[Rich66]

Kerbel looks to be Mr. Metronome.
This one came up and looks at it from a slightly different angle. kind of like half empty/half full:

Cancer Cell. 2008 Sep 9;14(3):263-73.
Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents.

Shaked Y, Henke E, Roodhart JM, Mancuso P, Langenberg MH, Colleoni M, Daenen LG, Man S, Xu P, Emmenegger U, Tang T, Zhu Z, Witte L, Strieter RM, Bertolini F, Voest EE, Benezra R, Kerbel RS.
Molecular and Cellular Biology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada. yshaked@tx.technion.ac.il
Comment in:

• Cancer Cell. 2008 Sep 9;14(3):195-6.

Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy. With respect to the latter, we show that certain chemotherapy drugs, e.g., paclitaxel, can rapidly induce proangiogenic bone marrow-derived circulating endothelial progenitor (CEP) mobilization and subsequent tumor homing, whereas others, e.g., gemcitabine, do not. Acute CEP mobilization was mediated, at least in part, by systemic induction of SDF-1alpha and could be prevented by various procedures such as treatment with anti-VEGFR2 blocking antibodies or paclitaxel treatment in CEP-deficient Id mutant mice, both of which resulted in enhanced antitumor effects mediated by paclitaxel, but not by gemcitabine.

PMID: 18772115


Especially interesting since there are others pointing out that antimitotics can trigger undesirable activities. Paclitaxel is an antimitotic, Gemcitabine is an antimetabolite.
http://her2support.org/vbulletin/sho...ht=antimitotic

But maybe metronomic delivery of all drugs reduces this?:
Metronomic Chemotherapy Have Opposite Effects on the Mobilization and Viability of Circulating Endothelial Progenitor Cells¹

http://cancerres.aacrjournals.org/cg...ull/63/15/4342

Francesco Bertolini², Saki Paul, Patrizia Mancuso, Silvia Monestiroli, Alberto Gobbi, Yuval Shaked and Robert S. Kerbel Division of Hematology-Oncology, Department of Medicine [F. B., S. P., P. M.] and Department of Experimental Oncology, IFOM-Fondazione Italiana per la Ricerca sul Cancro Institute of Molecular Oncology [S. M., A. G.], European Institute of Oncology, 20141 Milan, Italy; Molecular and Cell Biology Research, Sunnybrook and Women’s College Health Sciences Centre, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M4N 3M5 Canada [Y. S., R. S. K.]
There is growing evidence that vasculogenesis (progenitor cell-derived generation of new blood vessels) is required for the growth of some neoplastic diseases. Here we show that the administration of cyclophosphamide (CTX) at the maximum tolerable dose with 21-day breaks or at more frequent low-dose (metronomic) schedules have opposite effects on the mobilization and viability of circulating endothelial progenitors (CEPs) in immunodeficient mice bearing human lymphoma cells. Animals treated with the maximum tolerable dose CTX experienced a robust CEP mobilization a few days after the end of a cycle of drug administration, and tumors rapidly became drug resistant. CTX was associated with a consistent decrease in CEP numbers and viability and with more durable inhibition of tumor growth. Conversely, the administration of metronomic Our findings suggest that metronomic low-dose chemotherapy regimens are particularly promising for avoiding CEP mobilization and, hence, to potentially reduce vasculogenesis-dependent mechanisms of tumor growth.



and...maybe the process observed isn't important:



Int J Cancer. 2009 Oct 15;125(8):1771-7.
Endothelial progenitor cells do not contribute to tumor endothelium in primary and metastatic tumors.

Wickersheim A, Kerber M, de Miguel LS, Plate KH, Machein MR.
Tumor Angiogenesis Research Group, Department of Neurosurgery, University of Freiburg Medical School, D-79106 Freiburg, Germany.
Despite extensive research, the contribution of bone-marrow-derived endothelial progenitor cells (BM-EPC) to tumor angiogenesis remains controversial. In previous publications, the extent of incorporation of BM-EPCs into the endothelial cell (EC) layer in different tumor models has been reported as significant in some studies but undetectable in others. Here, we studied the differentiation of BM-EPCs and its contribution to tumor vessels in experimental and spontaneous lung metastasis (B16 melanoma and prostate carcinoma), in an autochthonous transgenic model of prostate tumorigenesis, in orthotopically implanted lung tumors [Lewis lung carcinoma (LLC)], in heterotopic subcutaneous models (LLC and C1 prostate carcinoma) growing in green fluorescent protein (GFP)-expressing bone marrow (BM) chimeras. Immunofluorescence was performed with a set of endothelial and hematopoietic markers and confocal microscopy was used to generate 3D reconstruction images. By performing rigorously conducted morphological studies, we found no evidence of BM-EPCs differentiation into tumor endothelium independently of tumor type, grade and organ site in primary and metastatic tumors. The vast majority of GFP(+) cells were trafficking leucocytes or periendothelial myeloid cells. To explore the possibility that local overexpression of vascular endothelial growth factor (VEGF) might increase the numbers of incorporated BM-EPCs, we analyzed tumors genetically manipulated to overexpress VEGF(164). Local VEGF production induces a massive infiltration of bone-marrow-derived cells, but did not lead to vessel wall integration of these cells. Collectively, these findings suggest that during tumor progression vascularization occurs primarily via classical tumor angiogenesis (e.g., sprouting of pre-existing ECs), whereas BM-EPCs do not incorporate into the vessel wall to any significant extent.

PMID: 19582874 [PubMed - indexed for MEDLINE]




NCI 2006
http://www.cancer.gov/ncicancerbulle...n_062706/page4

A New "Target" for Chemotherapy?

Although not typically considered a "targeted therapy" along the lines of drugs like trastuzumab (Herceptin) or gefitinib (Iressa), most chemotherapy does have a general target: rapidly dividing cells. This description applies well to cancer cells but, unfortunately, also describes some healthy cells, such as those in the bone marrow or gut, which also draw chemotherapy's wrath.
But chemotherapy drugs also have another target: endothelial cells that form the lining of newly formed blood vessels, such as those whose creation is orchestrated by tumors to fuel their growth. There is a considerable body of evidence that even very low, nontoxic doses of chemotherapy drugs, when delivered frequently for a prolonged period of time, can retard tumor blood vessel growth (or angiogenesis) by destroying endothelial cells.
Treatment approaches along these lines are now being tested in clinical trials, and they've been coined metronomic chemotherapy.
"The definition of metronomic chemotherapy varies, but generally it refers to repetitive, low doses of chemotherapy drugs designed to minimize toxicity and target the endothelium or tumor stroma as opposed to targeting the tumor," says Dr. Harold J. Burstein of the Dana-Farber Cancer Institute, who has led several early-stage trials of metronomic chemotherapy in women with breast cancer.
"It's definitely an interesting approach that opens up the possibility of using chemotherapy differently than we have traditionally considered," says Dr. Burstein.
The metronomic approach was initially proposed and tested in animal models by Dr. Timothy Browder in Dr. Judah Folkman's lab at Harvard Medical School. In the studies, standard maximum-tolerated dose (MTD) chemotherapy regimens caused cell death of endothelial cells in the blood vessels feeding to the tumor first, followed by tumor cells. But the long breaks needed between the MTD regimens allowed the damaged blood vessels, and thus the tumor, to recover.
But significantly lower doses given more frequently on a prolonged schedule proved to be far more effective, including complete tumor regressions, even in mice that were resistant to the same drug when used in a standard MTD regimen.
Since then, several research groups have confirmed these findings. And studies conducted in cell lines and animal models have also suggested that combining metronomic chemotherapy with targeted anti-angiogenesis agents is more effective than metronomic chemotherapy alone.
"I think the preclinical data together with the clinical trial results seen so far make a strong argument for testing metronomic chemotherapy more aggressively in larger trials, including trials where it's combined with different targeted agents," argues Dr. Robert Kerbel, of Sunnybrook Health Sciences Centre in Toronto, who has led many preclinical studies of metronomic chemotherapy.
A true metronomic regimen of frequent, low-dose chemotherapy over a longer period has yet to be tested in any phase III trials in the United States. A number of phase I and II trials have been conducted, however, yielding some provocative, if not altogether convincing, results.
Dr. Burstein presented data last December from a phase II clinical trial comparing a common metronomic regimen - a daily low dose of oral cyclophosphamide and a low dose of methotrexate twice a week - with or without the targeted anti-angiogenesis drug bevacizumab. The combination approach was superior to metronomic chemotherapy alone in delaying disease progression, but was not necessarily an improvement upon the results typically seen in similar patient populations treated with a standard MTD regimen.
Concerns about the toxic effects of conventional cancer treatments on pediatric patients also has prompted pediatric oncology researchers to investigate metronomic-like approaches to treatment. Some promising early results have been reported.
Based on the available clinical evidence, says Dr. Burstein, it's unclear in what setting metronomic chemotherapy might prove most useful.
"Those who are enthusiastic about it think it can be used anywhere," he says. "I think it's most likely to be used to treat more indolent, less threatening tumors because it may not work fast enough for those…with more aggressive disease."
Researchers like Dr. Kerbel, meanwhile, are making some headway on better understanding the nuts and bolts of metronomic chemotherapy, such as how to determine the lowest dose that can provide a potent benefit - the so-called optimal biological dose - and identifying biological markers that demonstrate whether the approach is having an anti-angiogenic effect.
Then there's this question: Can chemotherapy be delivered more frequently, even daily, at significantly higher doses than those used in most metronomic regimens but less than in MTD regimens? The toxicity might be greater than a "traditional" metronomic regimen, but so might the effectiveness, including in comparison with standard MTD regimens.
That's exactly what was shown in a phase III clinical trial presented earlier this month at the ASCO annual meeting. In women with locally advanced or inflammatory breast cancer, a presurgical (or neoadjuvant), metronomic-like regimen - using higher doses of cyclophosphamide, given daily; doxorubicin; and growth factor support to ensure the continued production of white blood cells - was superior to a standard MTD regimen at eliminating evidence of invasive cancer at the time of surgery. This outcome, explains Dr. Robert Livingston, a co-investigator on the Southwest Oncology Group-led trial, generally has been found to predict superior long-term outcome in patients.
The idea, according to Dr. Livingston, is to try to expose tumor cells to minimum concentrations of chemotherapy drugs for as long as possible.
"I think it's fair to call the regimen we have developed a hybrid," he says. "It can destroy tumor cells and, at the same time, the continuous exposure, particularly to cyclophosphamide, is having an anti-angiogenic effect."
By Carmen Phillips