25 days in the Hep3B xenograft over the dosage range (3 to 30 mg/kg). Sequential and simultaneous combinations with 317615.2HCl and 5-fluorouracil and gemcitabine resulted in increases in tumor growth delay on both schedules. Gemcitabine produced a 15-day tumor growth delay of the HS746T gastric carcinoma that was increased to 40 days when combined simultaneously with 317615.2HCl and to 30 days with the sequential treatment regimen. 5-Fluorouracil produced a 9-day tumor growth delay of the Hep3B hepatocellular carcinoma that increased to 31 days by simultaneous treatment with 317615.2HCl and to 43 days with the sequential treatment regimen. Treatment with the protein kinase C beta inhibitor 317615.2HCl decreased HS746T and Hep3B angiogenesis and improved treatment outcome with 5-fluorouracil and gemcitabine.     

Evaluation of the mTOR inhibitor, everolimus, in combination with cytotoxic antitumor agents using human tumor models in vitro and in vivo

The aim was to determine the potential of the allosteric mammalian target of rapamycin inhibitor, everolimus, to act in combination with cytotoxic anticancer compounds in vitro and in vivo. A concomitant combination in vitro showed no evidence of antagonism, but enhanced the antiproliferative effects (additive to synergistic) with cisplatin, doxorubicin, 5-fluorouracil, gemcitabine, paclitaxel, and patupilone. Everolimus (1-5 mg/kg/d orally) was evaluated for antitumor activity in vivo alone or in combination with suboptimal cytotoxic doses using athymic nude mice bearing subcutaneous human H-596 lung, KB-31 cervical, or HCT-116 colon tumor xenografts. Everolimus monotherapy was very well tolerated and caused inhibition of tumor growth, rather than regression, and this was associated with a dose-dependent decline in tumor pS6 levels, a key downstream protein of mammalian target of rapamycin. At the doses used, the cytotoxics inhibited tumor growth and caused tolerable body-weight loss. Concomitant combinations of cisplatin, doxorubicin, paclitaxel, or patupilone with everolimus produced cooperative antitumor effects, in some cases producing regressions without clinically significant increases in toxicity. In contrast, combinations with gemcitabine and 5-fluorouracil were less well tolerated. Alternative administration schedules were tested for cisplatin, gemcitabine, or paclitaxel combined with everolimus: these did not dramatically affect cisplatin or gemcitabine activity or tolerability but were antagonistic for paclitaxel. Everolimus showed promising maintenance activity after treatment with doxorubicin or paclitaxel ceased. Overall, the results confirm that everolimus is an effective, well-tolerated suppressor of experimental human tumor growth, and although it did not show strong potentiation of efficacy, antitumor activity in vivo was increased without marked increases in toxicity, supporting clinical use of everolimus as a partner for conventional cytotoxics.     

Sequence-dependent cytotoxicity of combination chemotherapy using paclitaxel, carboplatin and bleomycin in human lung and ovarian cancer

Combination chemotherapy for non-small cell lung cancer (NSCLC) and ovarian cancer typically consists of a regimen of a taxane such as paclitaxel and a platinum-containing agent. Bleomycin, which halts cell cycle progression at G2 phase, is an agent which might thereby increase taxane cytotoxicity. The goal of this study was to evaluate the effect of different paclitaxel-platinum or paclitaxel-bleomycin schedules on cytotoxicity in human NSCLC and ovarian cancer cells. The simultaneous combination of paclitaxel and carboplatin exhibited simple additivity in vitro, while sequential exposure studies indicated that carboplatin followed by paclitaxel produced greater than additive cytotoxicity using the isobologram analysis of combinatorial effects. In contrast, the simultaneous combination of paclitaxel and bleomycin consistently exhibited greater than additive effects indicating a potentially synergistic combination. Sequential exposure studies of bleomycin followed by paclitaxel produced similar synergistic findings. Experiments in SCID mice evaluating the combinations of paclitaxel and bleomycin supported the in vitro results, as significantly enhanced A549 lung tumor growth inhibition was observed when paclitaxel was administered 1 h after bleomycin. The synergistic activity shown by the combination of bleomycin and paclitaxel indicates a potentially beneficial novel combination for treatment of NSCLC and ovarian cancer.     

Docetaxel (taxotere) in the treatment of non-small cell lung cancer

Docetaxel is a new semi-synthetic anticancer agent derived from bacatin III of the needles of the European yew Taxus baccata. Docetaxel has a novel mechanism of action since it binds to tubulin inducing its polymerization and promoting stable microtubule formation. Several differences exist between docetaxel and paclitaxel: (i) broader activity of docetaxel against freshly explanted human tumors than paclitaxel; (ii) a 2-fold higher affinity than paclitaxel; (iii) 2.5-fold more potent than paclitaxel as an inhibitor of cell replication and (iv) docetaxel acts at the S-phase whereas paclitaxel at the G(2)/M phases of the cell cycle. Preclinical and phase II studies revealed that docetaxel is active against NSCLC. In chemotherapy-na ve patients with NSCLC response rates ranged from 19% to 54% with a median duration of survival ranging from 6.3 months to 11 months, and 1-year survival ranging from 21% to 71%. Docetaxel as single agent provided a survival as well as a clinical benefit over BSC in untreated patients with NSCLC. Docetaxel has been efficiently combined with cisplatin (ORR 33%-46%), carboplatin (ORR 30%-48%), vinorelbine (ORR 20%-51%), gemcitabine (ORR 37%-47%), with a median survival ranging from 5-14 months. A preliminary analysis of a multicenter randomized trial comparing docetaxel/CDDP with docetaxel/gemcitabine revealed that the two regimens had comparable activity in terms, of response rates, duration of response, TTP and overall survival; however, the docetaxel/gemcitabine combination has a most favourable toxicity profile compared to docetaxel/CDDP. Docetaxel has also demonstrated radiosensitizing properties and encouraging results have been achieved in combination with irradiation. Finally, docetaxel has shown an important activity in previously-treated patients with NSCLC with ORR ranging from 16% to 25% with a median survival ranging from 7.2 months to 10.5 months. Randomized trials revealed that second-line docetaxel confers a survival benefit over either BSC or ifosfamide/vinorelbine in pretreated patients with NSCLC.     

Antitumor mechanisms of systemically administered epidermal growth factor receptor antisense oligonucleotides in combination with docetaxel in squamous cell carcinoma of the head and neck

Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common malignancies worldwide, with low 5-year survival rates. Current strategies that block epidermal growth factor receptor (EGFR) have limited effects when administered as single agents. Targeting EGFR via intratumoral administration of phosphorothioate-modified antisense oligonucleotides has antitumor efficacy in xenograft models of SCCHN. Because intratumoral delivery of therapeutic agents has limited clinical application, the present study was undertaken to examine the therapeutic mechanisms of systemically delivered phosphorothioate-modified EGFR antisense oligonucleotides alone, or in combination with docetaxel, in a SCCHN xenograft model. EGFR antisense oligonucleotides were administered at 5 mg/kg i.p. daily in athymic mice bearing 1483 human SCCHN xenografts alone or in combination with docetaxel at 2.5 mg/kg i.p. once a week for 4 weeks. Administration of EGFR antisense oligonucleotides in combination with docetaxel improved antitumor efficacy and resulted in lower expression levels of EGFR, fewer proliferating cells, and more apoptotic cells in the tumors compared with controls. Systemic administration of phosphorothioated EGFR antisense oligonucleotides for 30 days increased the retention of docetaxel in the tumor by approximately 4-fold compared with tumors treated with docetaxel alone or docetaxel and EGFR sense oligonucleotides (P < 0.05). Combination of EGFR antisense oligonucleotides with low doses of docetaxel has antitumor efficacy, and it may be an effective treatment strategy for SCCHN.     

Heterogeneity of chemosensitivity of metastatic cutaneous melanoma.

Advanced melanoma has a poor prognosis and chemotherapy provides little benefit for most patients. This may be related to heterogeneity of chemosensitivity as well as frequent constitutive resistance to individual cytotoxic drugs. We have therefore examined the heterogeneity of chemosensitivity in metastatic cutaneous melanoma specimens using an ex vivo ATP-based chemosensitivity assay (ATP-TCA). Melanoma deposits (n=55) in skin or lymph node were tested using the ATP-TCA, performed in three separate laboratories. Analysis of the data collected (based on an arbitrary sensitivity index < 300) shows considerable heterogeneity of chemosensitivity. The most active single cytotoxic agents in the assay were identified as cisplatin, treosulfan, paclitaxel, vinblastine, gemcitabine and mitoxantrone. There was also a limited direct inhibition of melanoma cell growth by interferon-alpha2b, although this agent is known to have a number of indirect biological antitumor effects. Exposure of tumor cells to combinations of drugs at the concentrations tested as single agents showed the most active combinations to be treosulfan+gemcitabine, cisplatin+paclitaxel and vinblastine+paclitaxel. There was considerable heterogeneity of chemosensitivity: some tumors responded well to one agent or combination, while others showed no response to this and instead responded to one of the alternatives tested. Occasional highly resistant tumors showed no response to any of the single agents or combinations tested. The degree of heterogeneity observed suggests that the ATP-TCA could be used to select patients who might benefit from specific chemotherapeutic agents alone or in combination. This provides the rationale for future randomized controlled trials of ATP-TCA-directed chemotherapy versus physician's choice to determine whether assay-directed chemotherapy can improve patient response and survival.     

姜黄素与阿霉素联合用药的体外抗肿瘤作用

目的　了解姜黄素与阿霉素联合应用对人白血病K5 6 2细胞及人肝癌Bel 740 2细胞的杀伤作用。方法　采用MTT法测定药物的体外杀伤作用 ,应用金氏公式进行联合用药分析。结果　姜黄素 2 0 4μmol·L-1～ 16 2 9μmol·L-1,阿霉素 0 70 μmol·L-1～ 5 5 2 μmol·L-1同时给药对K5 6 2细胞及Bel740 2细胞可产生单纯相加至增强的协同杀伤效果。序贯给药法中先给姜黄素后给阿霉素结果为协同作用 ,先给阿霉素后给姜黄素为拮抗作用。结论　姜黄素与阿霉素同时联合用药可产生协同作用 ,序贯联合用药产生单向协同作用。     

Therapeutic targeting of the endothelin-A receptor in human ovarian carcinoma: efficacy of cytotoxic agents is markedly enhanced by co-administration with atrasentan

The endothelin-1/endothelin-A receptor autocrine pathway is overexpressed in ovarian carcinoma. We explored the efficacy of atrasentan (ABT-627), a small orally active endothelin- A receptor antagonist, in monotherapy and combination therapy on HEY ovarian carcinoma xenografts. Atrasentan (2 mg/kg per 24 hours i.p. for 21 days) induced similar inhibition of tumor growth as paclitaxel (20 mg/kg i.v. three times a day every 4 days) with a reduction of 65% compared to control. The co-administration of atrasentan enhanced the efficacy of cytotoxic agents, such as taxanes or platinum compounds. Administration of atrasentan in combination with paclitaxel caused a strong antitumor effect. Remarkably, four of ten mice bearing HEY xenografts had no histological evidence of tumors. Tumor growth inhibition was accompanied by a significant decrease of molecular effectors involved in angiogenesis and invasion and by enhanced tumor cell apoptosis. Moreover, although cisplatinum as a single agent (5 mg/kg i.p. on day 1) markedly inhibited HEY tumors, atrasentan was very effective in potentiating this effect, with partial or complete tumor regression. The antitumor, anti-angiogenic, and apoptotic activities obtained with atrasentan and the enhanced efficacy of cytotoxic agents provide a rationale for its clinical evaluation in ovarian carcinoma.     

YM155, a novel survivin suppressant, enhances taxane-induced apoptosis and tumor regression in a human Calu 6 lung cancer xenograft model

Survivin, an apoptotic inhibitor, is overexpressed in the majority of human tumor types and represents a novel target for anticancer therapy. Taxanes induce a mitotic cell-cycle block through the inhibition of microtubule depolymerization, with subsequent elevated expression/stabilization of survivin. We investigated the administration of survivin suppressant YM155 monobromide (YM155), in combination with docetaxel, in a human non-small-cell lung cancer (NSCLC) xenograft model. Animals received a 7-day continuous infusion of YM155, 2 mg/kg, and/or three bolus doses of docetaxel, 20 mg/kg, according to three dosing schedules: YM155 administered concomitantly with docetaxel, before docetaxel, and after docetaxel. YM155 administered either concomitantly with or before docetaxel showed significant antitumor activity (tumor regression ≥ 99%), with complete regression of the established human NSCLC-derived tumors in mice (eight of eight and seven of eight animals, respectively). Significantly fewer complete responses (three of eight animals) were achieved when YM155 was administered after docetaxel. No statistically significant decreases in body weight were observed in the combination versus docetaxel groups. YM155 administered concomitantly with docetaxel resulted in significant decreases in mitotic and proliferative indices, and in a significant increase in the apoptosis index. Elevated survivin expression was seen in tumors from mice treated with docetaxel alone; a significant reduction in survivin expression was seen in tumors from mice treated with YM155 alone or in combination with docetaxel, but not in the control group. These results indicate that in a human NSCLC xenograft model YM155 in combination with docetaxel diminished the accumulation of survivin by docetaxel and induced more intense apoptosis and enhanced antitumor activity, compared with single-agent YM155 or docetaxel.     

Enhanced efficiency of thermally targeted taxanes delivery in a human xenograft model of gastric cancer

Since successful chemotherapy with taxanes requires an improvement in their therapeutic index, especially by the reduction in unwanted systemic toxicity of either drug or adjuvants, we have investigated and are reporting results from an investigation of the use of a novel polymeric thermosensitive micellar delivery system for docetaxel and paclitaxel. Here we reported a novel metastable thermosensitive polymeric micelle for docetaxel and paclitaxel delivery [poly(N-isopropylacrylamide-co-acrylamide)-b-poly(DL-lactide), Poly(IPAAm-co-AAm)-b-PDLLA]. Previous in vitro efficacy studies indicated that, with hyperthermia, docetaxel-loaded micelles showed stronger cytotoxicity to different tumor cell lines than conventional docetaxel formulation while exhibiting slighter toxicity to normal cells. Present in vivo studies indicated that at the same dose level of docetaxel (paclitaxel), hyperthermia greatly enhanced the antitumor effect of micellar docetaxel (paclitaxel) in human gastric BGC mouse xenograft model by showing an extraordinary tumor volume and weight growth percentage inhibition of more than 80%. Meanwhile, acute toxicity tests features the lower LD(50) of the combination of hyperthermia and micellar docetaxel (paclitaxel) compared to that of the control group. The present results suggest that poly(IPAAm-co-AAm)-b-PDLLA micelles could be a clinically useful chemotherapeutic formulation and merit further research to evaluate the feasibility of clinical application.     

Antitumor effect and enhancement of cytotoxic drug activity by cetuximab in nasopharyngeal carcinoma cells

BACKGROUND: Nasopharyngeal carcinoma (NPC) is the most common head and neck cancer in southern China and South East Asia. Epidermal growth factor receptor (EGFR) has been proposed as a new target for anticancer therapy. EGFR was over-expressed in 85% of NPC tissues and was associated with poor prognosis. MATERIALS AND METHODS: EGFR protein expression in four NPC cell lines, CNE-2, HONE-1, HK1 and C666-1, was examined by Western immunoblotting. The antitumor effect of cetuximab was studied in the cell lines, either alone or in combination with cisplatin or paclitaxel. RESULTS: EGFR protein expression was highest in the HK1 cell line, moderate in CNE-2 and HONE-1, and lowest in C666-1. Single agent cetuximab demonstrated significant antitumor effect in the HK1 and HONE-1 cell lines, but minimal activity in CNE-2 and C666-1 cells. When cetuximab was combined with cisplatin or paclitaxel in the HK1 and HONE-1 cell lines, an additive enhancement of cytotoxic drug activity was demonstrated. CONCLUSION: Cetuximab demonstrated single agent activity selectively in NPC cell lines with moderate to high EGFR protein expression. Cetuximab could also additively enhance the antitumor effects of cisplatin or paclitaxel in these NPC cell lines. These results support the rationale of combining cetuximab with current standard chemotherapy to further improve the therapeutic ratio in the treatment of NPC. Future studies should aim at defining the predictive markers for response to cetuximab in order to select the responsive tumor for the correctly targeted agents.     

Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status

Nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) is an albumin-bound 130-nm particle form of paclitaxel that demonstrated higher efficacy and was well tolerated compared with solvent-based paclitaxel (Taxol) and docetaxel (Taxotere) in clinical trials for metastatic breast cancer. Nab-paclitaxel enhances tumor targeting through gp60 and caveolae-mediated endothelial transcytosis and the association with the albumin-binding protein SPARC (secreted protein, acidic and rich in cysteine) in the tumor microenvironment. The overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer has been shown to correlate with resistance to paclitaxel. To evaluate the importance of HER2 and SPARC status in determining the relative efficacy of nab-paclitaxel compared with polysorbate-based docetaxel, nude mice bearing six different human tumor xenografts were treated with nab-paclitaxel (MX-1: 15 mg/kg, once a week for 3 weeks; LX-1, MDA-MB-231/HER2+, PC3, and HT29: 50 and 120 mg/kg, every 4 days three times ; MDA-MB-231: 120 and 180 mg/kg, every 4 days three times) and polysorbate-based docetaxel (15 mg/kg). HER2 and SPARC status were analyzed by RT-PCR and immunohistochemical staining. MDA-MB-231 and MX-1 breast and LX-1 lung cancers were HER2 negative and low in SPARC expression. Nab-paclitaxel at submaximum-tolerated dosage was significantly more effective than polysorbate-based docetaxel at its maximum-tolerated dosage in these three HER2-negative tumors. The HER2-positive tumors had variable SPARC expression, with MDA-MB-231/HER2+ 相似文献   

晚期非小细胞肺癌个体化化疗的研究进展

非小细胞肺癌(NSCLC)全球发病率高、死亡病例多。第三代化疗药物(长春瑞滨、吉西他滨、紫杉醇、多西他赛)联合铂类的两药化疗方案仍是目前NSCLC一线治疗的常规方案。与化疗疗效相关的新靶标基因(切除修复交叉互补基因1与铂类耐药、核苷酸还原酶调节因子1与吉西他滨耐药、β微管蛋白与紫杉类耐药等)有可能作为预测化疗反应的生物标记。本文结合分子病理分型综述临床个体化化疗方案研究。     

Antitumor activity of doxorubicin in combination with docetaxel against human breast cancer xenografts

In this study we assessed the in vivo antitumor activity of combined docetaxel (DOCE) and doxorubicin (DXR) treatment using 2 human breast carcinoma cell xenografts (R-27 and MX-1) in the nude mouse model. The transplanted tumors were allowed to reach exponential growth, whereupon 10 or 40 mg DOCE per kg alone (i.p.), 8 mg DXR per kg alone (i.v.), or 10 mg/kg DOCE (i.p.) and 8 mg/kg of DXR (i.v.), in the sequence of DOCE followed by DXR, were administered. The in vivo antitumor activity of combined DOCE and DXR was synergistic against R-27 and additive against MX-1. P-glycoprotein (P-gp) was detected immunohistochemically, and was highly expressed in R-27, but not in MX-1. In conclusion, DOCE may increase the antitumor activity of DXR against P-gp-positive breast cancer xenografts, such that the DOCE and DXR combination may be a useful treatment in clinical breast cancer.     

Influence of dosing schedules on toxicity and antitumour effects of combined cisplatin and docetaxel treatment in mice

Objectives The combination of cisplatin and docetaxel shows a better cure rate against non‐small‐cell lung cancer than other drug combinations in clinical studies; however, severe myelosuppression and nephrotoxicity are dose‐limiting factors. The purpose of this study was to establish a suitable dosing schedule to reduce adverse effects and improve the antitumour effects. Methods Cisplatin and docetaxel were administered i.p. to male ICR mice simultaneously, or sequentially with either cisplatin or docetaxel first followed by the second drug 12 h later (docetaxel–cisplatin and cisplatin–docetaxel groups). Antitumour effects of these schedules were also tested in C57BL/6N mice bearing Lewis lung carcinomas. Key findings The simultaneous docetaxel/cisplatin group showed the lowest survival rate and the highest blood urea nitrogen (BUN) concentration. Cisplatin concentrations in the plasma and kidney were higher in the simultaneous dosing group than the sequential dosing groups. Antitumour effect was the greatest in the docetaxel–cisplatin group. Conclusions The docetaxel–cisplatin regimen inhibited tumour growth the best and reduced mortality and nephrotoxicity.     

Immunotherapy with tumor-targeted superantigens (TTS) in combination with docetaxel results in synergistic anti-tumor effects

In this study we explored the possibility of combining immunotherapy against cancer with the well-established cytostatic drug docetaxel. Tumor-targeted superantigens (TTS) utilizes the powerful T cell activating property of a superantigen such as staphylococcal enterotoxin A (SEA) in fusion with an anti-tumor Fab-fragment to target this T cell activity against tumor cells. TTS fusion proteins are efficient in a number of experimental tumor models including the B16 mouse melanoma transfected with a human tumor-associated antigen (GA733-2 or EpCam) recognized by the C215 monoclonal antibody. The distinct mechanisms of action of TTS and docetaxel provide the prerequisites for successful combination treatment. However, as a result of the anti-proliferative properties of cytostatic drugs, chemotherapy may modify TTS induced immune activation during combination treatment.Here we evaluated the anti-tumor effects of combining C215Fab-SEA with docetaxel against B16-C215 tumors growing in the lung of C57Bl/6 mice. Both compounds generated a significant reduction in the number of B16-C215 lung tumors when administered alone. Prior treatment with docetaxel at therapeutic doses did not interfere with superantigen induced T cell activation but rather appeared to enhance the response, while simultaneous treatment was suppressive. Combining TTS and docetaxel significantly improved tumor therapy, further reducing the number of lung tumors as compared to mono therapies. Importantly, the combination treatment at timely settings synergistically prolonged long term survival in B16-C215 tumor bearing mice. The results of this study demonstrate that TTS immunotherapy is highly compatible with docetaxel and suggest a significant potential of the combination for human cancer therapy.     

Combination bronchodilators: antagonism of airway smooth muscle contractions in vitro.

The component drugs of fixed-dose combination bronchodilators may interact in a synergistic manner to antagonize airway contractions. To examine this hypothesis, combinations of ephedrine (E) and theophylline (Th) or salbutamol (S) and theophylline were tested for their ability to relax contracted guinea-pig airway smooth muscle in vitro. The combination bronchodilator effect was compared to the summed effects of the component drugs given individually (i.e. a theoretical additive response, Ta). Relaxation responses to combination bronchodilators were considered less-than-additive if significantly less than Ta, additive if non-significant and greater-than-additive or synergistic if the values were significantly greater than Ta. It was found that the E-Th combinations interacted primarily in an additive fashion to relax contractions induced by histamine, acetylcholine and 5-hydroxytryptamine at concentrations that produced one-half maximal contractile response (ED50). Similarly S-Th combinations interacted in an additive manner to reverse histamine and acetylcholine contractions. In the case of both E-Th and S-Th combinations, the drugs were more effective in reducing the smooth muscle contractions when given during rather than prior to the response. It may be concluded that beta-sympathomimetics and methylxanthines when combined do not interact in a synergistic fashion to produce relaxation of contracted airway smooth muscle.     

Combination of oral fluoropyrimidine and docetaxel: reappraisal of synergistic effect against gastric carcinoma xenografts

BACKGROUND: The synergistic antitumor effect of a combination of docetaxel and capecitabine is reported to be attributable to docetaxel-mediated up-regulation of thymidine phosphorylase (dThdPase). MATERIALS AND METHODS: Intravenous docetaxel (15 mg/kg) was given to nude mice bearing xenografts of the gastric cancer cell lines MKN45 and MKN28. Mice were sacrificed on days 7, 10 and 22 and tumor samples were taken to measure the activities of thymidylate synthase, dihydropyrimidine dehydrogenase, dThdPase and orotate phosphoribosyltransferase. The efficacy of capecitabine or S-1, alone and in combination with docetaxel, was then evaluated in vivo. Docetaxel was administered intravenously on days 8 and 22 at 15 mg/kg, while capecitabine (269 mg/kg) or S-1 (7.5 mg/kg) were administered orally 5 times a week for 4 weeks. RESULTS: Tumor regression was observed only for a combination of capecitabine and docetaxel against MKN28, while additive growth inhibition was obtained by the combination of docetaxel and both S-1 and capecitabine on MKN45 tumor xenografts. Induction of dThdPase activity was observed only for MKN45. The activity of no other enzyme was significantly affected following administration of docetaxel. CONCLUSION: The combination of oral fluoropyrimidine and docetaxel showed augmented antitumor activity, but this may be attributed to mechanisms other than changes in 5-fluorouracil-metabolizing enzymes.