Low Dose Chemo Part 4 – Holistic Cancer Treatment – An Oasis of Healing

“The crises of our time, it becomes increasingly clear, are the necessary impetus for the revolution now under way. And once we understand nature’s transformative powers, we see that it is our powerful ally, not a force to feared our subdued.”

—Thomas Kuhn (1922-1996)

History repeats many themes. That is the one constant among the variables of history. One repetitive theme throughout history is revolution. The word revolution evokes memory of prominent revolutions thought out world history: the Scottish insurrection, the French Revolution, and of course the American revolution come to mind. Isn’t it interesting that most revolutions are equated with war?

Revolutions are not just confined to war though. They are found throughout all aspects of culture. Revolutions are found in the world of art, the world of literature, the world of the physical sciences, and the world of medicine. Revolutions in the world of science or medicine are called paradigm shifts. Alternative medicine or the Holistic, Integrative treatment of cancer are examples of one such paradigm shift in motion.

Paradigm Shift

The term paradigm shift was first credited to the American philosopher Thomas Kuhn in his 1962 book, The Structure of Scientific Revolutions. According to the Oxford dictionary, a paradigm shift is “a fundamental change in approach or underlying assumptions”. If a paradigm shift is a shift between paradigms, what is a paradigm? Thomas Kuhn described a paradigm as the “conceptual scheme theory prevalent of the time”. Restated, it is the prism of the time through which every problem is evaluated, debated, and practiced. It is what everybody is doing. Today, it is called the standard of care.

Paradigm shifts occur when the prevailing theory of thought cannot answer the questions generated by and in the prevailing paradigm theory. Huh? A paradigm shift occurs when what everybody is doing (standard of care) cannot meet the challenge of the questions of the time. Essentially, paradigm shifts are created by problem solvers when a problem cannot be properly evaluated or solved under the current paradigm. When new questions arise that cannot be answered according to the current paradigm, a paradigm shift occurs, leading to the birth of a new paradigm. A paradigm shift is a revolution of thought that leads to a revolution in action, not necessarily a revolution of war.

In a previous post, I discussed how low-dose chemotherapy has broad, overarching anti-cancer effects. In this post, I want to wade more into some of the specifics how low-dose chemotherapy inhibits the pro-cancer process called angiogenesis.

Angiogenesis is different, but similar, to a few terms you may read or hear about—vasculogenesis or neovascularization. Angiogenesis is the production of new blood vessels from pre-existing rapidly dividing endothelial cells. Vasculogenesis is the production of new blood vessels from circulating endothelial progenitor cells that originate from bone marrow. The difference may seem like semantics, but angiogenesis and vasculogenesis are distinct, but separate processes that are critical to the support of a growing tumor. Neovascularization refers to new vascular growth, which can include both angiogenesis and vasculogenesis.

Angiogenesis is vital to the genesis, progression, growth, and the metastatic spread of cancer. Angiogenesis is the new, rapid vascular growth that is essential to meet the high metabolic demand of the rapidly growing tumor. It is also the means to spread. This new vascular growth, called neovascularization, helps to deliver nutrients required to meet the high metabolic demand of cancer growth and eliminate the waste products that are a byproduct of the same growth. Needless to say, the targeting of angiogenesis with treatment provides a means to disable the process of cancer at a multitude of levels. The specific target of low-dose, metronomic chemotherapy in the process of angiogenesis are endothelial cells. Endothelial cells line the new vessel growth that is a part of this new, rapid vascularization process inherent to angiogenesis. In contrast to maximum to tolerated toxicity chemotherapy (MTTC), endothelial cells have shown to be particularly vulnerable to the repeated, low-dose exposure of chemotherapy [1]. In contrast, cancer cells are particularly prone to the development of chemo-resistance from the delivery of maximum to tolerated toxicity (MTTC) approach of conventional chemotherapy.

I must confess, I love biochemistry! I am a nerd for all things biochemistry, especially when it comes to the process of cancer and the mechanisms of natural therapies in the treatment of cancer. A beautiful article published in the journal Cancers in May 2020 entitled Inducing Angiogenesis, A Key Step in Cancer Vascularization, and Treatment Approaches highlights the balance of promoter and inhibitor signals vital to the process of angiogenesis [2]:


Angiogenesis is the result of the balance of signals that promote angiogenesis versus the balance of signals that inhibit angiogenesis.

Angiogenesis signal promoters include:

  • Chemokines
  • Fibroblast Growth Factor (FGF)
  • Hepatocyte Growth Factor (HGF)
  • Hypoxia-inducible factor (HIF)
  • Platelet-derived growth factor (PDGF)
  • Transforming growth factor (TGF)
  • Vascular endothelial growth factor (VEGF)

Angiogenesis signal inhibitors include:

  • Angiopoietin
  • Angiostatin
  • Chemokines
  • Endostatin
  • Interferons
  • Pigment epithelium-derived factor (PEDF)
  • Thrombospondin

The primary battle of these signals occurs in the tumor microenvironment. These signals are produced by the tumor cells and other cells present in the tumor microenvironment. The point here is not to highlight the specific details in the signaling balance that favors or inhibits angiogenesis. In fact, the balance of the signals that favors angiogenesis are well known. The point here is that this signaling balance knowledge lends itself for direct targeting with treatment. The pro-angiogenic balance of promoters to inhibitors leads to what is called the “angiogenic switch” [3] [4] [5]. The angiogenic switch is required for the transition of a premalignant tumor cell to a malignant tumor. It supplies the necessary vascular support to meet the metabolic demands required for rapid growth and metastatic spread.  In many ways, the angiogenic switch is the beginning of the snowball rolling down the hill.

As cliché as angiogenic switch may appear, at least as much as I have used it already, the contribution of angiogenesis to carcinogenesis may even occur prior to the angiogenic switch. The target is the tumor microenvironment. The tumor microenvironment was first likened to a chronic wound that won’t heal in 1986 publication [6]. It has been estimated that over 15% of cancer result from infections (bacterial, viral, and parasitic) and 25% of cancers are the result of chronic inflammation [7]. It is the chronic immune activation that is the result of chronic infections and chronic inflammation in a chronic wound that doesn’t heal that can trigger angiogenesis prior to the angiogenic switch [8]. Isn’t that a paradox, but that is so cliché.

Does low-dose, metronomic chemotherapy inhibit tumor angiogenesis?

Numerous studies have shown that lower, more frequent dosing of chemotherapy inhibits or suppresses tumor angiogenesis [9] [10] [11] [12] [13] [14] [15]. The evidence on this point is very, very strong. Did, I mention the evidence is very strong? Many individuals, conventional doctors included, look at Holistic, Integrative cancer therapies as unscientific; but, in actuality, it is the science that forces a move to Holistic, Integrative cancer therapies. That is if the reader first reads and then can be honest with themselves. Low-dose, metronomic chemotherapy is the perfect example.

The logical next question should be does maximum to tolerated toxicity chemotherapy (MTTC) induce angiogenesis? The short answer, is no, not really. The published literature does not provide positive evidence on this point here. In fact, additional angiogenic inhibitor therapies must be added to conventional MTTC to inhibit angiogenesis [16] [17]. A 2009 publication title said it all, “It takes two to tango…” [18]. The two being MTTC and additional angiogenic inhibitor drugs. But, what about conventional MTTC without angiogenic inhibitors? The literature shows that the MTTC approach shrinks the primary tumor while causing the metastatic spread at the same time? A 2015 article published in the journal Cancer Research, entitled The role of TLR4 in chemotherapy-driven metastasis highlights the paradox of MTTC induction of metastasis even while shrinking the primary tumor [19]. The specific chemotherapy drugs implicated here were paclitaxel, doxorubicin, 5-fluorouracil (5-FU), oxaliplatin, cyclophosphamide (CTX), and cisplatin. Another article, Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner, points to local recurrence and metastasis as a result of the chemotherapy paclitaxel [20]. Neither local recurrence or metastasis can occur without active angiogenesis.

I have written and discussed previously on how the conventional approach to the use chemotherapy induces cytokine storm, which leads to metastasis. There, in part, lies the answer of how MTTC induces angiogenesis. It is important to remember that cytokine storm is associated with an increase in IL-6 cytokine signaling. Research has shown that MTTC stimulates a storm of cytokines in the tumor microenvironment. Interleukin-6 secretion is one such cytokine. A 2004 article, Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy, found that IL-6 was increased with higher dose chemotherapy every 3 weeks compared to lower doses administered weekly [21]. This really was a study that was contrasting conventional MTTC given every 3 weeks, and lower-dose, metronomic chemotherapy given weekly. The conventional MTTC, IL-6 stimulation of metastasis cannot occur without angiogenesis. A 2015 article, Interleukin-6 Stimulates Defective Angiogenesis, highlights how IL-6 is similar to Vascular Endothelial Growth Factor (VEGF) in the stimulation not only of angiogenesis, but defective angiogenesis [22]. That is exactly what occurs in cancer. Vascular endothelial Growth Factor will be discussed in greater detail in part II of this post.

It is one thing for lightening to strike once; But twice or even three times? Eventually the repetitive lightening strikes become a storm of evidence. Following the first lightening strike via the 2004 study above, the second lightening strike was a 2017 publication, Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism [23] and the third was another 2019 publication, Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor [24]. The conventional MTTC metastasis lightening storm only continues [25] [26] [27] [28]. There is really only one determination to be taken from these studies: the fact that conventional MTTC stimulates metastasis. This can only occur with the co-existent stimulation of angiogenesis. Eventually, one must recognize the winds of change that accompany this lightening storm; or one denies and hides from the evidence of the storm.

It is not enough to say that the published evidence shows that low-dose, metronomic chemotherapy inhibits tumor angiogenesis; the evidence points to the details of how. Part II of this post on low-dose, metronomic chemotherapy and angiogenesis will include the specific details of how.


[1] Untergasser G, Koeck R, Wolf D, et al. CD34+/CD133‐ circulating endothelial precursor cells (CEP): characterization, senescence and in vivo application. Exp Gerontol 2006; 41: 600–8.

[2] Saman H, Raza SS, Uddin S, Rasul K. Inducing Angiogenesis, a Key Step in Cancer Vascularization, and Treatment Approaches. Cancers. 2020;12,1172.

[3] Folkman, J.; Watson, K.; Ingber, D.; Hanahan, D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature. 1989, 339, 58–61.

[4] Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Can. 2003;3:401-410.

[5] Lin EY, Pollard JW. Tumor-Associated Macrophages Press the Angiogenic Switch in Breast Cancer. Cancer Res. June 2007;67(11):5064-5066; DOI: 10.1158/0008-5472.CAN-07-0912

[6] Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med.1986;315:1650–9. doi: 10.1056/NEJM198612253152606

[7] Okada F. Inflammation-related carcinogenesis: current findings in epidemiological trends, causes and mechanisms. Yonago Acta Med. 2014;57:65–72.

[8] Aguilar-Cazares D, Chavez-Dominguez R, Carlos-Reyes A, Lopez-Camarillo C, Hernadez de la Cruz ON, Lopez-Gonzalez JS. Contribution of Angiogenesis to Inflammation and Cancer. Front Oncol. 2019;9:1399. Published 2019 Dec 12. doi:10.3389/fonc.2019.01399

[9] Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, et al. Continuous low-dose therapy with vinblastine and vegf receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;105:R15–24.

[10] Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O’Reilly MS, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000;60:1878–86.

[11] Bocci G, Nicolaou KC, Kerbel RS. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. Cancer Res. 2002;62:6938-6943.

[12]  Wang J, Lou P, Lesniewski R, Henkin J. Paclitaxel at ultra low concentrations inhibits angiogenesis without affecting cellular microtubule assembly. Anticancer Drugs. 2003;14: 13-19.

[13] Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4:423–36.

[14] Gately S, Kerbel R. Antiangiogenic scheduling of lower dose cancer chemotherapy. Cancer J. 2001;7:427–436.

[15] Shaked Y, Emmenegger U, Man S, et al. Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood. 2005;106:3058–3061.

[16] Cesca M, Bizzaro F, Zucchetti M, Giavazzi R. Tumor delivery of chemotherapy combined with inhibitors of angiogenesis and vascular targeting agents. Front Oncol. 2013;3:259. doi:10.3389/fonc.2013.00259

[17] Moschetta M, Cesca M, Pretto F, Giavazzi R. Angiogenesis inhibitors: implications for combination with conventional therapies. Curr Pharm Des. 2010;16(35):3921-31. doi: 10.2174/138161210794455021. PMID: 21158726.

[18] Boere IA, Hamberg P, Sleijfer S. It takes two to tango: combinations of conventional cytotoxics with compounds targeting the vascular endothelial growth factor-vascular endothelial growth factor receptor pathway in patients with solid malignancies. Cancer Sci. 2010 Jan;101(1):7-15. doi: 10.1111/j.1349-7006.2009.01369.x. Epub 2009 Sep 18. PMID: 19860846

[19] Ran S. The Role of TLR4 in Chemotherapy-Driven Metastasis. Cancer Res. 2015;75(12):2405-2410. doi:10.1158/0008-5472.CAN-14-3525

[20] Volk-Draper L, Hall K, Griggs C, Rajput S, Kohio P, DeNardo D, Ran S. Paclitaxel Therapy Promotes Breast Cancer Metastasis in a TLR4-Dependent Manner. Cancer Res. Oct 2014;75(19):5421-5434; DOI: 10.1158/0008-5472.CAN-14-0067

[21] Pusztai L, Mendoza TR, Reuben JM et al. Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine. Feb 2004;25(3):94-102.

[22] Gopinathan G, Milagre C, Pearce OMT, Reynolds LE, Hodivala-Dilke K, Leinster DA, Zhong H, Hollingsworth RE, Thompson R, Whiteford JR, Balkwill F. Interleukin-6 Stimulates Defective Angiogenesis. Cancer Res. Aug 2015;75(15);3098-3107; DOI: 10.1158/0008-5472.CAN-15-1227

[23] Karagiannis GS, et al. Sci Transl Med. 2017; 9:eaan0026. https://doi.org/10.1126/scitranslmed.aan0026.

[24] Gartung A, et al. Proc Natl Acad Sci U S A. 2019;116:1698–703. https://doi.org/10.1073/pnas.1803999116.

[25] Roca H, et al. Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone. J Clin Invest. 2018;128:248–266

[26] Stanford JC, et al. Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution. J Clin Invest. 2014;124:4737–4752

[27] Park SI, et al. Cyclophosphamide creates a receptive microenvironment for prostate cancer skeletal metastasis. Cancer Res. 2012;72:2522–2532.

[28] Ford CA, et al. Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma. Curr Biol. 2015;25:577–588.

Would you like to speak with a caring member of our team to answer your specific questions? Call (480) 834-5414