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Insulin Plus Low-Dose CMF as Neo-Adjuvant Chemohormonal Therapy for Breast Carcinoma. 

SGA, M.D., Donato Perez Garcia y Bellon, M.D., Donato Perez Garcia, Jr., M.D.    The Third International Congress on Neo-adjuvant Chemotherapy, Paris, France, February 6-9, 1991.  

Published on IPTQ by permission of Donato Perez Garcia, M.D.

ABSTRACT

Insulin may be used as a biological response modifier along with low-dose cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as neoadjuvant chemohormonal therapy for breast cancer. Insulin and insulin-like growth factor-1 (IGF-1) are autocrine and/or paracrine growth factors in human breast cancer cells (HBCC). We administer pharmacologic doses of insulin to manipulate these endogenous growth-promoting mechanisms, and to thereby potentiate anticancer drugs administered concurrently in a hypertonic glucose solution. Drug potentiation results from an insulin-induced increase in transmembrane passage and intracellular concentration of drug, and a recruitment of cells into S-phase of the cell replicative cycle by cross-reaction of insulin with IGF-1 receptors. The synergy between these insulin effects 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 lower total doses administered and reduced side-effects. A similar approach to chemohormonal therapy using estrogen has shown promising results in clinical trials. However, insulin and chemotherapy is more efficacious because estrogen recruits only estrogen-receptor positive HBCC, while insulin can recruit both estrogen-receptor positive and estrogen-receptor negative HBCC into S-phase. Also, only insulin can enhance the transmembrane passage of anticancer drugs. We report on four subjects treated with this regimen of low-dose anticancer drug therapy given in combination with insulin. Treatments produced complete and long-term regression of tumor masses in all subjects without adverse effects, and with excellent cosmetic results.

INTRODUCTION

We have developed a neo-adjuvant chemohormonal therapy for breast carcinomas without surgery or radiotherapy [1]. In this treatment approach, endogenous mechanisms in human breast cancer cells (HBCC) are manipulated with pharmacologic doses of exogenous insulin, resulting in a potentiation of the effects of anticancer drugs thus producing a more successful cell kill. In our preliminary experience with this neo-adjuvant protocol abroad, using insulin as a biological response modifier together with reduced doses of CMF [cyclophosphamide, methotrexate (MTX), and 5-fluorouracil (5-FU)], we have produced complete and long term tumor regressions in the majority of breast cancer patients treated.

INSULIN POTENTIATION THERAPY

This innovative approach is called insulin potentiation therapy, or IPT [2]. The underlying rationale here involves two actions which insulin has on HBCC. First, acting on insulin receptors (IR) on HBCC membranes, insulin increases the dose intensity of anticancer drug within the cancer cells. Second, cross-reacting with insulin-like growth factor-I receptors (IGFI-R) on these same cell membranes, it recruits an increased proportion of the HBCC into S phase of the cell replicative cycle and thus sensitizes them to the cytotoxic effects of the cell cycle phase-specific anticancer agents (MTX, 5-FU). Because of the synergy between these two insulin effects, greatly reduced doses of the
anticancer drugs may be administered thus eliminating their dose-related toxic side-effects.

With the IPT protocol, patients are afforded both the maximum in therapeutic benefit of the drugs used together with the minimum in negative physical and psychological concomitants usually observed with conventional breast cancer management. In addition to breast conservation, complete tumor regression, and marked reduction in dose-related side effects, patients are also subjected to a much shorter course of therapy. In that majority of patients reported to respond, in most cases successful results are produced after only six to nine weeks of treatment.

IPT PROTOCOL

Breast malignancies are histologically verified by fine needle biopsy. Insulin/chemotherapy cycles are repeated twice a week for three weeks, and then weekly for another three to six weeks depending on clinical findings. Fasting subjects receive insulin (0.4 U/kg) and, at onset of hypoglycemia, cyclophosphamide 50 mg/m2, methotrexate 5 mg/m2, and 5-fluorouracil 100 mg/m2, with 50% hypertonic glucose, intravenously. During the first six weeks of treatment only, on non- insulin / chemotherapy treatment days patients are also prescribed oral cyclophosphamide 50 mg and methotrexate 2.5 mg, one tablet each daily. Follow-up examinations are scheduled every three months for the first year, every six months for the next three years, and annually thereafter.

CASE PRESENTATIONS

CASE #1: A 32-year-old woman noticed a painless lump in her right breast in November 1988. Needle biopsy results showed an infiltrating ductal adenocarcinoma (Fig. 1). The patient presented for treatment in February 1989. Examination showed a 2 cm mass in the upper outer quadrant of the right breast, which was confirmed by xeromammogram (Fig. 2). There were no palpable axillary masses. Chest radiogram and bone scan results were negative. After eight IPT treatments over a six-week period, the breast mass was no longer palpable. A control xeromammogram at three months follow-up showed no evidence of tumor (Fig. 3).

CASE #2: A 53-year-old woman presented with a 6 cm mass in her right breast in August 1986. The breast was inflamed and ulcerated around the areola with a foul smelling discharge. The mass was fixed to the underlying pectoral fascia and extended into the right axilla. The patient had no use of her right arm because of pain and lymphedema caused by axillary involvement with tumor. 

A mammogram performed in May of 1985 had revealed findings suspicious for malignancy (Fig. 7). She then had a lumpectomy which revealed an infiltrating ductal adenocarcinoma* (Fig. 8). The patient had three sessions of radiation therapy following her surgery, and subsequently failed to complete the prescribed course of treatment.  She had received no other form of treatment at the time she presented for IPT with her condition as described above. After twelve weekly treatments with IPT, the breast mass resolved completely. There was coincident clearing of the axillary obstruction with full restoration of mobility to the affected limb. A control mammogram performed 28 October 1986 (Fig. 9), showed no calcifications or tumor masses and reported "there exists a notable improvement and/or cure". Four years after completing treatment, the patient remains in good clinical condition without any signs of recurrence.

*This case is one of adjuvant, as opposed to neo-adjuvant, chemotherapy management.

CASE #3: A 49-year-old woman developed several lumps in both breasts from January 1986 to January 1987. She had pain and tenderness in both breasts. 

A mammogram done in January 1987 confirmed the presence of numerous lesions suspicious for malignancy (Fig. 4). Needle biopsies reported infiltrating ductal adenocarcinomas bilaterally (Fig. 5). On examination, in addition to numerous small breast masses, there was a chain of four palpable nodes in the right axilla, each approximately 2 cm in diameter. The patient received IPT treatments twice a week for five weeks, and then weekly, for a total of fourteen treatments. After this course of therapy, her breast and axillary masses regressed completely.  A control mammogram done on 1 April 1987 showed no abnormalities (Fig. 6).

CASE #4: A 31-year-old woman presented in August of 1989 with a nine month history of a lump in her right breast. A needle biopsy had reported an infiltrating ductal adenocarcinoma. The lesion was 1.5 cm  in diameter, situated in the upper outer quadrant of the right breast.   There were two 1 cm nodes palpated in the right axilla. A xeromammogram confirmed the presence of the mass (Fig. 10). The patient received six weekly treatments with the IPT protocol which caused complete regression of the breast and axillary masses. 

A control xeromammogram on September 9, 1989, reported no evidence of tumor (Fig. 11).

GROWTH FACTORS IN HUMAN BREAST CANCER

Insulin and insulin-like growth factor-I (IGF-I) have been identified as autocrine and/or paracrine growth factors in HBCC [3-5]. The membranes of these cells also have receptors for both IGF-I and insulin. IGF-I receptors (IGFI-R) have been reported as ubiquitous in all breast cancer cell lines studied [5], and insulin receptors are up to six-fold more concentrated on HBCC membranes than on normal breast tissues [6, 7]. Together, these peptides and their receptors play a major role in promoting the serum-independent growth of HBCC. According to Sporn and Todaro, it is the inappropriate later expression of such growth factors, originally required by cells during normal embryogenesis, that accounts for their malignant transformation. Through this autonomous self-stimulation, cells overcome restriction points in the normal cell cycle, thus becoming cancerous [8].

We consider that insulin and IGF-I may be integral elements in the mechanism of malignancy. In health, this couplet of peptides also acts in concert - but as part of a system with higher levels of integrated control. Furthermore, these peptides operate in tissues which are equipped with receptors specific for these ligands. Human growth hormone, for example, activates IGF-I activity and simultaneously causes an increase in the blood glucose concentration, stimulating increased insulin secretion from the pancreas. Insulin then provides the mechanism to make energy available intracellularly to drive events in the cells directed by the activity of IGF-I.

In breast, and in a number of other malignancies, such as lung [9, 10], leukemic lymphoblasts [11], and an insulinoma cell line [12], this combination of insulin and IGF-I operates autonomously at the cellular level within the tumor, and this operation is free from any higher level of integrated control. The two work together in an autocrine and/or paracrine manner and in a complementary fashion, with IGF-I being the major anabolic hormone responsible for mediating messages about growth in the tumor, while insulin regulates and provides the fuel for these processes [13].

Recent studies have demonstrated that the concentration of insulin and IGF-I receptors on HBCC membranes is influenced to a degree by the steroid sex hormones. Insulin receptor elaboration is increased by the action of progesterone (Pg) in progesterone receptor positive (PgR+) cells [14], and estrogen (E2) causes an increased elaboration of IGFI-R in estrogen receptor positive HBCC [15]. Some consideration is now being given to a strategy of pretreating selected patients, based on their identified receptor status, with E2 and/or Pg to increase elaboration of the IGFI-R and IR necessary for insulinís effect in IPT, thereby increasing tumor reactivity and responsiveness. In this way, it is hoped that it may be possible to improve overall responsiveness in selected breast cancer patients.

There are other growth factors which contribute in regulating breast cancer tumor growth, such as insulin-like growth factor-II  (IGF-II), epidermal growth factor (EGF), transforming growth factor-alpha (TGF-a), transforming growth factor-beta (TGF-b), and platelet-derived growth factor (PDGF) [3, 16]. The role of IGF-II as a mitogen has not been characterized as clearly as that of IGF-I [17].  TGF-b is growth inhibitory for HBCC [18], while PDGF seems to be
involved more with paracrine stimulation of stromal elements within tumors [16]. Of all of these growth factors, IGF-I has been reported to be the most potent growth-promoting mitogen for breast cancer cells themselves [19]. This latter fact is considered a significant one from the perspective of the operative mechanics in IPT.

There is significant cross-reactivity between ligand and receptor with insulin and IGF-I. It is considered that their common metabolic effects are mediated by insulin receptors (IR) while the growth effects are mediated primarily by IGF-I receptors (IGFI-R). Insulin is 50- to 500-fold more potent than IGF-I for metabolic effects, and this ratio is reversed for the growth effects [20, 21]. Interestingly, supraphysiologic concentrations of insulin, such as are administered in the IPT protocol, have been shown to replace the IGF-I requirement in defined media through cross-reaction with IGF-I receptors [22]. This fact is also considered to be quite significant in relation to the workings of the IPT protocol.

The properties which the insulin/IGF-I peptides have in common comprise metabolic effects (stimulation of glucose transport and metabolism, antilipolysis) and growth effects (stimulation of DNA and RNA synthesis, protein synthesis, cell multiplication) [20]. Underscoring the relevance of insulin's role here is a report that the incidence of metastatic disease in patients with breast cancer is highly statistically correlated with maturity onset diabetes mellitus, a condition characterized by high circulating insulin levels [23].

INSULIN RECEPTORS, IGF-I RECEPTORS, AND INSULIN POTENTIATION THERAPY

While it has been reported in the literature that IGF-I is an autocrine growth factor elaborated by HBCC [4], more recent evidence has demonstrated that breast cancer cells themselves elaborate no IGF-I mRNA. It is now considered that IGF-I is secreted by stromal elements within breast tumors, and that this then acts on breast cancer cells in a paracrine manner [24]. The receptors for IGF-I are ubiquitous on HBCC membranes (5), and in ER+ tumor cells the concentration of IGFI-R is stimulated by E2 [15]. As for insulin receptors, these two are reported to be present on all breast cancer cell membranes, and in plentiful numbers. Autoradiographic studies have demonstrated that breast cancer cell membranes have a higher concentration of insulin receptors than fat and fibrous tissue elements within tumors [6]. Another study showed a six-fold greater insulin receptor content in HBCC than in normal breast and other tissues in the body, such as liver [7].

As it is logical to assume a correlation between receptor number and degree of ligand effect [25], the impact of the drug-potentiating effects from IPT treatments would be more selective for breast  cancer cells rather than for normal tissues within the host. This is thought to play a role in the factor of safety for the host, which has been consistently observed in the practice of IPT.

We administer pharmacologic doses of exogenous insulin to patients with breast cancer and, at onset of hypoglycemia, follow this with low doses of anticancer drugs in a 50% hypertonic glucose solution. The reaction of insulin with IR and cross-reaction with IGFI-R produces two significant effects in host breast cancer tissues which serve to potentate the cytotoxic effects of anticancer drugs. These two effects are: i) a membrane effect to enhance intracellular drug accumulation, and ii) a growth effect, or recruitment into S-phase, rendering populations of HBCC more susceptible to the pharmacologic effects of anticancer drugs - particularly the cell-cycle phase specific agents.

With respect to the assumption about a membrane effect, insulin has been shown to increase the cytotoxic effect of methotrexate (MTX) in MCF-7 HBCC in vitro by a factor of up to ten thousand [26]. In another in vitro study, insulin preincubation of MDA-MB-231 HBCC caused an enhancement of cellular uptake of ellipticine, a DNA intercalating agent, with a concomitant increase in cytotoxicity [27].

Insulin-induced changes in cellular lipid synthesis and membrane lipid profile could produce changes in membrane fluidity, and enhance drug transport [28, 29]. In fact, insulin activates the enzyme delta-9 desaturase which converts stearic acid into mono-unsaturated oleic acid [30]. The melting-point of the triacylglycerol of stearic acid is 73oC while that of the corresponding trioleic moiety is 5.5oC. At physiologic temperatures, such a transformation could account for significant changes in biomembrane fluidity and permeability [31]. Other possibilities for insulin enhancement of transport of drug molecules into cells include reports of receptor-mediated endocytosis of chimeric drug-insulin molecules [32, 33], or the adsorption of drug molecules onto glucose which might then be internalized into cells via the insulin-activated glucose transport protein [34].

Acting in synergy with this presumed membrane effect is the growth effect of insulin on HBCC. Whether due to direct reaction with its specific IR or to cross-reaction with IGFI-R, insulin has a definite mitogenic effect on these cells [3-5]. Stimulating DNA synthesis and recruiting cells into S-phase of the cell replicative cycle renders an increased proportion of cells more sensitive to chemotherapy agents [35]. In vitro, sixteen hours after adding insulin to an asynchronous population of breast cancer cells, the S-phase fraction was 66% compared to only 37% in the non-insulin treated controls [36]. In addition, insulin has rapid early effects to stimulate protein and fatty acid synthesis (1 hour), stimulation of uridine incorporation into RNA (3 hours), and the later effects on thymidine incorporation into DNA (16 hours) [4]. While the timing of the important S-phase recruitment would not coincide immediately with the original cycle of administered chemotherapy, insulin's membrane effect would allow for increased drug to be present at the site of DNA replication. At subsequent chemotherapy cycles, the DNA recruitment then would enter into the IPT equation.

These membrane and growth effects of insulin serve to create ideal pharmacokinetic circumstances for the chemotherapy of breast cancer. An increased dose intensity of drug is made available  intracellularly, and the degree of this drug potentiating effect predominates in HBCC because of their denser distribution of IR.  [6,7,25] Insulin also serves to activate the biochemical processes in HBCC which determine the cytotoxic process via an increase in the S-phase fraction. Complete tumor regression can therefore be obtained, more rapidly and with reduced dose-related side-effects, using low-dose CMF in conjunction with the controlled administration of insulin according to this protocol.

In relation to IPT, there is an elegant "deus ex machina" phenomenon here. These endogenous mechanisms - insulin and IGF-I ligand-receptor interactions - which breast cancer cells rely on for their autonomous nourishment and growth are precisely the ones manipulated in IPT with pharmacologic doses of exogenous insulin.  The effects of this, together with the administration of reduced doses of anticancer drugs, creates a safer and more effective method of killing these same cells.

Insulin-potentiation of chemotherapy is similar in concept to one employing estrogen-recruitment of breast cancer cells to enhance chemotherapy. [37, 38] Estrogen acts on its intra-nuclear receptor in estrogen-receptor positive (ER+) HBCC, and causes elaboration of species of mRNAs that encode a variety of autocrine and paracrine growth factors (EGF, PDGF, TGFa, and IGF-II, as well as the IGF-I receptor) [3, 15, 39-42]. These activities of estrogen depend on the presence of insulin [43], possibly via its requirement for stimulation of nuclear envelope nucleoside triphosphatase (NTPase), the enzyme that regulates mRNA efflux from the nucleus [44].

Insulin is capable of mimicking estrogen's mitogenic effect in ER+ HBCC, and of recruiting ER- cells to some degree as well [43], although ER- HBCC, constitutively, have more active growth characteristics than ER+ ones [45]. Furthermore, insulin has its membrane effect to increase anticancer drug concentration inside of cells. For these reasons, the chemohormonal strategy using insulin-potentiation rather than estrogen-recruitment would have better efficacy, as well as better safety because of the lower total doses of drugs used.

CONCLUSION

The virtue of current endocrine therapy using antiestrogens for the treatment of breast cancer is that, while such agents may only be cytostatic, they have a remarkably low incidence of side effects.  Chemotherapy on the other hand is cytocidal, but this therapeutic advantage is gained at the expense of safety, as anticancer drugs have considerable host toxicity. The foregoing discussion on IPT relates how this particular combination of endocrine/growth factor and low-dose chemotherapy might possibly afford the best of both worlds here. While the concept is compelling and supported by basic scientific research evidence from the medical literature, the fact remains that the reported clinical results with IPT to date have been purely anecdotal.  Carcinomas of the breast comprise a heterogeneous group of diseases due to their differences in tumor size, regional lymph node status,  estrogen and progesterone receptor content, S-phase fraction, DNA ploidy, and cathepsin-D production. None of these factors have been  studied in the anecdotal cases reported here. Therefore, definitive pronouncements on the actual safety and efficacy of insulin potentiation therapy in the management of selected carcinomas of the breast must await the completion of well-designed prospective clinical trails.

REFERENCES

1) SGA, Perez Garcia y Bellon D, Perez Garcia Jr D.  Neoadjuvant low-dose chemotherapy with insulin in breast carcinomas.  Eur J Cancer 26:1261-2, 1990

2) SGA, Perez Garcia Y Bellon D, Perez Garcia Jr D. Insulin potentiation therapy: a new concept in the management of chronic degenerative disease. Medical Hypotheses 20:199-210, 1986

3) Lippman ME, Dickson RB, Kasid A, et al. Autocrine and paracrine growth regulation of human breast cancer. J Steroid Biochem 24:147-154, 1986

4) 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 Laboratory, 1981, 317-337.

5) Cullen JK, Yee D, Sly WS, et al. Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res 50:48-53, 1990

6) Holdaway IM, Freisen HG. Hormone binding by human mammary carcinoma. Cancer Res 37:1946-1952, 1977 

7) Papa V, Pezzino V, Constantino A, et al. Elevated insulin receptor content in human breast cancer. J Clin Invest 86:1503-1510, 1990

8) Sporn MB, Todaro GJ. Autocrine secretion and malignant transformation of cells. N Engl J Med 308:487-490, 1980

9) Jaques G, Rotsch M, Wegmann C, et al. Production of immunoreactive insulin-like growth factor 1 and response to exogenous IGF-1 in small cell lung cancer cell lines. Exp Cell Res 176:336-343, 1988

10) Nakanishi Y, Mulshine JL, Kasprzyk PG, et al. Insulin-like growth factor-1 can mediate autocrine proliferation of human small cell lung cancer cell lines in vitro. J Clin Invest 82:354-359, 1988

11) Lee PDK, Rosenfeld RG, Hintz RL, Smith SD. Characterization of insulin, insulin-like growth factors I and II, and growth hormone receptors on human leukemic lymphoblasts. J Clin Endocr Metab 62:28-35, 1986

12) Colman PG, Harrison LC. Structure of insulin/insulin-like growth factor-1 receptors on the insulinoma cell, RIN-m5F. Biochem Biophys Res Commun 124:657-662, 1984

13) Zapf J, Froesch ER. Insulin-like growth factors/somatomedins:  structure, secretion, biological actions and physiological role. Hormone Res 24:121-130, 1986

14) Papa V, Constance CR, Brunetti A, et al. Progestins increase insulin receptor content and insulin stimulation of growth in human breast carcinomas. Cancer Res 50:7857-7862, 1990

15) Stewart AJ, Johnson MD, May REB, Westley RB. Role of insulin-like growth factors and the type I insulin-like growth factor receptor in the estrogen-stimulated proliferation of human breast cancer cells. J Biol Chem 265:21172-21178, 1990

16) Eppenberger U. New aspects in the molecular growth regulation of mammary tumors. In: Eppenberger U, Goldhirsch A, eds. Recent Results in Cancer Research, Vol. 113: Endocrine Therapy and Growth Regulation of Breast Cancer. Berlin-Heidelberg, 1989, 1-3

17) DeLeon DD, Bakker B, WIlson RL, et al. Demonstration of insulin-like growth factor (IGF-I and IGF-II) receptors and binding protein in human breast cancer cell lines. Biochem Biophys Res Commun 152:398-405, 1988

18) Knabbe C, Zugmaier G, Dickson RB, Lippman ME.  Transforming growth factor-beta and other growth inhibitory polypeptides in human breast cancer. 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, Ltd. 1988, 231-233

19) Karey KP, Sirbasku DA. Differential responsiveness of human breast cancer cell lines MCF-7 and T47D to growth factors and 17B-estradiol. Cancer Res 48:4083-4092, 1988

20) King GL, Kahn CR, Rechler MM, Nissley SP. Direct demonstration for separate receptors for growth and metabolic activities of insulin and multiplication-stimulating activity (an insulin-like growth factor) using antibodies to the insulin receptor. J Clin Invest  66:130-140, 1980

21) Jacobs S, Cook S, Svoboda M, Van Wyk JJ. Interaction of the monoclonal antibodies alpha-IR-1 and alpha-IR3 with insulin and somatomedin-C receptors. Endocrinol 118:223-226, 1986

22) Goustin AS, Leof EB, Shipley GD, Moses HL. Growth factors and cancer. Cancer Res 46:1015-1029, 1986

23) Unterburger P, Sinop A, Noder w, et al. Diabetes mellitus and breast cancer: a retrospective follow-up study. Onkologie 13:17-20, 1990

24) Yee D, Palk S, Lebovic GS, et al. Analysis of insulin-like growth-factor I gene expression: evidence for a paracrine role in human breast cancer.  Mol Endocrinol 3:509-517, 1990

25) Hilf R. Primary and permissive actions of insulin in breast cancer. In: Leung BS, ed. Hormonal regulation of mammary tumors.  Montreal, Eden Press, 1982, Vol. 2, 123-137

26) Alabaster O, Vonderhaar BK, Shafie SM. Metabolic modification by insulin enhances methotrexate cytotoxicity in MCF-7 human breast cancer cells. Eur J Cancer Clin Oncol 17:1223-1228, 1981

27) Oster JB, Creasey WA. Enhancement of cellular uptake of ellipticine by insulin preincubation. Eur J Cancer Clin Oncol 17:1097-1103, 1981

28) Schilsky RL, Bailey BD, Chabner BA. Characteristics of membrane transport of methotrexate by cultured human breast cancer cells. Biochem Pharmacol 30:1537-1542, 1981

29) Shinitzky M, Henkart P. Fluidity of cell membranes - current concepts and trends. Int Rev Cytol 60:121-147, 1971

30) Jeffcoat R, Jame AT. The regulation of desaturation and elongation of fatty acids in mammals. In : Numa S, ed. Fatty Acid Metabolism and its Regulation. Elsevier Science Publishers BN. 1984, 85-112

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32) Gasparro FP, Knobler RM, Yemul SS, Bisaccia E, Edelson RL.  Receptor mediated photo-cytotoxicity: synthesis of a photoactivatable psoralen derivative conjugated to insulin. Biochem Biophys Res Comm 141:502-209, 1986

33) Poznansky MJ, Singh R, Singh B. Insulin: carrier potential for enzyme and drug therapy. Science 223:1304-1306, 1984

34) SGA. New approaches to the delivery of drugs to the brain.  Med Hypotheses 29:283-291, 1989

35) 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 Publishing Company, 1985, 41-60

36) Gross GE, Boldt DH, Osborne CK. Perturbation by insulin of human breast cancer cell kinetics. Cancer Res 44:3570-3575, 1984

37) Conte PF, Fraschini G, Alama A, et al. Chemotherapy following estrogen-induced expansion of the growth fraction of human breast cancer. Cancer Res 45:5926-5930, 1985

38) 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 22:728, 1986

39) Vignon F, Briozzo P, Capony F, et al. Estrogen-induced mitogens in breast cancer and their prognostic value. In: Eppenberger U, Goldhirsch A, eds. Recent Results in Cancer Research, Vol 113:  Endocrine Therapy and Growth Regulation of Breast Cancer.  Berlin-Heidelberg, 1989, 29-31

40) Salomon DS, Kidwell WR, Kim N, et al. Modulation by estrogen and growth factors of transforming growth factor-alpha and epidermal growth factor receptor expression in normal and malignant human mammary epithelial cells. In : Eppenberger U, Goldhirsch A, eds.  Recent Results in Cancer Research, Vol 113: Endocrine Therapy and Growth Regulation of Breast Cancer. Berlin-Heidelberg, 1989, 57-69.

41) Dickson RB, Lippman ME. Estrogenic regulation of growth and polypeptide growth factor secretion in human breast carcinoma.  Endocr Rev 8:29-43, 1987

42) Lippman ME, Huff KK, Jakesz R, et al. Estrogens regulate production of specific growth factors in hormone-dependent human breast cancer. Ann NY Acad Sci 464:11-16, 1986

43) 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 RGB, Lippman ME, Raynaud JP, eds. Progress in Cancer Research and Therapy, vol. 35: Hormones and Cancer 3. New York, Raven Press, Ltd. 1988, 231-233.

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