Exposure of cancer cells to chemotherapeutic agents may result in reduced sensitivity to structurally unrelated agents, a phenomenon known as multidrug resistance, MDR. The purpose of this study is to investigate cell growth inhibition of wild type and the corresponding MDR cells by Tumor Treating Fields - TTFields, a new cancer treatment modality that is free of systemic toxicity. The TTFields were applied alone and in combination with paclitaxel and doxorubicin.
Three pairs of wild type/MDR cell lines, having resistivity resulting from over-expression of ABC transporters, were studied: a clonal derivative (C11) of parental Chinese hamster ovary AA8 cells and their emetine-resistant sub-line EmtR1; human breast cancer cells MCF-7 and their mitoxantrone-resistant sub lines MCF-7/Mx and human breast cancer cells MDA-MB-231 and their doxorubicin resistant MDA-MB-231/Dox cells. TTFields were applied for 72 hours with and without the chemotherapeutic agents. The numbers of viable cells in the treated cultures and the untreated control groups were determined using the XTT assay. Student t-test was applied to asses the significance of the differences between results obtained for each of the three cell pairs.
TTFields caused a similar reduction in the number of viable cells of wild type and MDR cells. Treatments by TTFields/drug combinations resulted in a similar increased reduction in cell survival of wild type and MDR cells. TTFields had no effect on intracellular doxorubicin accumulation in both wild type and MDR cells.
The results indicate that TTFields alone and in combination with paclitaxel and doxorubicin effectively reduce the viability of both wild type and MDR cell sub-lines and thus can potentially be used as an effective treatment of drug resistant tumors.
Tumor treating fields (TTFields) are low intensity, intermediate frequency, alternating electric fields used to treat cancerous tumors. This novel treatment modality effectively inhibits the growth of solid tumors in vivo and has shown promise in pilot clinical trials in patients with advanced stage solid tumors. TTFields were tested for their potential to inhibit metastatic spread of solid tumors to the lungs in two animal models: (1) Mice injected with malignant melanoma cells (B16F10) into the tail vein, (2) New Zealand White rabbits implanted with VX-2 tumors within the kidney capsule. Mice and rabbits were treated using two-directional TTFields at 100–200 kHz. Animals were either monitored for survival, or sacrificed for pathological and histological analysis of the lungs. The total number of lung surface metastases and the absolute weight of the lungs were both significantly lower in TTFields treated mice then in sham control mice. TTFields treated rabbits survived longer than sham control animals. This extension in survival was found to be due to an inhibition of metastatic spread, seeding or growth in the lungs of TTFields treated rabbits compared to controls. Histologically, extensive peri- and intra-tumoral immune cell infiltration was seen in TTFields treated rabbits only. These results raise the possibility that in addition to their proven inhibitory effect on the growth of solid tumors, TTFields may also have clinical benefit in the prevention of metastatic spread from primary tumors.
Tumor treating fields; Metastases; Immune response
Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor, and has a median survival of only 10 to 14 months with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM) is nearly universal, and further decreases the median survival to only five to seven months with optimal therapy. Tumor-treating fields (TTField) therapy is a novel treatment technique that has recently received CE and FDA approval for the treatment of RGBM, and is based on the principle that low intensity, intermediate frequency electric fields (100 to 300 kHz) may induce apoptosis in specific cell types. Our center was the first to apply TTField treatment to histologically proven GBM in a small pilot study of 20 individuals in 2004 and 2005, and four of those original 20 patients are still alive today. We report two cases of GBM and two cases of RGBM treated by TTField therapy, all in good health and no longer receiving any treatment more than seven years after initiating TTField therapy, with no clinical or radiological evidence of recurrence.
Glioblastoma multiforme; Recurrent glioblastoma multiforme; Tumor-treating fields; Long-term survival
Melanoma is considered a chemotherapy-resistant tumor, but in fact several chemotherapeutic agents show single-agent activity at the level of 10% to 15%, similar to the efficacy of the chemotherapeutic armamentarium used against other tumor types. Several combination chemotherapy regimens have been tested, but no survival benefit has been demonstrated. Few of these trials have been compared with standard dacarbazine (DTIC) in an adequately powered randomized trial, and even the largest of these trials were only powered to detect unrealistically large improvements in overall survival. In this article, the authors review past chemotherapy trials and the current state of chemotherapy for melanoma. Looking to the future, the authors are encouraged by recent observations that the addition of sorafenib to DTIC (or temozolomide) can increase response rates and survival. The authors suggest that this could form the core on which additional active chemotherapeutic drugs could be added with the hope of developing a regimen that improves overall survival. This paradigm of stepwise addition of active chemotherapeutic drugs has been successful in the development of chemotherapy regimens that improve survival in other solid tumor systems. In colon carcinoma, for example, the current regimens were built on fluorouracil (5FU)/leucovorin, which has similar activity to DTIC in melanoma. This could serve as a model for studies on melanoma.
Dacarbazine; Temozolomide; Cisplatin; Sorafenib; Combination chemotherapy
Overexpression of the apoptosis-related protein clusterin is associated with breast cancer development and tumor progression. We describe the use of clusterin-specific antisense oligonucleotides and antibodies to sensitize breast carcinoma cells to anticancer drugs routinely used in breast cancer therapy.
MCF-7 and MDA-MB-231 cells were treated with the oligonucleotide or antibody, chemotherapeutic agents (doxorubicin or paclitaxel), tamoxifen, or with combinations of these.
Treatments that include antisense clusterin oligonucleotide or antibody to clusterin have been shown to reduce the number of viable cells more effectively than treatment with the drugs alone. We also demonstrate that dexamethasone pretreatment of breast cancer cell lines inhibits chemotherapy-induced cytotoxicity and is associated with the transcriptional induction of clusterin. However, anticlusterin treatment increases chemotherapy-induced cytotoxicity, even in the presence of glucocorticoids, suggesting a possible role for these proteins in glucocorticoid-mediated survival.
These data suggest that combined treatment with antibodies to clusterin or antisense clusterin oligodeoxynucleotides and paclitaxel, doxorubicin, or tamoxifen could be a novel and attractive strategy to inhibit the progression of breast carcinoma by regulation of the clusterin function. Moreover, glucocorticoid activation in breast cancer cells regulates survival signaling by the direct transactivation of genes like clusterin which encode proteins that decrease susceptibility to apoptosis. Given the widespread clinical administration of dexamethasone before chemotherapy, understanding glucocorticoid-induced survival mechanisms is essential for achieving optimal therapeutic responses.
The objective of this paper is to review the data supporting the use of docetaxel in the treatment of breast cancer, focusing on pharmacokinetics, efficacy in adjuvant and metastatic trials alone and in combination with chemotherapeutic and targeted agents, and the toxicity of docetaxel in comparison to paclitaxel. Docetaxel is a semisynthetic product derived from the European yew tree Taxus baccata L. It promotes the assembly of microtubules, stabilizes them, and thereby prevents their depolymerization. Docetaxel has been incorporated into neo-adjuvant chemotherapy regimens, both with and without anthracyclines. The inclusion of taxanes such as docetaxel in polychemotherapy regimens in early breast cancer is associated with a statistically significant reduction in mortality. As a single agent, docetaxel is highly active in the treatment of metastatic breast cancer. In first-line treatment of metastatic breast cancer, the combination of docetaxel and capecitabine was associated with an improvement in overall survival; however, toxicity was higher. The toxicity profile of docetaxel has been well documented and is predictable; the most frequent adverse effects are neutropenia and febrile neutropenia. Taxane-specific adverse effects, such as peripheral neuropathy, are also expected but are manageable with appropriate dosing and scheduling.
taxanes; docetaxel; clinical trial; adverse effects; peripheral neuropathy; neutropenia
This study assessed response rates to combination dacarbazine (DTIC), BCNU (carmustine), cisplatin and tamoxifen (DBPT) chemotherapy in patients with progressive metastatic melanoma previously treated with DTIC, as an evaluation of DBPT as a second-line regimen, and as an indirect comparison of DBPT with DTIC. Thirty-five consecutive patients received DBPT. The patients were divided into two groups. Group 1 comprised 17 patients with progressive disease (PD) on DTIC + tamoxifen therapy who were switched directly to DBPT. Group 2 comprised 18 patients not immediately switched to DBPT and included patients who had either a partial response (PR; one patient) or developed stable disease (SD; four patients) with DTIC, or received adjuvant DTIC (nine patients). All except four patients had received tamoxifen at the time of initial DTIC treatment. Median times since stopping DTIC were 22 days (range 20–41) and 285 days (range 50–1240) in Groups 1 and 2 respectively. In Group 1, one patient developed SD for 5 months and the remainder had PD. In Group 2, there were two PRs, four patients with SD (4, 5, 6, and 6 months), and 11 with PD. These results indicate that the DBPT regimen is not of value in melanoma primarily refractory to DTIC. There were responses in patients not directly switched from DTIC to DBPT, suggesting combination therapy may be of value in a small subgroup of melanoma patients. © 2000 Cancer Research Campaign
melanoma; DTIC; Dartmouth regimen
Purpose. The present prospective randomized adjuvant trial was
carried out to compare the toxicity, feasibility and efficacy of augmented chemotherapy
added to hyperfractionated accelerated radiotherapy after wide or marginal resection of grade
2 and grade 3 soft tissue sarcoma (STS).
Patients and methods. Fifty-nine patients underwent primary surgery
by wide or marginal excision and were subsequently randomized to receive radiotherapy
alone or under the addition of six courses of ifosfamide (1500 mg/m2
, days 1–4), dacarbazine
(DTIC) (200 mg/m2
, days 1–4) and doxorubicin (25 mg/m2
, days 1–2) administered in
14-day-intervals supported by granulocyte-colony stimulating factor (30 × 106
on days 5–13. According to the randomization protocol, 28 patients received radiotherapy
only, whereas 31 patients were treated with additional chemotherapy.
Results. The relative ifosfamide–doxorubicin–DTIC (IFADIC) dose
intensity achieved was 93%. After a mean observation period of 41±19.7 months
(range, 8.1–84 months), 16 patients (57%) in the control group versus 24 patients (77%) in the
chemotherapy group were free of disease (p>0.05).Within the control group, tumor relapses
occurred in 12 patients (43%;six patients with distant metastases, two with local relapse,
four with both) versus seven patients (23%; five patients with distant metastases, one with
local recurrence, one with both) from the chemotherapy group. Relapse-free survival (RFS)
(p=0.1), time to local failure (TLF) (p=0.09), time to distant failure (TDF) (p=0.17) as well as
overall survival (OS) (p=0.4) did not differ significantly between the two treatment groups.
Treatment-related toxicity was generally mild in both treatment arms.
Conclusion. We conclude that the safety profile of intensified IFADIC
added to radiotherapy was manageable and tolerable in the current setting. Inclusion
of intensified IFADIC was not translated into a significant benefit concerning OS, RFS,
TLF andTDF as compared with radiotherapy only, although a potential benefit of
chemotherapy for grade 3 STS patients needs to be validated in prospective randomized
trials including larger patient numbers.
The administration and combination of a variety of chemotherapeutic agents for treatment of advanced or recurrent uterine cancer of different histologies is under current debate. Mixed Mullerian Tumors (MMTs), which contain both adenocarcinoma and sarcoma components, are the most rate histologic type and it is therefore difficult to conduct clinical trials to determine if they should be treated like endometrial adenocarinomas or like sarcomas. Flexible Heteroarotionoids (Flex-Hets) are a promising class of anti-cancer drugs with low toxicity that have demonstrated activity against a wide variety of cancer types, but their efficacy in uterine cancers is unknown. The objective of this study was to determine if cell lines established from endometrial carcinoma (HEC-1-A), uterine sarcoma (SK-UT-1) and MMT (MES-SA) cancers exhibit differential sensitivities to cisplatin, carboplatin, paclitaxel, docetaxel, doxorubicin and SHetA2, if SHetA2 can enhance sensitivity to the chemotherapeutic drugs and if SHetA2 exhibits a differential effect on uterine cancer cells in comparison to normal endometrial cells using a cytotoxicity assay. These cell lines did not differ in their sensitivities to platinum or taxel drugs. Doxorubicin was active against the sarcoma but not the adenocarcinoma or MMT cell lines. SHetA2 decreased the survival of all three cell lines, but did not enhance their sensitivities to the chemotherapeutic agents. Two of the three uterine cancer cell lines were more sensitive to SHetA2 in comparison to normal endometrial cells. In conclusion, doxorubicin appears to have a greater effect against sarcoma than other uterine histology types. SHetA2 is affective against uterine cancer cell lines, but does not enhance their sensitivities to chemotherapeutic agents.
Uterine cancer; adenocarcinoma; MMT; sarcoma; doxorubicin; Flex-Het
Ovarian carcinoma is a rarely curable disease, for which new treatment options are required. As agents that block HMG-CoA reductase and the mevalonate pathway, the statin family of drugs are used in the treatment of hypercholesterolemia and have been shown to trigger apoptosis in a tumor-specific manner. Recent clinical trials show that the addition of statins to traditional chemotherapeutic strategies can increase efficacy of targeting statin-sensitive tumors. Our goal was to assess statin-induced apoptosis of ovarian cancer cells, either alone or in combination with chemotherapeutics, and then determine these mechanisms of action.
The effect of lovastatin on ovarian cancer cell lines was evaluated alone and in combination with cisplatin and doxorubicin using several assays (MTT, TUNEL, fixed PI, PARP cleavage) and synergy determined by evaluating the combination index. The mechanisms of action were evaluated using functional, molecular, and pharmacologic approaches.
We demonstrate that lovastatin induces apoptosis of ovarian cancer cells in a p53-independent manner and synergizes with doxorubicin, a chemotherapeutic agent used to treat recurrent cases of ovarian cancer. Lovastatin drives ovarian tumor cell death by two mechanisms: first, by blocking HMG-CoA reductase activity, and second, by sensitizing multi-drug resistant cells to doxorubicin by a novel mevalonate-independent mechanism. This inhibition of drug transport, likely through inhibition of P-glycoprotein, potentiates both DNA damage and tumor cell apoptosis.
The results of this research provide pre-clinical data to warrant further evaluation of statins as potential anti-cancer agents to treat ovarian carcinoma. Many statins are inexpensive, off-patent generic drugs that are immediately available for use as anti-cancer agents. We provide evidence that lovastatin triggers apoptosis of ovarian cancer cells as a single agent by a mevalonate-dependent mechanism. Moreover, we also show lovastatin synergizes with doxorubicin, an agent administered for recurrent disease. This synergy occurs by a novel mevalonate-independent mechanism that antagonizes drug resistance, likely by inhibiting P-glycoprotein. These data raise important issues that may impact how statins can best be included in chemotherapy regimens.
Taxanes are highly active chemotherapeutic agents in the treatment of early-stage and metastatic breast cancer. Novel formulations have been developed to improve efficacy and decrease toxicity associated with these cytotoxic agents. nab-paclitaxel is a solvent free, albumin-bound 130-nanometer particle formulation of paclitaxel (Abraxane®, Abraxis Bioscience), which was developed to avoid toxicities of the Cremophor vehicle used in solvent-based paclitaxel. In a phase III clinical trial, nab-paclitaxel demonstrated higher response rates, better safety and side-effect profile compared to conventional paclitaxel, and improved survival in patients receiving it as second line therapy. Higher doses can be administered over a shorter infusion time without the need for special infusion sets or pre-medications. It is now approved in the US for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant therapy, where prior therapy included an anthracycline. Recently, several phase II studies have suggested a role for nab-paclitaxel as a single agent and in combination with other agents for first-line treatment of metastatic breast cancer.
nab-paclitaxel; nab-technology; paclitaxel; metastatic breast cancer; taxanes
Although the anticancer drugs paclitaxel and doxorubicin are commonly used to treat many solid tumors, their effectiveness is highly variable due to tumor cell resistance. Therefore, it is important to find mechanisms that can be targeted to increase the sensitivity of cancer cells to current chemotherapeutic agents. NIMA-related kinase 2 (Nek2), a serine/threonine kinase is emerging as an important oncogene because of its regulatory role in mitosis. Thus, regulation of the Nek2 expression levels may prove important as a target for cancer treatment. The purpose of our study was to determine whether drug sensitivity was increased in the triple negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 by using small interfering RNA (siRNA) and antisense oligo-nucleotides (ASOs) against Nek2. To this end, MDA-MB-231 and MDA-MB-468 breast cancer cells transfected with Nek2 siRNA or ASO were exposed to various concentrations of paclitaxel and doxorubicin. Cell viability, cell cycle distribution and apoptosis were evaluated. We observed that drug susceptibility in these transfected cells was dramatically increased compared with either agent alone. FACS results showed that apoptosis was induced in siRNA- and ASO-transfected cells as expected due to the regulatory function of Nek2 in centrosome duplication. Interestingly, the cell cyle was not arrested in transfected cells. We found that siRNA and ASO against Nek2 worked synergistically with paclitaxel and doxorubicin by promoting cell apoptosis. Our results suggest that these drugs in combination with Nek2 siRNA or ASO treatment may improve the sensitivity of cancer cells during chemotherapy treatments.
NIMA-related kinase 2; small interfering RNA; antisense oligonucleotide; paclitaxel; triple-negative breast cancer
Successful treatment of cancer patients with a combination of monoclonal antibodies (mAb) and chemotherapeutic drugs has spawned various other forms of additional combination therapies, including vaccines or adoptive lymphocyte transfer combined with chemotherapeutics. These therapies were effective against established tumors in animal models and showed promising results in initial clinical trials in cancer patients, awaiting testing in larger randomized controlled studies. Although combination between immunotherapy and chemotherapy has long been viewed as incompatible as chemotherapy, especially in high doses meant to increase anti-tumor efficacy, has induced immunosuppression, various mechanisms may explain the reported synergistic effects of the two types of therapies. Thus direct effects of chemotherapy on tumor or host environment, such as induction of tumor cell death, elimination of regulatory T cells, and/or enhancement of tumor cell sensitivity to lysis by CTL may account for enhancement of immunotherapy by chemotherapy. Furthermore, induction of lymphopenia by chemotherapy has increased the efficacy of adoptive lymphocyte transfer in cancer patients. On the other hand, immunotherapy may directly modulate the tumor's sensitivity to chemotherapy. Thus, anti-tumor mAb can increase the sensitivity of tumor cells to chemotherapeutic drugs and patients treated first with immunotherapy followed by chemotherapy showed higher clinical response rates than patients that had received chemotherapy alone. In conclusion, combination of active specific immunotherapy or adoptive mAb or lymphocyte immunotherapy with chemotherapy has great potential for the treatment of cancer patients which needs to be confirmed in larger controlled and randomized Phase III trials.
Cancer; Immunotherapy; Chemotherapy; Antibody; Vaccine; Lymphocyte
Statement of translational relevance
Despite significant efforts over the last two decades aimed at improving the efficacy of standard treatment (maximum tolerated dose (MTD) of dacarbazine), there has been no significant increase in the median survival of patients suffering from metastatic melanoma. Given the lack of success achieved, a rethinking of alternative treatment strategies is needed. Using preclinical models of advanced melanoma metastasis, we show that metronomic chemotherapeutic combinations results in improved survival, which is achieved with minimal toxicity. These results compare favorably with minimal effectiveness achieved by MTD dacarbazine therapy (alone or in combination with other chemotherapeutic agents or a VEGFR-blocking antibody), often accompanied by higher toxicity. Successes in preclinical setting of metastatic breast cancer have led to a clinical trial to examine the efficacy of metronomic therapy. A similar extension of the metronomic chemotherapeutic combinations presented here into the clinical setting of melanoma metastasis may be warranted.
The development of effective therapeutic approaches for treatment of metastatic melanoma remains an immense challenge. Present therapies offer minimal benefit. While dacarbazine (DTIC) chemotherapy remains the standard therapy, it mediates only low response rates, usually of short duration, even when combined with other chemotherapeutic agents. Thus, new therapeutic strategies are urgently needed.
Using a newly developed preclinical model, we evaluated the efficacy of various doublet metronomic combination chemotherapy against established, advanced melanoma metastasis and compared these to the standard maximum tolerated dose (MTD) DTIC (alone or in combination with chemotherapeutic agents or VEGFR-blocking antibody)
Whereas MTD DTIC therapy did not cause significant improvement in median survival, a doublet combination of low-dose metronomic (LDM) vinblastine (Vbl) and LDM cyclophosphamide (CTX) induced a significant increase in survival with only minimal toxicity. Furthermore, we show that the incorporation of the LDM Vbl/LDM CTX combination with a LDM DTIC regimen also results in a significant increase in survival, but not when combined with MTD DTIC therapy. We also show that a combination of metronomic Vbl therapy and a VEGFR2-blocking antibody (DC101) results in significant control of metastatic disease and that the combination of LDM Vbl/DC101 and LDM DTIC induced a significant improvement in median survival.
The effective control of advanced metastatic melanoma achieved by these metronomic-based chemotherapeutic approaches warrants clinical consideration of this treatment concept given the recent results of a number of metronomic-based chemotherapy clinical trials.
melanoma; spontaneous metastasis; vinblastine; cyclophosphamide; DC101; metronomic chemotherapy
The purpose of this study was to compare the response rate, overall and 1-year survival in patients with advanced melanoma treated with a standard therapy, dacarbazine and interferon-alpha (DTIC/IFN), or combination chemotherapy, consisting of dacarbazine, BCNU, cisplatin and tamoxifen (DBCT). Treatment toxicity and time spent in hospital were secondary end points. One hundred and five patients (of whom 100 were eligible) were randomized to receive either DTIC/IFN or DBCT. The trial was designed to detect a 25% absolute difference in response rate or in 1-year survival with 80% power. There was no significant difference in response rate: this was 17.3% with DTIC/IFN and 26.4% with DBCT. Median overall survival was similar at 199 and 202 days respectively. One-year survival rate favoured standard treatment (30.6 vs 22.6%), but did not differ significantly between arms. DBCT was associated with significantly greater haematological toxicity, and a greater need for time spent in hospital (5.75 days/treatment cycle vs 2.29 with dacarbazine and interferon). DBCT combination therapy cannot be recommended as standard treatment for advanced melanoma. Dacarbazine remains the standard chemotherapy for this condition. © 2000 Cancer Research Campaign
Advanced pancreatic adenocarcinoma is a deadly disease and is considered incurable. For the past two decades, gemcitabine remained the major chemotherapeutic drug with modest clinical benefit. Many chemotherapy and targeted agents were combined with gemcitabine but failed to demonstrate improvement in pancreatic cancer (PC) survival. Taxanes (paclitaxel, docetaxel) were introduced in the clinic as anti-microtubule agents and showed activity against PC cells in vitro; however, clinical efficacy was limited. Nab-paclitaxel (Abraxane) is an albumin-bound paclitaxel that has shown clinical activity in advanced breast and lung cancer. Recently, nab-paclitaxel was tested in a large Phase III clinical trial in combination with gemcitabine for the treatment of advanced PC. The data showed that the addition of nab-paclitaxel improved the response rate (7% in gemcitabine alone versus 23% in combination), progression-free survival (from 3.7 months to 5.5 months), and overall survival from 6.7 months to 8.5 months, compared to single agent gemcitabine. Through this review, we provide the preclinical and clinical progress in the development of nab-paclitaxel for the treatment of metastatic PC.
pancreatic adenocarcinoma; nab-paclitaxel; abraxane; gemcitabine
Metformin, the first-line drug for treating diabetes, selectively kills the chemotherapy-resistant, sub-population of cancer stem cells in genetically distinct types of breast cancer cell lines. In mouse xenografts, injection of metformin and the chemotherapeutic drug doxorubicin near the tumor is more effective than either drug alone in blocking tumor growth and preventing relapse. Here, we show that metformin is equally effective when given orally together with paclitaxel, carboplatin, and doxorubicin indicating that metformin works together with a variety of standard chemotherapeutic agents. In addition, metformin has comparable effects on tumor regression and preventing relapse when metformin combined with a 4-fold reduced dose of doxorubicin that is not effective as a monotherapy. Lastly, the combination of metformin and doxorubicin prevents relapse in xenografts generated with prostate and lung cancer cell lines. These observations provide further evidence for the cancer stem cell hypothesis for cancer relapse, as well as an experimental rationale for using metformin as part of combinatorial therapy in a variety of clinical settings and for reducing the chemotherapy dose in cancer patients.
metformin; chemotherapy; xenografts; cancer stem cells
Triolimus is a first-in-class, multi-drug loaded micelle containing paclitaxel, rapamycin and 17-AAG. In this study, we examine the anti-tumor mechanisms of action, efficacy and toxicity of Triolimus in vitro and in vivo. In vitro cytotoxicity testing of Triolimus was conducted using two aggressive adenocarcinomas including the lung cancer cell line, A549, and breast cancer cell line, MDA-MB-231. The three-drug combination of paclitaxel, rapamycin and 17-AAG displayed potent cytotoxic synergy in both A549 and MDA-MB-231 cell lines. Mechanistically, the drug combination inhibited both the Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. Triolimus was advanced into tumor xenograft models for assessment of efficacy, toxicity and mechanisms of action. In vivo, a three-infusion schedule of Triolimus inhibited A549 and MDA-MB-231 tumor growth far more potently than paclitaxel-containing micelles and effected tumor cures in MDA-MB-231 tumor-bearing animals. Tumor growth delays resulted from a doubling in tumor cell apoptosis and a 50% reduction in tumor cell proliferation compared to paclitaxel-containing micelles. Enhanced anti-tumor efficacy was achieved without clinically significant increases in acute toxicity. Thus, Triolimus displays potent synergistic activity in vitro and anti-tumor activity in vivo with comparable toxicity to paclitaxel. These observations provide strong support for further development of Triolimus and an important proof of concept for safe, effective nanoparticle-based delivery of three complementary anti-cancer agents.
Multi-targeting; Hsp90; mTOR; paclitaxel; micelles
Polyamine analogues have demonstrated significant activity against human breast cancer cell lines as single agents as well as in combination with other cytotoxic drugs. This study evaluates the ability of a polyamine analogue N1, N11-bis(ethyl)norspermine (BENSpm) to synergize with six standard chemotherapeutic agents, 5-fluorouracil (FU), fluorodeoxyuridine, cis- diaminechloroplatinum(II) (DDP), paclitaxel, docetaxel, and vinorelbine, in four human breast cancer cell lines and one immortalized, non-tumorigenic mammary epithelial cell line. BENSpm exhibited synergistic inhibitory effect on cell proliferation in combination with 5-FU or paclitaxel in human breast cancer cell lines (MDA-MB-231 and MCF-7) and either antagonistic or less effective in the non-tumorigenic MCF-10A cell line. Synergism was highest with 120 hour concomitant treatment or pre-treatment with BENSpm for 24 hours followed by concomitant treatment for 96 additional hours. Since the cytotoxic effects of many polyamine analogues and cytotoxic agents are believed to act, in part, through induction of the polyamine catabolic enzymes SSAT and SMO, the role of these enzymes on synergistic response was evaluated in MDA-MB-231- and MCF-7-treated with BENSpm and 5-FU or paclitaxel. Combination treatments of BENSpm with 5-FU or paclitaxel resulted in induction of SSAT mRNA and activity in both cell lines compared to either drug alone, while SMO mRNA and activity were increased only in MDA-MB-231 cells. Induction was greater with BENSpm/paclitaxel combination than BENSpm/5-FU. Further, RNAi studies demonstrated that both SSAT and SMO play a significant role in the response of MDA-MB-231 cells to treatment with BENSpm and 5-FU or paclitaxel. In MCF-7 cells, only SSAT appears to be involved in the response to these treatments. In an effort to translate combination studies from in vitro to in vivo, and to form a basis for clinical setting, the in vivo therapeutic efficacy of BENSpm alone and in combination with paclitaxel on tumor regression was evaluated in xenograft mice models generated with MDA-MB-231 cells. Intraperitoneal exposure to BENSpm or taxol singly and in combination for 4 weeks resulted in significant inhibition in tumor growth These findings help elucidate the mechanisms involved in synergistic drug response and support combinations of polyamine analogues with chemotherapeutic agents which could potentially be used in the treatment of breast cancer.
BENSpm; polyamine analogue; combination study; breast cancer
The increased incidence of malignant melanoma in recent decades, along with its high mortality rate and pronounced resistance to therapy pose an enormous challenge. Novel therapeutic strategies, such as immunotherapy and targeted therapy, are urgently needed for melanoma. In this study, a new active targeting drug delivery system was constructed to combine chemotherapy and active specific immunotherapy.
The chemotherapeutic drug, dacarbazine (DTIC), that induces apoptosis through the intrinsic pathway which typically responds to severe DNA damage, was used as a model drug to prepare DTIC-loaded polylactic acid (PLA) nanoparticles (DTIC-NPs), which were covalently conjugated to a highly specific targeting functional TRAIL-receptor 2 (DR5) monoclonal antibody (mAb) that can contribute directly to cancer cell apoptosis or growth inhibition through the extrinsic pathway.
Our in vitro experiments demonstrated that DTIC-PLA-DR5 mAb nanoparticles (DTIC-NPs-DR5 mAb) are an active targeting drug delivery system which can specifically target DR5-overexpressing malignant melanoma cells and become efficiently internalized. Most strikingly, compared with conventional DTIC-NPs, DTIC-NPs-DR5 mAb showed significantly enhanced cytotoxicity and increased cell apoptosis in DR5-positive malignant melanoma cells.
The DTIC-NPs-DR5 mAb described in this paper might be a potential formulation for targeting chemotherapy and immunotherapy to DR5-overexpressing metastatic melanoma.
malignant melanoma; DR5 monoclonal antibodies; dacarbazine; apoptosis; chemoimmunotherapy; active targeting nanoparticles
Exploiting the sensitivity of cancer cells to reactive oxygen species (ROS) has been suggested as a strategy for the selective elimination of cancer cells. In this study, the ROS-generating sphingolipid safingol was combined with various conventional chemotherapeutics, and the potential synergism of the safingol-based combination regimen was assessed using a panel of cancer cell lines. The IC50 values of safingol using as a single agent were 1.4-6.3 µM, which are concentrations that are clinically achievable. While synergism was dependent on the drug molar ratios, a 4:1 molar ratio of safingol to conventional chemotherapeutics exhibited a moderate to strong synergism in MDA-MB-231, JIMT-1, SKOV-3, U937 and KB cells, with combination indices ranging from 0.07 to 0.77. Furthermore, the addition of safingol may reduce the concentrations of conventional chemotherapeutics required to achieve 90% cell-kill by 1 to >3 log-folds. A significant reduction in the cytotoxicity of safingol-based drug combinations was observed in the presence of N-acetyl-L-cysteine, suggesting that ROS is an important factor in mediating the observed synergism. Taken together, our results suggest that the use of safingol-based drug combinations is promising as an effective strategy for cancer therapy and should be investigated.
Purpose. Patients with soft tissue sarcoma (STS) who have previously received standard chemotherapy including
adriamycin (doxorubicin), ifosfamide, cyclophosphamide and DTIC (dacarbazine) have very limited therapeutic options.
It is important to identify new drugs with some activity in this disease and we therefore undertook this trial to determine
the antitumor activity of paclitaxel (Taxol).
Methods. We conducted a phase II study of paclitaxel in patients with STS who had received prior standard
chemotherapy. Paclitaxel was administered at a starting dose of 200 mg m-2 as a 24-h infusion with STS premedication,
every 21 days or upon hematologic recovery (absolute granulocyte count (AGC) ≥ 1500/μl,
platelets ≥ 100 000/μl).
Neupogen was not used routinely. The study was conducted based on a two-stage design proposed by Simon. Responses
were assessed radiographically using standard criteria.
Results. Nineteen eligible patients were treated in the first stage of the study. The median age was 50 years (range 20–68
years), and there were nine females and 10 males with Zubrod performance status of 1 or 2. One patient achieved a minor
response. Median AGC nadir was 0.1/μl on day 12 with absolute neutropenia lasting 5 days. Median platelet nadir was
171 000/μl on day 9. There were no grade 3/4 non-hematologic toxicities and no deaths related to treatment.
Discussion. Paclitaxel, at this dose and schedule, is well tolerated but inactive in this
Soft tissue sarcomas comprise less than 1% of all solid malignancies. The presentation and behavior of these tumors differs depending on location and histological characteristics. Standard therapy consists of complete surgical resection in combination with adjuvant radiotherapy. The role of chemotherapy is not clearly defined and is largely restricted to clinical trials. Only a limited number of agents have proved to be effective in soft tissue sarcomas. The use of doxorubicin, epirubicin and ifosfamide allowed response rates of more than 20%. In addition, recent chemotherapy trials did not demonstrate any significant differences in efficacy for various histological subtypes.
The objective of this study was to gain additional information about the chemosensitivity of soft tissue sarcomas to seven 7 different chemotherapy agents as single drugs and 4 combinations. Therefore we used an established ATP based in-vitro testing system and examined 50 soft tissue sarcomas. Chemosensitivity was assessed using a luciferin-luciferase-based luminescence assay providing individual chemosensitivity indices for each agent tested.
The sensitivity varied widely according to the histological subtypes. The tumors state of cellular dedifferentiation played a crucial role for the efficiency of the chemotherapeutic agents. The sensitivity also depended on the presentation of the sarcoma as a primary or recurrent tumor. The highest sensitivity was demonstrated for actinomycin D as a single agent, with 74% of the tumor samples exhibiting a high-grade sensitivity (20% low sensitivity, no resistance). The combination of actinomycin D and ifosfamide yielded a high sensitivity in 76% (2% resistance). Doxorubicin as a mono-therapy or in combination with ifosfamide achieved high sensitivity in 70% and 72%, respectively, and resistance in 6% of the samples.
Chemosensitivity testing is feasible in soft tissue sarcomas. It can be used to create sensitivity and resistance profiles of established and new cytotoxic agents and their combinations in soft tissue sarcomas. Our data demonstrate measurable discrepancies of the drug efficiency in soft tissue sarcomas, sarcoma subtypes and tumor recurrencies. However, current therapeutic regime does not take this in consideration, yet.
soft tissue sarcoma; chemotherapy; chemosensitivity; ATP-TCA
Adjuvant treatment for early breast cancer is an evolving field. Since the advent of the initial cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimens, which reduced risk for recurrence and death, anthracyclines and subsequently taxanes were added to the cytotoxic armamentarium for use sequentially or in combination in the adjuvant setting. The efficacy and toxicity of each chemotherapy regimen must be viewed within the context of host co-morbidities and the specific biologic phenotype of the tumor. In the era of mammographic screening, small, node-negative breast cancer is the most frequent presentation of the disease. Patient selection for adjuvant chemotherapy has become a key issue. Traditional prognostic factors continue to be of value in determining the risk for relapse, but new and sophisticated genomic tools (such as Oncotype Dx® and Mammaprint®) are now available and may improve our ability to select patients. For those patients who do require adjuvant chemotherapy, the 'one size fits all' paradigm should never again feature in the treatment of early breast cancer, following the important insights yielded by biomarker research to identify those who will benefit the most from a particular drug. In this review we focus on some of the current controversies and potential future steps in adjuvant chemotherapy for treatment of early breast cancer.
Fucoidan, a fucose-rich polysaccharide isolated from brown alga, is currently under investigation as a new anti-cancer compound. In the present study, fucoidan extract (FE) from Cladosiphon navae-caledoniae Kylin was prepared by enzymatic digestion. We investigated whether a combination of FE with cisplatin, tamoxifen or paclitaxel had the potential to improve the therapeutic efficacy of cancer treatment. These co-treatments significantly induced cell growth inhibition, apoptosis, as well as cell cycle modifications in MDA-MB-231 and MCF-7 cells. FE enhanced apoptosis in cancer cells that responded to treatment with three chemotherapeutic drugs with downregulation of the anti-apoptotic proteins Bcl-xL and Mcl-1. The combination treatments led to an obvious decrease in the phosphorylation of ERK and Akt in MDA-MB-231 cells, but increased the phosphorylation of ERK in MCF-7 cells. In addition, we observed that combination treatments enhanced intracellular ROS levels and reduced glutathione (GSH) levels in breast cancer cells, suggesting that induction of oxidative stress was an important event in the cell death induced by the combination treatments.
fucoidan extract; chemotherapeutic agents; anti-cancer activity; apoptosis; breast cancer