Ayre SG, Garcia y Bellon DP, Garcia DP Jr.
The endogenous molecular biology of cancer cells involves autocrine and paracrine secretion of insulin and insulin-like growth-factors I and II, which subserve energy production and growth stimulation, respectively, in these cells. These activities confer on cancer its malignant potential, working as they do autonomously, free from higher levels of integrated control. Taking advantage of cancer's mechanisms of malignancy by employing exogenous insulin as a biologic response modifier, it is possible to potentiate the cytotoxic effects of chemotherapeutic agents for improved treatment of cancer. A synergy between certain membrane and metabolic effects of insulin on cancer cell molecular biology increases anticancer drug efficacy, and it does so with reduced doses of the drugs, enhancing their safety. This treatment strategy has been applied abroad over the last five decades with very promising clinical results. Copyright 2000 Harcourt Publishers Ltd.
PMID: 11000062 [PubMed - indexed for MEDLINE]
In clinical applications of IPT, pharmacologic doses of insulin - 0.4 units per kilogram body weight (Humalog, Lilly) - are administered to manipulate the endogenous mechanisms of malignancy in cancer cells via the mechanisms described. Naturally, insulin delivery is done in conjunction with glucose monitoring and appropriate hypertonic glucose administration. Drug potentiation results from an insulin-induced increase in transmembrane passage and intracellular accumulation of drug, along with a recruitment of cells into S-phase of the cell replicative cycle by cross-reaction of insulin with IGF receptors. A synergy between these two effects of insulin and the pharmacokinetics of anticancer drug
therapy greatly enhances cytotoxicity, particularly for the cell cycle phase-specific anticancer drugs.
As well as improved efficacy, this regimen also increases safety because of the lower total doses that may be effectively used, with corresponding reduced drug side effects. Typically, reductions of seventy-five to ninety percent of the usual and customary doses of anticancer medication are given, employing combinations of chemotherapy agents standard for the diagnosis and stage of the particular disease. Augmenting both elements of safety and efficacy here is IPT's "smart bomb" effect caused by the relative selectivity of insulin action on cancer cells, as compared to normal somatic cells, due to the excess of insulin and IGF receptors on their cell membranes.
Insulin Potentiation Therapy is an empirically derived innovation for which good scientific evidence now exists to affirm its formulation. Being consistent with the natural biology of cancer cells, the operative mechanisms in IPT make it an ideal process for the medical treatment of cancer. In its turn, IPT strongly affirms the appropriateness of chemotherapy in cancer management, creating the possibility of expanding the scope of application for chemotherapy as primary treatment for certain malignancies. These are two important affirmations. First, the strong anecdotal and supporting scientific evidence for IPT makes this a potential boon for the medical profession to be able to manage cancer more effectively. Second, relying as it does on chemotherapy there is little that is truly "alternative" about Insulin Potentiation Therapy, a similar boon for important sectors of the medical industry that provide us with the tools for treating cancer.
Cancer Chemother Pharmacol (2004) 53: 220–224 Insulin-induced enhancement of antitumoral response to methotrexate in breast cancer patients. Full Text (PDF) Archived full text
Lasalvia-Prisco E, Cucchi S, Vazquez J, Lasalvia-Galante E, Golomar W, Gordon W.
Department of Medicine, School of Medicine, University of Uruguay, Montevideo, Uruguay.
PURPOSE. It has been reported that insulin increases the cytotoxic effect in vitro of methotrexate by as much as 10,000-fold. The purpose of this study was to explore the clinical value of insulin as a potentiator of methotrexate. PATIENTS AND METHODS. Included in this prospective, randomized clinical trial were 30 women with metastatic breast cancer resistant to fluorouracil + Adriamycin + cyclophosphamide and also resistant to hormone therapy with measurable lesions. Three groups each of ten patients received two 21-day courses of the following treatments: insulin + methotrexate, methotrexate, and insulin, respectively. In each patient, the size of the target tumor was measured before and after treatment according to the Response Evaluation Criteria In Solid Tumors. The changes in the size of the target tumor in the three groups were compared statistically. RESULTS. Under the trial conditions, the methotrexate-treated group and the insulin-treated group responded most frequently with progressive disease. The group treated with insulin + methotrexate responded most frequently with stable disease. The median increase in tumor size was significantly lower with insulin + methotrexate than with each drug used separately. DISCUSSION. Our results confirmed in vivo the results of previous in vitro studies showing clinical evidence that insulin potentiates methotrexate under conditions where insulin alone does not promote an increase in tumor growth. Therefore, the chemotherapy antitumoral activity must have been enhanced by the biochemical events elicited in tumor cells by insulin. CONCLUSIONS. In multidrug-resistant metastatic breast cancer, methotrexate + insulin produced a significant antitumoral response that was not seen with either methotrexate or insulin used separately.
PMID: 14655024 [PubMed - as supplied by publisher]
Abstract—Insulin, which activates and modifies metabolic pathways in MCF-1 human breast cancer cells, is shown to increase the cytotoxic effect of methotrexate up to ten thousand-fold in vitro. This enhanced Cytotoxicity is not due to an increased bound intracellular drug level, an increased growth rate or an increase in S phase cells, but may involve the modification or activation of biochemical pathways associated with cell growth, even in cells not undergoing DNA synthesis. This observation supports the hypothesis that tumor cell sensitivity to chemotherapy could be increased by using agents that can activate the biochemical or metabolic pathways that determine the cytotoxic process
Acta Pharmacol Sin. 2007 May;28(5):721-30. Pretreatment with insulin enhances anticancer functions of 5-fluorouracil in human esophageal and colonic cancer cells.
Zou K, Ju JH, Xie H.
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
AIM: To investigate the effects of insulin on enhancing 5-fluorouracil (5-FU) anticancer functions and its mechanisms in the human esophageal cancer cell line (Eca 109) and human colonic cancer cell line (Ls-174-t). METHODS: The effect of insulin/5-FU combination treatment on the growth of Eca 109 and Ls-174-t cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. After insulin treatment or insulin/5-FU treatment, cell cycle distribution of both cell lines was analyzed by flow cytometry. Western blot assay was used to assess the expression of caspase-3 and thymidylate synthase (TS). Apoptosis was detected by flow cytometry, DNA fragmentation assay, and terminal transferase dUTP nick end labeling assay (TUNEL). Moreover, the changes of 5-FU uptake after insulin pretreatment were detected by HPLC assay and Western blot analysis. RESULTS: We found that insulin enhanced the inhibitory effect of 5- FU on cell proliferation when Eca 109 cells and Ls-174-t cells were pretreated with insulin for the appropriate time. Insulin increased the cell number of the S phase and the uptake of 5-FU. Insulin/5-FU treatment enhanced apoptosis of tumor cells and upregulated the expression of cleaved caspase-3 compared with 5-FU treatment. Moreover, insulin/5-FU treatment induced the changes of free TS and the TS ternary complex level compared with 5-FU treatment in Eca 109 and Ls-174-t cells. CONCLUSION: These data suggest that insulin enhances anticancer functions of 5- FU when it is treated before 5-FU for the appropriate time in human esophageal and colonic cancer cell lines.
PMID: 17439729 [PubMed - indexed for MEDLINE]
Cancer Res. 1984 Aug;44(8):3570-5. Perturbation by insulin of human breast cancer cell cycle kinetics.
Gross GE, Boldt DH, Osborne CK.
The growth of cultured human breast cancer cells is sensitive to physiological concentrations of insulin suggesting that it may regulate breast cancer growth in vivo. The mechanisms for the growth effects of insulin are poorly defined. In the present study, we examine the effects of insulin on the cell cycle kinetics of asynchronous MCF-7 human breast cancer cells growing in serum-free medium. When the [3H]thymidine labeling index is used to estimate the S-phase fraction, insulin added to asynchronously growing cells results in a time-dependent increase in the proportion of cells engaged in DNA synthesis. Computer analysis of DNA histograms obtained by flow cytometry of mithramycin-stained cells also shows a time-dependent progression of cells into and through the S-phase compartment. Sixteen hr after adding insulin to asynchronous cells, 66% of cells are in S-phase compared to 37% in controls. The effect of insulin on the cell cycle progression of MCF-7 cells is also dose dependent. Stimulation is observed with physiological insulin concentrations of 0.1 to 1.0 nM; maximal effects are observed with 1.0 to 10 nM insulin. Various insulin analogues enhance the progression of cells into S phase in proportion to their ability to bind to the insulin receptor in MCF-7 cells (porcine greater than or equal to chicken greater than guinea pig greater than deoctapeptide insulin), while unrelated peptide hormones have no effect on the cell cycle kinetics. Cell cycle analysis after the addition of colchicine to prevent mitosis and the reentry of cells into G1 demonstrates a shortened G1 in response to insulin. Continuous [3H]thymidine-labeling studies after the addition of colchicine suggest that the growth fraction is about 88% with or without insulin. In summary, insulin causes a marked perturbation of the cell cycle kinetics of MCF-7 human breast cancer cells by facilitating the transit of cells through G1. The data also suggest that this effect is mediated via the insulin receptor.
SGA, Donato Perez Garcia y Bellon and Donato Perez Garcia, Jr
European Journal of Cancer 1990; 26(11-12):1262-3
Published on IPTQ by permission from Donato Perez Garcia, M.D.
WE HAVE developed a neoadjuvant chemohormonal therapy for breast carcinomas without surgery or radiotherapy. Cyclophosphamide, methotrexate, and 5-fluorouracil are administered, with insulin as a biological response modifier to potentiate anticancer drug effects . This regimen affords maximum breast conservation and minimum patient discomfort.
Breast malignancies are histologically verified by fine needle biopsy. Insulin/chemotherapy cycles are repeated twice a week for 3 weeks, and then weekly for another 3—6 weeks depending on clinical findings. Fasting subjects receive insulin (0.3 U/kg) and, at onset of hypoglycaemia, cyclophosphamide 8 mg/rn2, methotrexate 3 mg/rn2, and 5-fluorouracil 50 mg/rn2 with 50% hypertonic glucose, intravenously. On non-treatment days, patients are given oral cyclophosphamide 50 mg and rnethotrexate 2.5 mg.
A 32-year-old woman found a lump in her right breast in November 1988. Xeromammography confirmed the presence of a lesion (Fig. 1), and a biopsy revealed an infiltrating ductal adenocarcinoma. After 8 weeks of chemohormonal therapy, the breast mass was no longer palpable. A xeromammogram at 3 months showed no evidence of tumour (Fig. 1).
Insulin and insulin-like growth factor-1 (IGF-1) have been identified as autocrine and/or paracrine growth factors in human breast cancer cells [2—4]. We administer pharmacological doses of insulin to manipulate membrane and metabolic activities of these endogenous growth-promoting mechanisms, thereby potentiating anticancer drug effects. Drug potentiation results from an insulin-induced increase in the transmembrane passage of anticancer drugs in human breast cancer cells [5, 6], and a recruitment of cell populations into S-phase of the replicative cycle by cross-reaction of insulin with IGF-1 receptors . The cell-killing effects of anticancer drugs, particularly the chemotherapy agents specific for cell cycle phase, are greatly augmented . Therefore, ideal pharmacokinetic circumstances for the chemotherapy of breast cancer are created. As well as improved efficacy, this regimen increases safety because of lower total doses administered and reduced side-effects.
Chemohormonal therapy with oestrogen has shown promising results in preliminary trials . However, insulin and chemotherapy is more efficacious, as not only can insulin mimic oestrogen’s cell-recruiting effects in oestrogen receptor positive human breast cancer cells , but insulin also stimulates recruitment in oestrogen receptor negative cells. Unlike oestrogen, insulin can increase the transmembrane passage and intracellular accumulation of anticancer drugs. The administration of low-dose anticancer drug therapy with insulin can produce complete and long-term regression of tumour masses in treated subjects. Therapy is tolerated without adverse effect and in our case produced excellent cosmetic results.
Fig. 1. Patient 1: xeromammogram on 3 February (left)
and 15 June (right) 1989.
1. SGA, Perez Garcia y Bellon D, Perez Garcia D Jr. Insulin potentiation therapy: a new concept in the management of chronic degenerative disease. Med Hypotheses 1986,20, 199—210.
2. Hilf R. The actions of insulin as a hormonal factor in breast cancer. In: Pike MC, Siiteri PK, Welsch CW, eds. Hormones and Breast Cancer. Cold Spring Harbor, Cold Spring Harbor Laboratory, 1981, 317—337.
3. Lippman ME, Dickson RB, Kasid A, et al. Autocrine and paracrine growth regulation of human breast cancer. J Steroid Biochem 1986, 24, 147—154.
4. Cullen JK, Yee D, Sly WS, et al. Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res 1990, 50,48—53.
5. Alabaster 0, Vonderhaar BK, Shafie SM. Metabolic modification by insulin enhances methotrexate cytotoxicity in MCF-7 human breast cancer cells. Eur J Cancer Clin Oncol 1981, 17, 1223—1228.
6. Oster JB, Creasey WA. Enhancement of cellular uptake of ellipticine by insulin preincubation. Eur 3 Cancer Clin Oncol 1981, 17, 1097—1103.
7. Van Wyk JJ, Graves DC, Casella SJ, Jacobs S. Evidence from monoclonal antibody studies that insulin stimulates deoxyribonucleic acid synthesis through the type 1 somatomedin receptor. 3 Clin Endocrinol Metab 1985, 61,639—643.
8. Shackney SE, Cell kinetics and cancer chemotherapy. In: Calabresi
P, Schein PS, Rosenberg SA, eds. Medical Oncology: Basic Principles and Clinical Management of Cancer, New York, Macmillan, 1985, 41—60.
9. Paridaens R, Klijn JGM, Julien JP, et al. Chemotherapy with estrogenic recruitment in breast cancer: experimental background and clinical studies conducted by the EORTC breast cancer cooperative group. Eur J Cancer Clin Oncol 1986,22,728.
10. Van der Burg B, de Laat SW, van Zoelen EJJ. Mitogenic stimulation of human breast cancer cells in a growth-factor defined medium: synergistic action of insulin and estrogens. In: Brescani F, King RJB, Lippman ME, Raynaud JP, eds. Progress in Cancer Research and Therapy, vol. 35: Hormones and Cancer 3. New York, Raven Press, 1988,231—233.
One outstanding advantage IPTLD™ has over traditional treatment is that a much lower dose of chemotherapeutic drugs is required. IPTLD™ more selectively targets cancer cells while affecting relatively few normal cells. Therefore, patients do not suffer the severe side effects that commonly occur with conventional chemotherapy, such as hair loss, vomiting, fatigue and depression. Thus, the quality of a patient's life is significantly improved in comparison to that many patients experience when undergoing conventional treatment experience.
A Closer Look at How it Works
Cancer cells derive energy from an unlimited supply of glucose, which they get by secreting their own insulin. They also stimulate their own growth by producing insulin-like growth factors (IGF). These are the mechanisms of malignancy.
Insulin and IGF each work by attaching to specific cell membrane receptors, which are much more concentrated on cancer cell membranes than on normal ones. Attachment to these receptors is key to the success of IPTLD™ and helps explain why it is able to use lower doses of drugs that mainly target the cancer cells, kill them more effectively, and avoid the dose-related side effects of traditional chemotherapy.
In effect, IPTLD™ kills cancer cells by using the same mechanisms that cancer cells use to kill people. A One-Two Punch
Insulin, in addition to its ability to help deliver higher-levels of the chemotherapy drugs into the cancer cells, also causes these cells to go into their growth phase where they actually become more vulnerable to the chemotherapy drugs. The cells are hit harder and at a time when they are most vulnerable to the assault, thus maximizing results.
In 1981, a study conducted at George Washington University showed that the chemotherapy drug, methotrexate, when used with insulin, increased the drug's cell-killing effect by a factor of 10,000!
This study was done in conjunction with the Laboratory of Pathophysiology at NCI which studied the impact of methotrexate on breast cancer with and without insulin. The study concluded that 10-10 methotrexate without insulin was equivalent to 10-6 when combined with insulin. This 1981 study found a specific enhancement of a particular carrier system for methotrexate, but launched additional interest in studying IPTLD™ and its broader applications. Additional research found that because insulin recruits resting cancer cells to become active in protein and DNA synthesis, they become more vulnerable to the targeted activity of chemotherapy. As an added advantage, insulin assists debilitated cancer patients appetite and metabolism, helping to resolve the wasting that accompanies the disease and its therapy Alabaster, O. Metabolic modification by insulin enhances methotrexate cytotoxicity in MCF-7 human breast cancer. Europ J Cancer Oncol. 1981; 17:1223-1228.
What Are the Risks?
If hypoglycemia is unchecked by glucose administration, it can lead to insulin shock, which can bring about anemia, kidney, liver, or heart damage, loss of consciousness or coma. This is easily managed, however, during the treatment.
A treatment that capitalizes on the PET/Glucose mechanism:
Controlling Cancer Growth
At the Nevada Center we use a form of chemotherapy called Insulin Potentiation Therapy (IPT). IPT is a simple, safe medical treatment that exploits the fact that cancer cells, unlike healthy cells, are not able to metabolize fat for energy. They rely completely on glucose (sugar/carbohydrates) for their energy supply. This is a weakness of cancer cells, and we use this weakness to control them. We use the hormone insulin to do this. When insulin is injected it has the effect of causing the patient’s blood sugar to drop. As the blood sugar drops, the patient’s healthy cells simply shift over to fat metabolism, but the patient’s cancer cells become seriously compromised. Since they rely entirely on sugar metabolism, they go into an emergency mode and open all of their membranes in an effort to get sugar. In this state they are very vulnerable to chemotherapy drugs. Once the blood sugar has reached a low enough level for the treatment to be effective, we then inject the chemotherapy drugs. This is immediately followed by an intravenous infusion of large amounts of sugar. What happens next is that the cancer cells, weakened and starved for sugar, take up the chemotherapy drugs in large amounts as they take up the sugar they so desperately need.
The effect of this technique is two-fold. First, the cancer cells will take up much larger amounts of chemotherapy medications than they ordinarily would without the insulin application. Secondly, since they are in such a weakened and vulnerable state from the lack of sugar, they are much more sensitive to the toxic effects of the drugs. The result is a level of cancer cell death and growth control comparable to standard chemotherapy. But there is one very big difference. IPT Is Gentle
Because the IPT technique results in a higher concentration of the chemo-therapeutic drugs in the cancer cells, we are able to use much lower chemo-therapy doses than are normally used to get the same intracellular levels. In general, we usually use about one tenth of the standard dose. A recent soon to be published review of patients treated with IPT shows that the cancer growth controlling effect of IPT isequal to that of standard chemotherapy.
The fact that we can use a lower dose of medication and yet have the same results leads to two very important advantages to IPT. First, the lower dose means that there are little to no side effects. Our patients typically feel as good as ever – even immediately after the treatments. Secondly, and perhaps more importantly, because the doses are so low, IPT treatments can be used as long as they are needed without the concern of long-term toxicity to healthy cells and tissues.
Insulin Potentiation Therapy (IPT) is a questionable cancer therapy that uses insulin as an adjunct agent to potentiate the effect of chemotherapy and other medications. This therapy was developed in Mexico by Dr. Donato Perez Garcia in the 1930's and has been used together with other unconventional therapies for many years (1). Advocates of IPT believe that cancer cells consume more sugar than healthy cells and therefore cancer cells are more sensitive to insulin and insulin-like growth factor (IGF) (2)(7). Insulin is also believed to increase the permeability of cell membranes, increasing the intracellular concentration and cytotoxic effect of anticancer drugs (1). According to the theory behind the therapy, if cancer cells can be activated by exogenous insulin, a reduced dose (up to one-tenth the normal dose) of a chemo drug can provide the same cytotoxic effects with less severe adverse reactions. No clinical trials have been performed to validate these claims. In addition, the pharmacokinetic profiles on concurrent use of insulin and chemo drugs are lacking and it is unclear whether the insulin also potentiates the toxic effects of chemotherapy on healthy cells. Although proponents have cited many anecdotal case reports suggest that IPT may be effective, currently there is no data comparing the efficacy of IPT to conventional chemotherapy. Most of the medications used, such as insulin and other chemo drugs, are approved by the FDA, but the IPT clinics administer them 'off-label.' Some clinics that administer IPT are not operated or staffed by oncologists. Side effects of IPT include hypoglycemic reaction. A systematic review of 21 studies showed a correlation between circulating levels of IGF-I, IGFBP3 (IGF-binding protein) and an increased risk of common cancers (8). IPT remains an unproven cancer therapy until there are more studies available to validate its benefit.
No doubt IPT is controversial/alternative. But the Warburg effect and glycolysis has been around and ignored for a long time. There are numerous indications (eg. Metformin) the concept has some merit. Whether IPT has merit is hard to tell considering the lack of formal trials. But at an admittedly simplistic level, it seems to exploit the same mechanisms that Glucose based PET imaging does. They've known for many years to keep diabetics from taking their Metformin because it interferes with tumor activity. Well...common sense would tell you that's a good thing. Now, many years later, science seems to be saying "Maybe metformin is good." IPT looks like an attempt to harness the same mechanism in a more aggressive fashion. Just saying Metformin was basically sitting under their nose for years. Maybe IPT is the same. And taking it a little further, maybe the supposed myth of "sugar feeds cancer" is at the core. The connections between cancer, metabolism and diabetes continue to be discovered. http://www.reuters.com/article/healt...5AO4VO20091125 http://www.ncbi.nlm.nih.gov/pubmed/14713323 Metabolic syndrome
Many researchers are piling on to the idea that PET scan uptake a short time after treatment can show whether a given chemo is reaching and affecting (slowing down) the tumor cells. Again, common sense. It would be interesting to see how IPT treated tumor cells look a few days after treatment. Although not primed with extensive sugar deprivation via insulin, it would be very interesting to look at existing cancer patients' records who had chemo immediately after glucose injection/PET scan.
I've heard oncologists say more aggressive cancers respond better to chemo. Maybe their increased activity separates them more readily from normal cells and makes them a more visible target for chemo. Maybe deprivation, then giving cancer cells a temporary sugar rush makes them more targetable in the same way.
Maybe a middle ground (avoids insulin injections) would be to use metformin or ultra low carb diet between treatments but stop it prior to chemo in the same way as Metformin is stopped before PET. If you can't get a glucose shot or IV, maybe a six pack of Orange crush after chemo infusion would do the trick. Not sure I'm joking.
100% of people over 60, upon autopsy, have undiagnosed cancer kept in check by immune system:
Women aged 40+: 40% have BC in one breast, 25% in one breast, i.e. 33% never diagnosed and inconsequential
Proposed course for cancer treatment:
Warburg effect (sugar metabolism issues) decreases oxidation. Poor oxidation levels common in cancer.
Liver dysfunction(hampered O2, fat and sugar issues) common to stage III and IV cancer.
Vegetarian diet to reduce toxicities.
Coffee enemas (ouch) as direct line to liver trigger release of bile and associated toxicities.
Stress undermines ability to control cancer, needs addressing.
Intra-cellular analysis via www.spectracell.com identifies immune system deficiencies
Possible adjustment with mushrooms, ozone and hormone replacement strategies.
Kill the cancer
assess individualized chemo susceptibility through blood analysis.
Chemosensitivity (CTC/blood based) lab mentioned: http://www.rgcc-genlab.com/html/about.html
Indicates sensitivity to chemo as well as natural supplement(Vit C, Quercetin, Hyd perox)and anti-angiogenics.
The problem with traditional chemo is dosage. Sensitivity and phase targeting reduces dose.
Insulin potentiation therapy (IPT) to make cancer cells more suceptible to identified/targeted chemo at reduced dose:
Breast cancer cells have many insulin receptors.
Healthy non-brain cells can live on fat. Cancer cells need glucose. Insulin can be applied to reduce blood sugar just above point that brain needs, while damaging cancer cells. In so doing, insulin induced sugar starvation for 5 minutes followed by sugar puts sugar-starved cancer cells into hyperactive S-phase where they are more susceptible to chemo. 10x more chemo is ingested into cancer cells, with 20 x more cancer cells in chemo vulnerable S-phase. 10x more susceptibilty means 1/10 of normal chemo needed for sensitivity informed killing.
Longo also discussed a promising new approach to protecting healthy cells from the harmful side effects of chemotherapy through fasting.
Starved healthy cells go into survival mode, Longo explained, characterized by extreme resistance to stresses. In essence, these cells are waiting out the lean period, much like hibernating animals. But cancerous tumors respond differently to starvation; they do not stop growing, nor do they hibernate because their genetic pathways are stuck in an “on” mode.
Longo realized that the starvation response might differentiate healthy cells from cancer cells by their increased stress resistance and that healthy cells might withstand much more chemotherapy than cancer cells.
Not a Magic Bullet, But a Magic Shield
USC biologists discover a way to protect healthy cells against chemotherapy.
Fasting for two days protects healthy cells against chemotherapy, according to a study appearing online the week of March 31 in PNAS Early Edition.
Mice given a high dose of chemotherapy after fasting continued to thrive. The same dose killed half the normally fed mice and caused lasting weight and energy loss in the survivors.
The chemotherapy worked as intended on cancer, extending the lifespan of mice injected with aggressive human tumors, reported a group led by Valter Longo of the USC Davis School of Gerontology and USC College.
Test tube experiments with human cells confirmed the differential resistance of normal and cancer cells to chemotherapy after a short period of starvation.
Making chemotherapy more selective has been a top cancer research goal for decades. Oncologists could control cancers much better, and even cure some, if chemotherapy was not so toxic to the rest of the body.
Experts described the study as one of a kind.
“This is a very important paper. It defines a novel concept in cancer biology,” said cancer researcher Pinchas Cohen, professor and chief of pediatric endocrinology at UCLA.
“In theory, it opens up new treatment approaches that will allow higher doses of chemotherapy. It’s a direction that’s worth pursuing in clinical trials in humans.”
Felipe Sierra, director of the Biology of Aging Program at the National Institute on Aging, said, “This is not just one more anti-cancer treatment that attacks the cancer cells. To me, that’s an important conceptual difference.”
Sierra was referring to decades of efforts by thousands of researchers working on “targeted delivery” of drugs to cancer cells. Study leader Longo focused instead on protecting all the other cells.
Sierra added that progress in cancer care has made patients more resilient and able to tolerate fasting, should clinical trials confirm its usefulness.
“We have passed the stage where patients arrive at the clinic in an emaciated state. Not eating for two days is not the end of the world,” Sierra said.
“This could have applicability in maybe a majority of patients,” said David Quinn, a practicing oncologist and medical director of USC Norris Hospital and Clinics. He predicted that many oncology groups would be eager to test the Longo group’s findings and advised patients to look for a clinical trial near home.
Longo, an anti-aging researcher who holds joint appointments in gerontology and biological sciences at USC, said that the idea of protecting healthy cells from chemotherapy may have seemed impractical to cancer researchers because the body has many different cells that respond differently to many drugs.
“It was almost like an idea that was not even worth pursuing,” Longo said. “In fact it had to come from the anti-aging field because that’s what we focus on: protecting all cells at once.”
According to Cohen, “What really was missing was a perspective of someone from the aging field to give this field a boost.”
The idea for the study came from the Longo group’s previous research on aging in cellular systems, primarily lowly baker’s yeast.
About five years ago, Longo was thinking about the genetic pathways involved both in the starvation response and in mammalian tumors. When the pathways are silenced, starved cells go into what Longo calls a maintenance mode characterized by extreme resistance to stresses. In essence, the cells are waiting out the lean period, much like hibernating animals.
But tumors by definition disobey orders to stop growing because the same genetic pathways are stuck in an “on” mode.
That could mean, Longo realized, that the starvation response might differentiate normal and cancer cells by their stress resistance and that healthy cells might withstand much more chemotherapy than cancer cells.
The shield for healthy cells does not need to be perfect, Longo said. What matters is the difference in stress resistance between healthy and cancerous cells.
During the study, conducted both at USC and in the laboratory of Lizzia Raffaghello at Gaslini Children’s Hospital in Genoa, Italy, the researchers found that current chemotherapy drugs kill as many healthy mammalian cells as cancer cells.
“(But) we reached a two to five-fold difference between normal and cancer cells, including human cells in culture. More importantly, we consistently showed that mice were highly protected while cancer cells remained sensitive,” Longo said.
If healthy human cells were just twice as resistant as cancer cells, oncologists could increase the dose or frequency of chemotherapy.
“We were able to reach a 1,000-fold differential resistance using a tumor model in baker’s yeast. If we get to just a 10–20 fold differential toxicity with human metastatic cancers, all of a sudden it’s a completely different game against cancer,” Longo said.
“Now we need to spend a lot of time talking to clinical oncologists to decide how to best proceed in the human studies.”
Edith Gralla, a research professor of chemistry at UCLA, said, “It is the sort of opposite of the magic bullet. It’s the magic shield.”
Funding from the study came from the National Institute on Aging (part of the National Institutes on Health), the USC/Norris Cancer Center and the Associazione Italiana per la Lotta al Neuroblastoma.
USC graduate student Changhan Lee and Gaslini’s Raffaghello performed key experiments. The other authors were Fernando Safdie, Min Wei and Federica Madia of USC and Giovanna Bianchi of Gaslini.
Longo has been studying aging at the cellular level for 15 years and has published in the nation’s leading scientific journals. He is the Albert L. and Madelyne G. Hanson Family Trust Associate Professor at the USC Davis School with joint appointments as associate professor of biological sciences at USC College and in the Norris Cancer Center. For Clinicians and Patients
Fasting before chemotherapy has unknown risks and benefits for humans, Longo cautioned. Only clinical trials can establish the effectiveness and safety of fasting before chemotherapy.
“Don’t try and do this at home. We need to do the studies,” said Quinn, the USC Norris oncologist.
Dr. Len Lichtenfeld, deputy chief medical officer for the American Cancer Society, in an article response to the Cancer Genome Project says, "We're going to be able to take a cancer specimen, analyze it, and follow those genetic changes that influence particular pathways, then we'll use one, two, three or more targeted therapies, perhaps simultaneously, and be able to completely interrupt the flow of the cancer process."
According to Dr. Arny Glazier, a cancer researcher (former oncology fellow at Johns Hopkins), in his book Cure: Scientific, Social and Organizational Requirements for the Specific Cure of Cancer, "the consistent and specific cure or control of cancer will require multiple drugs administered in combination targeted to abnormal patterns of normal cellular machinery that effect or reflect malignant behavior. Finding the 'patterns' of malignant cells and developing a set of 5 to10 drugs in order to cure or control cancer."
So the consistent and specific cure of cancer requires therapy that can target the set of "all" malignant cells that could evolve in the human body. It is thought that each anti-cancer drug needs to be given at a dose sufficient to kill cells that express the pattern targeted by the individual drug. In order to kill "all" patterns of malignant cells, you need to give full doses of all drugs (5-10) in combination.
However, it is not possible to give five to ten existing drugs together in combination, the toxicity would be prohibitive. They have overlapping toxicity, which means you need to cut the doses when you give them together, so you get down to homeopathic dose levels.
This could be overcomed with Potentiation Therapy (IPT) or "low dose chemotherapy," which makes cell membranes more permeable and increases uptake of drugs into cells. IPT selectively targets tumor cells, which usually have more insulin receptors than normal cells. Makes tumor cells more susceptible to chemo by modifying cell metabolism. As a result, cancer patients can greatly reduce chemo dosage (reduce it to only 10-15%), while at the same time, receive the 5-10 drugs in order to effectively cure or control cancer, and eliminate most side effects while increasing the effectiveness of chemo (chemo synthesizer).
Given the current state of the art, in vitro drug sensitivity testing could be of significant clinical value. Upgrading clinical therapy by using drug sensitivity assays measuring "cell death" of three dimensional microclusters of live "fresh" tumor cells, can improve the situation by allowing more drugs to be considered. The more drug types there are in the selective arsenal, the more likely the system is to prove beneficial.
Cell culture assays tests with cell-death endpoints are the Rosetta Stone which allows for identification of clinically relevant gene expression patterns which correlate with clinical drug resistance and sensitivity for different drugs in specific diseases. There is no single gene whose expression accurately predicts therapy outcome, emphasizing that cancer is a complex disease and needs to be attacked on many fronts.
A number of cell culture assay labs across the country have data from tens of thousands of fresh human tumor specimens, representing virtually all types of human solid and hematologic neoplasms. Cell culture assay labs have the database necessary to define sensitivity and resistance for virtually all of the currently available drugs in virtually all types of human solid and hematologic neoplasms.
I had a book on Insulin Potentiation Therapy. Once again I only skimmed the articles you put on. The impression got was that cancer cells are sugar starved because they metabolize glucose anaerobically and inefficiently. Thats the Warburg phenomenon of 1933.Wow 1933. They use Insulin to lower the blood sugars to about 40mg% and the cancer cell membranes open up to push in the needed glucose. Then chemo is given IV. The same chemos but a much lower dose is needed because the cancer cells absorb them much better. I dont know if it is more efficacious but it probably isnt any less useful and is much less toxic. Of cours Quack watch and co is dead against it.