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For Tumor Tissue in L1210 Leukemic Mice1 [CANCER RESEARCH 45, 2512-2515, June 1985) Effect of Pretreatment with a-Difluoromethylornithine on the Selectivity of Methylglyoxal Bis(guanylhydrazone) for Tumor Tissue in L1210 Leukemic Mice1 Debora L. Kramer,2B. Paul, and Carl W. Porter3 Grace Cancer Drug Center, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14263 ABSTRACT although this has not been subsequently confirmed by others (11). A number of studies have demonstrated that pretreatment of DFMO is an irreversible inhibitor of omithine decarboxylase tumor-bearing animals with the inhibitor of polyamine biosyn (12) and, when applied to cellular systems, results in depletion thesis, a-difluoromethylomithine (DFMO), potentiates the antitu- of the polyamines, PUT and SPD. Although MGBG also inhibits mor activity of methylglyoxal bis(guanylhydrazone) (MGBG). The polyamine biosynthesis [through reversible inactivation of S- present study examines whether this phenomenon is related to adenosyl-L-methionine decarboxylase (13)], the basis for the a DFMO-mediated increase in the selectivity of MGBG for tumor drug interaction in in vitro systems, at least, appears to derive tissue. Specifically, the effect of DFMO pretreatment on the from increased MGBG transport into cells. Alhonen-Hongisto ef tissue distribution and content of MGBG was investigated in al. (14) have clearly shown that the decrease in intracellular SPD mice bearing ascites L1210 leukemia. At 3 and 18 h following a single i.v. injection of [14C]MGBG (50 mg/kg), L1210 cells and brought about by DFMO pretreatment results in the enhanced uptake of MGBG by cells. At the IDM concentrations achieved seven tissues from nonpretreated (control) and DFMO-pre- ¡ntracellularly(15), MGBG not only exerts profound effects on treated (3% by drinking water for 3 days) animals were compared for their [1*C]MGBG content. In control mice, the greatest polyamine metabolism but also alters the structure and function of mitochondria (16-18). It is this latter effect that is believed to amount of drug was found in L1210 cells, small intestine, and account for the potent cytotoxicity of the drug (19) as opposed kidney (in decreasing order of magnitude) at both 3 and 18 h. to pure inhibitors of polyamine biosynthesis, such as DFMO, This distribution was not altered following DFMO pretreatment, which tend to be cytostatic (12). but the relative MGBG content of other tissues was shifted. On For enhanced MGBG uptake to apply as a mechanism of an average, DFMO pretreatment increased the accumulation of potentiation in in vivo systems, DFMO would have to selectively MGBG by 30% in normal tissues and 32% in tumor tissues at 3 increase MGBG uptake into tumor tissue; otherwise, the severe h and 56% and 69%, respectively, at 18 h. Thus, pretreatment host toxicities of MGBG would persist as a limiting factor in its of leukemic mice with DFMO fails to improve the selectivity of efficacy. Thus far, inquiries into this area have been inconclusive MGBG for L1210 cells. It is possible that other tumor systems might demonstrate sufficient DFMO-mediated increases in and/or conflicting. Seppanen ef a/. (1, 2) found that DFMO pretreatment enhanced MGBG uptake to a greater extent in MGBG uptake to enhance drug selectivity but not without sig Ehrlich ascites tumor cells than in liver, small intestine, or bone nificantly increasing MGBG uptake (and hence toxicity) in normal marrow of the mouse, following single and multiple injections. tissues. However, the experimental design of those studies may have favored this finding, since MGBG was introduced directly into INTRODUCTION the ascites fluid by i.p. injection. Kallio ef al. (20) reported that DFMO increased MGBG levels in certain normal tissues of the A potentially significant development in the clinical application of the anticancer agent MGBG4 could be its sequential adminis mouse but, because tumor tissues were not included, selectivity could not be evaluated. Heston ef al. (21) reported that DFMO tration with the inhibitor of polyamine biosynthesis, DFMO. When pretreatment of rats bearing a variant (R3327MAT-Lu) of the tested in a number of in vivo model systems including Ehrlich ascites carcinoma (1, 2), murine L1210 leukemia (3-5), R3327 Dunning prostate tumor increased MGBG uptake into kidney but not other normal or tumor tissues, while Herr ef a/. rat prostate cancer (6, 7), and murine renal adenocarcinoma (8), the DFMO-MGBG combination has been shown to be therapeu- (7), using another variant of the R3327 tumor, found that DFMO increased MGBG levels in liver and, to a much greater extent, in tically more effective than either drug alone. More importantly, tumor cells. These same investigators (8) also observed that favorable clinical results with a small series of leukemia patients DFMO increases the uptake of [14C]MGBG almost exclusively have been reported after treatment with this combination (9,10), into the tumor tissue in mice bearing renal adenocarcinoma. 'This investigation was supported by Research Grant CA-22153 and Core In the present study, the effect of DFMO pretreatment on the Grant CA-24538 from the National Cancer Institute, Department of Health, Edu distribution of [14C]MGBG among 7 host tissues and ascites cation, and Welfare. 2 Recipient of NIH Training Grant Fellowship CA-09072. L1210 cells has been examined. The drugs were administered 3 To whom requests for reprints should be addressed. 4The abbreviations used are: MGBG, 1,l'-|(methylethanediylideno)dinitrilo|di- by the same routes used with patients (5,9); namely, mice were guanidine, also known as methylglyoxal bis(guanylhydrazone), methyl-G, or methyl- given DFMO by drinking water for 3 days and MGBG by a single GAG; DFMO, a-difluoromethylomithine; PBS, phosphate-buffered saline (0.8% i.v. injection. Tissue samples were removed 3 or 18 h later. The NaCI-0.115% Na2HPO4-0.02% KH2PO4-2H2O-0.02% KCI, pH 7.4); PUT, putres- crine; SPD, spermidine; SPM, spermine. results suggest that DFMO pretreatment does not enhance the Received 12/31/84; revised 3/8/85; accepted 3/11/85. selectivity of MGBG for tumor tissues in terms of uptake. CANCER RESEARCH VOL. 45 JUNE 1985 2512 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1985 American Association for Cancer Research. DFMO EFFECTS ON MGBG SELECTIVITY MATERIALS AND METHODS RESULTS Synthesis of [14C]MGBG. Amino [14C]guanidine hydrochloride was Mice inoculated with 10* L1210 cells survived an average of obtained from Amersham Corp. (Arlington, IL) and dissolved in distilled 7.6 days (Table 1). Treatment with 3% DFMO by drinking water water at a 0.2 HIM concentration (5.1 mCi/mmol) Of this stock solution, from Days -2 to 5 extended survival by an average of 1.6 days, 0.5 ml was diluted with 2 ml of 0.1 N hydrochloric acid and cooled on ice. A 0.5-ml aliquot of 0.1 mw methylglyoxal (Sigma Chemical Co., St. while MGBG (50 mg/kg) given i.v. on Days 1 to 5 increased Louis, MO) was added with stirring at 4°C for 16 h and at room survival by an average of 3.8 days. The combination of the 2 temperature for an additional 2 h. The solution was evaporated in vacuo agents extended life span by an average of 5.9 days, which is at 30°C,redissolved in 5 ml of water, and evaporated. The last 2 steps only slightly longer than expected for an additive drug interaction were repeated 8 times to remove all traces of acid residues. High- (5.4 days). pressure liquid chromatography, performed by Dr. Wayne Cowens of Individual mice consumed, on an average, 2.5 ml of drinking this Center, showed a single peak corresponding to authenic MGBG, water per day. For those treated with DFMO, this amounted to and all radioactivity was contained within this peak. The specific activity about 3.8 g/kg/day for a total of 3 days. In order to demonstrate of the preparation was calculated to be 10.2 mCi/mmol. The preparation that this treatment was effective in altering polyamine biosyn was found to have the same cytotoxic activity against cultured L1210 thesis, L1210 cells and representative host tissues were ex cells (50% inhibitory concentration, 1 IM at 48 h) as did unlabeled MGBG. tracted and analyzed by high-pressure liquid chromatography for Determination of Antileukemic Activity. L1210 murine leukemia cells their polyamine content. From Table 2, it is apparent that DFMO (108), obtained from the peritoneal cavity of female DBA/2J mice 5 to 6 treatment inhibited polyamine biosynthesis. In all tissues, PUT days following implantation, were inoculated i.p. into female recipient and SPD concentrations were reduced, while those of SPM mice on Day 0. Pretreatment with DFMO as a 3% solution in drinking pools were unaffected. Of the tissues sampled, the greatest water was initiated on Day -2 and continued until Day 5. MGBG in 0.9% reduction in SPD occurred in the leukemic cells (84%), which NaCI solution at 50 mg/kg was injected i.v. once daily for 5 days were probably the most actively proliferating. By contrast, the beginning on Day 1. Mice were monitored twice daily for deaths. Survival SPD content of normal cells (splenic lymphocytes and associated time was expressed as the average for 5 mice per treatment group. cells) was decreased by 38%. Drug effect was expressed as survival time of treated to control x 100. The effect of DFMO pretreatment on the tissue content and [MC]MGBG Tissue Distribution Studies. L1210 leukemia cells were distribution of [14C]MGBG 3 h following injection is presented in maintained in DBA/2J mice by weekly i.p. passage. On Day 0, mice were given injections i.p. with 106 L1210 cells. In order to obtain sufficient Table 3.
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