Ultra low dose Taxol

Summary

This is a very interesting, accessible and low cost therapy focused on immune system modulation and anti angiogenesis effects. It can be used in parallel with therapies directly targeting cancer cells such as 3BP, Salinomycin, etc.

In addition it can be used in combination with immunotheraphies such as Dendritic cells. Indeed it has been reported that “low-dose chemotherapy (using paclitaxel) before intratumoral delivery of dendritic cells might be associated with beneficial alterations of the intratumoral microenvironment and thus support antitumor immunity.” Ref.

Anecdotal reports/stories

There was a clinic in the Netheralnds using this treatment in combination with MPS1 inhibitors and showing great results but it has been closed by the authorities. Anecdotal reports (by people I personally know), that these combination led to >50% tumor reduction of large tumors, in a few weeks time frame.

Mechanism

Anti angiogenesis and Immunomodulation (see references below)

Safety/Toxicity

Non-toxic to normal cells

Preparation & Administration

4.5 mg taxol and 5ml DMSO (>99% and sterile) in 100ml saline administrated in about 30min.

Note that teh dose above may be 100 smaller than the dose used for chemo therapies and is non toxic to normal cells.

Source & Cost

Available without prescription at online pharmacies – cost is below 100 euro.

Synergists &Antagonists

MPS1 inhibitors (Reversine, AZ3146, etc) and Taxol in synergy: http://www.ncbi.nlm.nih.gov/pubmed/23933817

ClinicsTreating Patients withultra low dose Taxol

There was a clinic in the Netheralnds using this treatment in combination withMPS1 inhibitors and showing great results but it has been closed by the authorities.

References:

Low-Dose Chemomodulation and Cancer Vaccines http://omicsonline.org/open-access/lowdose-chemomodulation-and-cancer-vaccines-2157-7560.1000e126.pdf

Origin and pharmacological modulation of tumor-associated regulatory dendritic cells http://onlinelibrary.wiley.com/doi/10.1002/ijc.28590/abstract

Protumorigenic activity of immune regulatory cells has been proven to play a major role in precluding immunosurveillance and limiting the efficacy of anticancer therapies. Although several approaches have been offered to deplete myeloid-derived suppressor cells (MDSC) and regulatory T cells, there are no data on how to control suppressive dendritic cell (DC) accumulation or function in the tumor environment. Although immunosuppressive function of DC in cancer was implicated to immature and plasmacytoid DC, details of how conventional DC (cDC) develop immunosuppressive properties remain less understood. Here, we show that the development of lung cancer in mice was associated with fast accumulation of regulatory DC (regDC) prior to the appearance of MDSC. Using the in vitro and in vivo approaches, we demonstrated that (i)both cDC and MDSC could be polarized into protumor regDC in the lung cancer environment; (ii) cDC [RIGHTWARDS ARROW] regDC polarization was mediated by the small Rho GTPase signaling, which could be controlled by noncytotoxic doses of paclitaxel; and (iii) prevention of regDC appearance increased the antitumor potential of DC vaccine in lung cancer. These findings not only bring new players to the family of myeloid regulatory cells and provide new targets for cancer therapy, but offer novel insights into the immunomodulatory capacity of chemotherapeutic agents used in low, noncytotoxic doses.

Low-dose paclitaxel prior to intratumoral dendritic cell vaccine modulates intratumoral cytokine network and lung cancer growth. http://www.ncbi.nlm.nih.gov/pubmed/17875775

PURPOSE: The main goal of this study was to provide the “proof-of-principle” that low-dose paclitaxel is able to change the tumor microenvironment and improve the outcome of intratumoral dendritic cell vaccine in a murine lung cancer model.

EXPERIMENTAL DESIGN: We evaluated the antitumor potential and changes in the intratumoral milieu of a combination of low-dose chemotherapy and dendritic cell vaccine in the Lewis lung carcinoma model in vivo.

RESULTS: The low-dose paclitaxel, which induced apoptosis in approximately 10% of tumor cells, was not toxic to bone marrow cells and dendritic cells and stimulated dendritic cell maturation and function in vitro. Although tumor cells inhibited dendritic cell differentiation in vitro, this immunosuppressive effect was abrogated by the pretreatment of tumor cells with low-dose paclitaxel. Based on these data, we next tested whether pretreatment of tumor-bearing mice with low-dose paclitaxel in vivo would improve the antitumor potential of dendritic cell vaccine administered intratumorally. Significant inhibition of tumor growth in mice treated with low-dose paclitaxel plus intratumoral dendritic cell vaccine, associated with increased tumor infiltration by CD4(+) and CD8(+) T cells and elevated tumor-specific IFN-gamma production by draining lymph node cells, was revealed. Using a novel intratumoral microdialysis technique and Luminex technology for collecting and characterizing soluble factors released within the tumor bed for several days in live freely moving animals, we showed that low-dose paclitaxel altered the cytokine network at the tumor site.

CONCLUSIONS: Our data indicate that low-dose chemotherapy before intratumoral delivery of dendritic cells might be associated with beneficial alterations of the intratumoral microenvironment and thus support antitumor immunity.

Myeloid-derived suppressor cells: the dark knight or the joker in viral infections? http://www.ncbi.nlm.nih.gov/pubmed/23947357

Myeloid derived suppressor cells (MDSCs) are immature cells of myeloid origin, frequently found in tumor microenvironments and in the blood of cancer patients. In recent years, MDSCs have also been found in non-cancer settings, including a number of viral infections. The evasion of host immunity employed by viruses to establish viral persistence strikingly parallels mechanisms of tumor escape, prompting investigations into the generation and function of MDSCs in chronic viral infections. Importantly, analogous to the tumor microenvironment, MDSCs effectively suppress antiviral host immunity by limiting the function of several immune cells including T cells, natural killer cells, and antigen-presenting cells. In this article, we review studies on the mechanisms of MDSC generation, accumulation, and survival in an effort to understand their emergent importance in viral infections. We include a growing list of viral infections in which MDSCs have been reported. Finally, we discuss how MDSCs might play a role in establishing chronic viral infections and identify potential therapeutics that target MDSCs.

Paclitaxel at ultra low concentrations inhibits angiogenesis without affecting cellular microtubule assembly. http://www.ncbi.nlm.nih.gov/pubmed/12544254

Many conventional chemotherapeutics, such as the microtubule-stabilizing anticancer drug paclitaxel (Taxol), have been shown to have anti-angiogenic activity and clinical application of a continuous low dose of these agents has been suggested for cancer therapy. In this study, we show that paclitaxel selectively inhibits the proliferation of human endothelial cells (ECs) at ultra low concentrations (0.1-100 pM), with an IC50 = 0.1 pM, while it inhibits non-endothelial type human cells at 10(4) – to 10(5) -fold higher concentrations, with IC50 = 1-10 nM. The selectivity of paclitaxel inhibition of cell proliferation is also species specific, as mouse ECs are not sensitive to paclitaxel at ultra low concentrations. They are inhibited by higher concentrations of paclitaxel with IC50 = 1-10 nM. Inhibition of human ECs by paclitaxel at ultra low concentrations does not affect the cellular microtubule structure, and the treated cells do not show G2/M cell cycle arrest and apoptosis, suggesting a novel but as yet unidentified mechanism of action. In an in vitro angiogenesis assay, paclitaxel at ultra low concentrations blocks human ECs from forming sprouts and tubes in the three-dimensional fibrin matrix. In summary, paclitaxel selectively inhibits human EC proliferation and in vitro angiogenesis at low picomolar concentrations. The data support a clinical application of continuous ultra-low-dose paclitaxel to treat cancer.

The pharmacological bases of the antiangiogenic activity of paclitaxel. http://www.ncbi.nlm.nih.gov/pubmed/23389639

In the mid 1990s, researchers began to investigate the antiangiogenic activity of paclitaxel as a possible additional mechanism contributing to its antineoplastic activity in vivo. In the last decade, a number of studies showed that paclitaxel has antiangiogenic activity that could be ascribed to the inhibition of either tubule formation or cell migration, and to an antiproliferative effect towards activated endothelial cells. Furthermore, paclitaxel was shown to downregulate VEGF and Ang-1 expression in tumor cells, and to increase the secretion of TSP-1 in the tumor microenvironment. Moreover, the new pharmaceutical formulations of paclitaxel (such as liposome-encapsulated paclitaxel, ABI-007, and paclitaxel entrapped in emulsifying wax nanoparticles) enhanced the in vivo antiangiogenic activity of the drug. Thus, the preclinical data of paclitaxel may be exploited to implement a novel and rational therapeutic strategy to control tumor progression in patients.

The Emergence of Immunomodulation: Combinatorial Immuno-Chemotherapy Opportunities for the Next Decade http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119495/

In the past decade we have witnessed important advances in the treatment of gynecological cancers and have recognized their potential immunogenicity. This has opened the door to explore immune therapy not only in HPV-induced cancers but also in ovarian and endometrial cancers. Here we will review the off target immune effects of select chemotherapy drugs commonly used to treat gynecologic cancers and novel tools that can stimulate both the adaptive and innate immune mechanisms such as novel pleiotropic cytokines, Toll-like receptors, and powerful antibodies that can target inhibitory checkpoints thereby activating effector cellular immune mechanisms and neutralizing suppressor cells. We will also review how existing drugs can be used for combinatorial tumor therapy.

Enhancement of tumor radioresponse by docetaxel: Involvement of immune system.http://www.ncbi.nlm.nih.gov/pubmed/11179493/

Thus, our results showed that docetaxel stimulates tumor infiltration with immune cells, which then participate in antitumor action of docetaxel alone or when combined with radiotherapy.

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