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Cancer Chemother Pharmacol (2004) 53: 220–224DOI 10.1007/s00280-003-0716-7 Eduardo Lasalvia-Prisco Æ Silvia CucchiJesu´s Va´zquez Æ Eduardo Lasalvia-GalanteWilson Golomar Æ William Gordon Insulin-induced enhancement of antitumoral responseto methotrexate in breast cancer patients Received: 31 March 2003 / Accepted: 29 August 2003 / Published online: 4 December 2003Ó Springer-Verlag 2003 Abstract Purpose: It has been reported that insulin in- tumor in the three groups were compared statistically.
creases the cytotoxic effect in vitro of methotrexate by as Results: Under the trial conditions, the methotrexate- much as 10,000-fold. The purpose of this study was to treated group and the insulin-treated group responded explore the clinical value of insulin as a potentiator of most frequently with progressive disease. The group methotrexate. Patients and methods: Included in this treated with insulin + methotrexate responded most prospective, randomized clinical trial were 30 women frequently with stable disease. The median increase in with metastatic breast cancer resistant to fluorouracil + tumor size was significantly lower with insulin + Adriamycin + cyclophosphamide and also resistant to methotrexate than with each drug used separately.
hormone therapy with measurable lesions. Three groups Discussion: Our results confirmed in vivo the results of each of ten patients received two 21-day courses of the previous in vitro studies showing clinical evidence that following treatments: insulin + methotrexate, metho- insulin potentiates methotrexate under conditions where trexate, and insulin, respectively. In each patient, the size insulin alone does not promote an increase in tumor of the target tumor was measured before and after treatment according to the Response Evaluation Criteria activity must have been enhanced by the biochemical In Solid Tumors. The changes in the size of the target events elicited in tumor cells by insulin. Conclusions: Inmultidrug-resistant metastatic breast cancer, metho-trexate + insulin produced a significant antitumoralresponse that was not seen with either methotrexate or Department of Medicine, School of Medicine,University of Uruguay, Montevideo, Uruguay Keywords Breast Cancer Æ Chemotherapy Æ Insulin Æ S. Cucchi Æ J. Va´zquez Æ E. Lasalvia-Galante Æ W. Golomar E. Lasalvia-PriscoInterdoctors Medical Center,Montevideo, Uruguay E. Lasalvia-Prisco Æ J. Va´zquez Æ E. Lasalvia-GalanteW. GolomarNational Cancer Institute, It is known that slowly growing cancers have tumor cell populations with a low-growth fraction and are less sensitive to chemotherapy than rapidly growing tumors with high-growth fractions [11]. Slowly growing malig- nancies have relatively more cells in a noncycling status and fewer cells in a cycling status than rapidly growing (Former Director of the Department of Medicine, malignancies. It has been demonstrated that insulin as a School of Medicine, University of Uruguay, pharmacological agent induces the switch from a non- Montevideo, Uruguay and National Cancer Institute, cycling to a cycling status in tumor cells [5]. In MCF-7 Montevideo, Uruguay),Research & Development Department, human breast cancer cells, insulin has been shown to increase the cytotoxic effect of methotrexate up to 10,000-fold in vitro [1]. Ellipticine uptake is also increased by insulin [9]. It has been suggested that E-mail: research@pharmablood.comTel.: +1-305-9442544 insulin is effective in potentiating most chemotherapy drugs. This insulin-induced potentiation has been proposed as a strategy for breast cancer treatment, but confirmed the committeeÕs criteria because no significant differences confirmatory clinical trials are still lacking [2]. This were found in tumor growth either between the insulin-alone groupand the methotrexate-alone group or between before and after study was carried out to confirm insulin-induced clinical treatment in the insulin-alone group.
potentiation of the antitumoral effect of methotrexate assuggested by preclinical studies and to establish amechanism of action for this antitumoral effect.
All the patients included in the study received two 21-day courses of treatment separated by a 7-day interval without treatment be-tween courses. In group 1, the treatment course was intravenoushuman recombinant insulin (0.3 U/kg body weight every other day) followed 20 min later by a 15-min intravenous infusion ofmethotrexate (2.5 mg/m2 in 50 ml 30% glucose). If symptomatic The study was conducted in 30 patients with breast cancer admitted hypoglycemia was observed, the 30% glucose solution containing to medical centers that reported medical data to the Cooperative methotrexate was infused immediately. An oral glucose supplement Trials Center (CTC) of PharmaBlood, R&D Department, Florida.
was also prescribed to prevent delayed hypoglycemic symptoms. In A prospective, randomized trial was carried out. All patients met group 2, insulin was omitted and methotrexate was administered the following eligibility criteria: histologically confirmed breast intravenously at the same dose and in the same solution (2.5 mg/m2 carcinoma, metastatic stage (M1); Eastern Cooperative Oncology in 50 ml 30% glucose) as in group 1. In group 3, methotrexate was Group (ECOG) performance status (PS) £ 2; age £ 74 years; and omitted, insulin was administered at the same dose as in group 1, adequate hematological function (WBC count ‡4000/ll, neutrophil and 30% glucose solution was also administered intravenously ‡2000/ll, hemoglobin level ‡9.0 g/dl, platelet count 20 min after insulin or sooner if hypoglycemic symptoms were ‡10·104/ll), renal function (serum creatinine £ 1.5 mg/dl, 24-h creatinine clearance £ 60 ml/min), liver function (total bilirubin£ 2.0 mg/dl, serum transaminases not more than twice the upperlimit of the normal range), and respiratory function (PaO2‡60 Torr). The patients included had measurable lesions, as required by the Response Evaluation Criteria In Solid Tumors(RECIST) system of tumor assessment [13], and if they had a After 8 weeks (two 3-week courses plus 1 week interval after each positive estrogen receptor status, they had been treated with and course), the response to treatment was assessed in each patient become resistant to hormone therapy.
using RECIST criteria [13]. The sum of the longest diameter of All patients included in the study had progressive disease measurable target lesions and the number of non-target lesions (RECIST criteria) after chemotherapy with at least four series of were recorded immediately before and after this 8-week period.
fluorouracil + Adriamycin + cyclophosphamide (FAC) and had Skin nodules and palpable lymph nodes were measured using not been treated with any other chemotherapy. They were ran- calipers. Lung and liver target lesions were measured by a CAT domly allocated to three groups of ten patients each: group 1 was scan. Responses were confirmed by repeating the assessment treated with insulin + methotrexate as described below, group 2 4 weeks after status assignment. Three independent reviewers per- was treated with methotrexate without insulin, and group 3 was formed all image measures (Telemedical Organization, North treated with insulin without methotrexate. Written informed con- sent, including detailed information about risks and benefits, was The distribution of RECIST status (progressive disease, stable approved and signed by all the patients included in the study.
disease, or remission) in each group was recorded. This distribution Central computerized remote randomization was performed, with was dependent on treatments that showed statistical significance patients being allocated to one of the groups through random se- according to the Chi-squared test. The data from the RECIST quence generation by the permuted block method. An assessment measurements of the change in tumor size of the patients in each of the results after 30 patients had completed the trial showed that treatment group, expressed as a percentage of pretreatment this sample size was enough. The patients were recruited from two measurements, were compared using StudentÕs t-test. Additionally, oncological medical centers in Montevideo, Uruguay (first at the increases in tumor size were expressed as a proportion of the initial National Cancer Institute and then at Interdoctors Medical Cen- value and analyzed by the two-proportion test comparing pairs of ter), both of which participated with their data in the network groups: group 3 vs group 1, and group 2 vs group 1. The sample operated and sponsored by the Cooperative Trials Center (CTC) of size was assessed after analysis of the results when the trial was finished for the 30 patients allocated to the three groups. The above The institutional ethics committee of PharmaBlood and the pairs of groups were analyzed for the proportion of progressive institutional review boards of the participating medical centers disease in each. Ten patients in each group was the required sample approved the trial. The ethical reviewers considered that an 8-week size for an 80% chance of rejecting the hypothesis of equal pro- delay before starting second-line chemotherapy after FAC had portions at the 0.05 level of significance when the true proportions failed in all the patients included in the trial was acceptable. This were those shown by the study. Statistical analysis was performed determination was consistent with the standard of care in this using StatsDirect software and an independent expert was con- clinical situation which has been recently well summarized [3]: Despite almost 30 years of clinical cancer research, the trueimpact of second and subsequent lines of chemotherapy on theoutcome of metastatic breast cancer patients, especially on the duration of survival, is still unknown. In the virtually incurablemetastatic setting, issues like quality of life and patientsÕ pref- The characteristics of the patients included are shown in Table 1. The three groups were comparable in the most The accepted protocol was resubmitted to the committee for relevant prognostic parameters for the clinical condition review in order to obtain approval for treatment of patients with studied. Previous treatments were also comparable. The insulin alone considering the potentially harmful effect through the similar range of sizes of target lesions measured before activation of receptors for insulin/insulin-like growth factors. Thecommittee confirmed the approval on the basis of reports of no treatment was especially significant, allowing the change harmful effect of this treatment [6, 7]. The results of the study in size to be measured as a percentage of initial size.
Table 1 Clinical characteristicsof the 30 women with Fig. 1 Post-treatment RECIST status of measurable target lesions.
After the respective treatment, the change in the measurable lesions Fig. 2 Increase in size of measurable target lesions (RECIST selected as targets in each patient was evaluated and the status of assessment). After each treatment, the change in the measurable therapeutic response, defined in terms of the RECIST criteria, was lesions selected as targets in each patient was evaluated in terms of recorded. Under the conditions of this study, two response statuses the RECIST criteria and expressed as a percentage of the measured were recorded: stable disease (less than 20% increase or less than pretreatment size. For each treatment group, the mean±SD and 30% decrease in the sum of largest diameters of targets) and 95% CI for the values of this response were calculated: group 1 progressive disease (more than 20% increase in the sum of (insulin + methotrexate) 13.51±3.01% (95% CI 11.35–15.67%); diameters). Stable disease, the best response obtained, was more group 2 (methotrexate) 20.21±2.27% (95% CI 18.58–21.84%); frequent in the group treated with insulin + methotrexate (nine of group 3 (insulin) 21.04±2.17% (95% CI 19.49–22.59%). The ten) than in methotrexate-treated group (three of ten) or insulin- increase in size of lesions in group 1 (insulin + methotrexate) was treated group (two of ten). The distribution of RECIST type significantly lower (StudentÕs t-test) than the increase in size in responses (stable disease or progressive disease) was dependent on the treatments tested and statistically significant (P<0.01, Chi- (P<0.001). Group 2 showed no significant difference from group Figure 1 shows the RECIST status assessed under the insulin + methotrexate than in those treated with study conditions. Progressive disease was the most fre- insulin alone and significantly lower than in those trea- quent response in two of the three groups: in group 2 (treated with methotrexate alone) there were seven From the same set of measurements, Figs. 1 and 2 progressive disease and three stable disease, and in show the clinical and biological effects of the treatments, group 3 (treated with insulin alone) there were eight respectively. Figure 1 indicates that the decrease in tu- progressive disease and two stable disease. In group 1 mor growth induced by insulin + methotrexate reached (treated with insulin + methotrexate), stable disease was the level of a clinically confirmed antitumoral response the most frequent response (nine stable disease, one because more patients in this group achieved stable progressive disease). The distribution of RECIST type disease. Figure 2 shows that insulin + methotrexate responses (stable disease and progressive disease) was treatment reduced tumor growth. All patients completed dependent on the treatments tested, and was statistically the study. Hypoglycemia was induced in all patients significant (P<0.01, Chi-squared test).
receiving insulin as part of their protocol. Eight patients Figure 2 shows the means and 95% confidence in group 1 and nine patients in group 3 showed no intervals (CI) of the percentage increase in tumor size hypoglycemic symptoms during the 20 min after insulin after treatment in the three groups. Increases in tumor injection; they showed a mean blood glucose level of size were significantly lower in patients treated with 456 mg/dl (range 376–520 mg/dl). Two patients in group Table 2 Maximum recorded WHO toxicity grade in the patients used here as a description of the clinical effect of a included in the trial comparing insulin + methotrexate (group 1), reduction in the proportion of patients showing pro- methotrexate (group 2) and insulin (group 3). The numbers of patients with each toxicity grade (0 to 4) in the three groups areshown. No other toxicities referred to in the WHO criteria were Therefore, as reported previously, our results support the hypothesis that insulin can potentiate the antitu-moral effect of methotrexate [2] and confirm in vivo previously reported in vitro results [10]. Our results also show insulin potentiation of methotrexate in this con-dition, where insulin alone did not promote an increase in tumor growth (group 3). This effect is in agreement with previous results from in vitro models where insulin enhancement of cytotoxicity was not a direct conse- quence of an insulin-dependent increase in the growth rate of tumor cells [1, 10]. The same in vitro models do not allow an explanation of the insulin potentiation of methotrexate in terms of the known effects of insulintreatment upon the specific metabolism of methotrexate which include a decrease in intracellular pH induced by glucose metabolism and tight binding of the drug to its target, dihydrofolate reductase. Insulin potentiation of other antitumoral drugs has been reported [9].
If we discount the promotion of tumor cell growth and the interaction with the specific target as the mechanism of potentiation of methotrexate by insulin,we can hypothesize that this mechanism could involveanother general insulin-dependent biochemical pathway 1 and one patient in group 3 showed hypoglycemic as has been previously suggested to explain the in vitro symptoms within 20 min of insulin injection (13, 16 and potentiation of methotrexate by insulin [1]: protein 19 min), but recovered immediately after starting the synthesis in tumor cells is one of the biochemical path- glucose infusion. There was no evidence of any harmful ways activated by insulin [8]. Most chemotherapy drugs sequelae attributable to the hypoglycemia induced.
that have been tested using insulin to increase cytotox- Table 2 shows the toxicities associated with antitu- icity are known modifiers of protein structure that act at moral chemotherapy (according to WHO criteria) the genetic or epigenetic level [12]. High levels of mu- tated or epigenetically modified proteins could beresponsible for the cytotoxic mechanism elicited by theinsulin-dependent increase in protein synthesis associ- ated with chemotherapy drugs. The relative selectivity ofthis mechanism of action for insulin + methotrexate in The methotrexate dose used in this study was chosen malignant cells is attributed to the agonism of insulin because a similar dose of methotrexate had been used and insulin-like receptors in tumor cells. Certainly, the previously in patients receiving low-dose combined response to insulin is more intense in most tested cancer chemotherapy potentiated with insulin [2]. In addition, cells than in most normal cells. This is probably because the cumulative monthly dose was no higher than the cancer cells are richer in receptors for insulin-like growth monthly dose used in the well-known standard protocol factors that are cross-stimulated by insulin [4].
of methotrexate + fluorouracil + cyclophosphamide(CMF). Indeed, each individual methotrexate injection(2.5 mg/m2) was less than the dose usually considered optimal in non-potentiated protocols but is within thepresumed range of effective dose for a potentiation The in vitro potentiation of methotrexate cytotoxicity by similar to the one observed in vitro. The results of this insulin in human breast cancer cell lines was previously study confirmed the expected safety of the selected known. We report the results of a randomized, con- methotrexate dose. The toxicities in the methotrexate- trolled trial that confirmed, at the clinical level, the alone group were not relevant (WHO grades 1/2) and potentiation by insulin of the antitumoral effect of they were even lower when methotrexate was associated methotrexate in women with advanced breast cancer.
with insulin, only producing a grade 1 mucositis. In this The term antitumoral is used as a description of the study, methotrexate at this safe low dose did not have an clinical effect of a reduction in the proportion of patients antitumoral effect when used alone (group 2), but it did with progressive disease. Under the conditions of this produce a significant antitumoral effect when adminis- study, the dose of insulin used did not increase tumor tered after insulin (group 1). The term antitumoral is growth. Therefore, we suggest that, as has been reported in vitro, methotrexate potentiation by insulin was not a 5. Gross GE, Boldt DH, Osborne CK (1984) Perturbation by direct consequence of the expansion of the tumor cycling insulin of human breast cancer cell kinetics. Cancer Res44:3570–3575 cell population but a consequence of some of the bio- 6. Kath R, Schiel R, Muller UA, Hoffken K (2000) Malignancies chemical events that are simultaneously activated. The in patients with insulin-treated diabetes mellitus. J Cancer Res enhancement of methotrexate uptake by tumor cells and/or the promotion of protein synthesis in a muta- 7. Mink PJ, Shahar E, Rosamond WD, Alberg AJ, Folsom AR genic intracellular environment are hypothesized to be (2002) Serum insulin and glucose levels and breast cancerincidence: the atherosclerosis risk in communities study. Am mechanisms of potentiation. It is known that both events are promoted by insulin acting as a cross-agonist 8. Osborne CK, Bolan G, Monaco ME, Lippman ME (1976) of the highly expressed receptors for insulin-like growth Hormone responsive human breast cancer in long-term tissue culture: effect of insulin. Proc Natl Acad Sci U S A 73:4536–4540 These mechanisms, which are shared with other pri- 9. Oster JB, Creasey WA (1981) Enhancement of cellular uptake mary tumor cells and with other chemotherapeutic of ellipticine by insulin preincubation. Eur J Cancer Clin Oncol agents suggest that it would be worthwhile to pursue further study of these phenomena in other tumors and 10. Schilsky RL, Bailey BD, Chabner BA (1981) Characteristics of membrane transport of methotrexate by cultured human breast cancer cells. Biochem Pharmacol 30:1537–1542 11. Shackney SE, McCormack GW, Cocheral GJ (1978) Growth rate patterns of solid tumors and their relation to responsive- ness to therapy. Ann Intern Med 89:107–121 12. Silva JM, Garcia JM, Dominguez G, Silva J, Rodriguez R, Portero JL, Corbacho C, Provencio M, Espana P, Bonilla F 1. Alabaster A, Vonderhaar B, Shafie S (1981) Metabolic modi- Silva JM, Garcia JM, Dominguez G, et al (2000) DNA fication by insulin enhances methotrexate cytotoxicity in damage after chemotherapy correlates with tumor response MCF-7 human breast cancer cells. Eur J Cancer Clin Oncol and survival in small cell lung cancer patients. Mutat Res 2. Ayre SG, Perez Garcia y Bellon D, Perez Garcia D Jr (1990) 13. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan Neoadjuvant low-dose chemotherapy with Insulin in breast RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New 3. Cardoso F, Di LA, Lohrisch C, Bernard C, Ferreira F, Piccart guidelines to evaluate the response to treatment in solid tu- M (2002) Second and subsequent lines of chemotherapy for mors. European Organization for Research and Treatment of metastatic breast cancer: what did we learn in the last two Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 4. Cullen KJ, Yee D, Sly WS, Perdue J, Hampton B, Lippman ME, Rosen N (1990) Insulin-like growth factor receptorexpression and function in human breast cancer. Cancer Res50:48–53

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