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CANCER RESEARCH56. 538-543. February I. 19961

ABSTRACT

MKT-077 (formerly known as FJ-776) is a newly synthesized, highlywater-soluble (>200 mg/mI) rhodacyanine dye that exhibits significantantitumor activity in a variety of model systems. In culture, MKT-077inhibits the growth off'ive human cancer cell lines (colon carcinoma CX-1,breast carcinoma MCF-7, pancreatic carcinoma CRL142O, bladder tran.sitional cell carcinoma U, and melanoma LOX) but not monkey kidneyCV-!, an indicator cell line for normal epithelial cells. In nude mice,MKT.077 inhibits the growth of s.c. implanted human renal carcinomaA498 and human prostate carcinoma DU145 and prolongs the survival ofmice bearing i.p. implanted human melanoma LOX (tumor:control 344%). Subcellular localization indicates that MKT-077 is taken upand retained by mitochondria, and flow cytometric analysis suggests thatCX-! cells take up MKT-077 to a much greater extent than CV-! cells.Quantitation of MKT-077 uptake by ethanol extraction shows that CX-1cells accumulate 65-fold more MKT.077 than do CV-1 cells. MKT-077 isthe first delocalized lipophilic cation with a favorable pharmacologicaland toxicological profile in preclinical studies. MKT-077 is now beinginvestigated in Phase I clinical trials.

INTRODUCTION

Epithelial tumors, which constitute more than 85% of human cancers, are the major cause of death in the United States. Unfortunately,conventional chemotherapy, which is responsible for the cure ofchildhood leukemias, has met only limited success in the treatment ofcarcinomas. It underscores an urgent need for novel anticarcinomatherapy that exploit hitherto untapped molecular targets and unexplored mechanisms.

Considerable efforts have been made to develop DLCs2 into potential anticarcinoma agents (1â€”13).DLCs are accumulated by mitochondria in response to plasma and mitochondrial membrane potentials (negative inside; Refs. 1â€”3).Since carcinoma cells, particularlythose of human origin, display an increased mitochondrial membranepotential when compared with normal epithelial cells ( 1), DLCs havebeen proposed as potential anticarcinoma agents. DLCs exploredpreviously for this purpose include rhodamine 123 (4â€”6), dequalinium (7, 8), N'-bis(2-ethyl-l,3-dioxolane)-krytocyanine (9), Victoriablue BO (10), tetraphenylphosphonium (1 1), thiacarbocyanines (12),and thiopyrylium AA-l (13). Although many of these compounds

exhibit significant antitumor activity in culture and/or animal models,none of them have met the stringent criteria required for clinicaldevelopment, in particular, with respect to water solubility, untowardeffects, and pharmacokinetics.

In an effort to identify DLCs suitable for clinical trials, we haveundertaken a screening program to examine as many of the 200,000DLCs registered in the Chemical Abstract as is possible. A wide

Received 6/7/95; accepted 11/17/95.The costs of publication of this article were defrayed in part by the payment of page

charges. This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section 1734 solely to indicate this fact.

@ To whom requests for reprints should be addressed, at Dana-Farber Cancer Institute,M840, 44 Binney Street. Boston, MA 021 15. Phone: (617) 632-3386; Fax: (617)863-5917.

2 The abbreviations used are: DLC, delocalized lipophilic cation; T/C, tumor:control.

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variety of DLCs from a library of more than 100,000 organic compounds at Fuji Photo Film Co., Ltd., has been chosen and screened.Rhodacyanine dyes, well-known in the photographic industry as sensitizers for silver halides (14), were found to be unique. They exhibitmarked anticarcinoma activity with relatively low toxicity. Upon theiridentification, we designed and synthesized over 1000 rhodacyanines,with careful consideration taken regarding structure-activity relationships. We examined characteristics including solubility, stability, toxicity, pharmacokinetics, and antitumor activity in culture and in nudemice. Based on this extensive study, the best rhodacyanine, MKT-077(formerly known as FJ-776), was chosen for further characterization.MKT-077 is a highly water-soluble (>200 mg/ml) lipophilic cornpound that displays significant anticarcinorna activity. MKT-077, as thefirst DLC with a favorable pharmacological and toxicological profile inpreclinical studies, has been chosen for clinical development.

MATERIALS AND METHODS

MKT-077. l-ethyl-2- {[3-ethyl-5-(3-methylbenzothiazolin-2-yliden)]-4-oxothiazolidin-2-ylidenemethyl)pyridium chloride (MKT-077, formerlyknown as FJ-776; C21H22N3OS2C1,molecular weight 432.01) was chemicallysynthesized. The structure was determined by X-ray analysis of its crystal and

various spectroscopic data (I H-nuclear magnetic resonance,@ 3C-nuclear mag

netic resonance, infrared, and mass). The peak temperature from the DSCspectrum was 261.3Â°C.MKT-077 is orange-colored (Amax495 nm) and highlysoluble in water (> 200 mg/ml). It is very stable and can be stored even inaqueous solution at 4Â°Cfor more than 1 year. The purity of MKT-077 used inthis study was >99%, as determined by high-pressure liquid chromatography

analysis. For cell culture studies, MKT-077 at 1 mg/ml in DMSO was prepared

as a stock solution. For animal studies, MKT-077 was dissolved in 5%dextrose at 10 mg/mI and sonicated for 5 mm in a bath sonicator (Bransonic;Bronson Ultrasonics Corp., Danbury, CT). All MKT-077 solutions were protected from light and stored at 4Â°C.Concentrations of MKT-077 were determined by absorption spectra to avoid weighing errors.

Cell Cultures. All cell lines were grown in a 50:50 mix of DMEM andRPMI 1640(GIBCO Laboratories, Grand Island, NY) supplemented with 10%calf serum (Hyclone Laboratories, Inc., Logan, UT) and antibiotics at 37Â°C

under 5% CO2. 95% air and 100% humidity. CRL-l420 (human pancreaticcarcinoma) and CV-1 (normal African green monkey kidney) were from theAmerican Type Culture Collection (Rockville, MD). CX-l (human coloncarcinoma) and LOX (human melanoma) were from Dr. M. Wolpert (NationalCancer Institute, Bethesda, MD). EJ (human bladder transitional cell carcinoma) was from Dr. IC. Summerhayes (Harvard Medical School, Boston,MA). MCF-7 was from Dr. M. Rich (Michigan Cancer Foundation, Detroit,Ml).

Clonogenic Assay and Measurement of Growth Rate. For the clonogenic assay, cells were seeded at 2000 cells/well in 6-well plates (BectonDickinson Labware, Lincoln Park, NJ). On the following day, cells weretreated with MKT-077, cisplatin (from Bristol-Meyer), or Adnamycin (AdriaLab) at varying concentrations in 2.5 ml of culture medium for 24 h. Afterrinsing, cells were incubated in drug-free medium for 1â€”2weeks. Colonies

were stained with 2% crystal violet in 70% ethanol and counted by anautomated colony counter (Artek counter model 880; Dynatech Laboratory,Inc., Chantilly, VA). The assay was performed in duplicate. For the inhibitionof cell growth in mass cultures, cells were seeded on day 0 at 1 X 106cells/l00-mm dish, followed by the daily addition of MKT-077 at 3 @.tg/mlon

MKT-077, a Novel Rhodacyanine Dye in Clinical Trials, Exhibits AnticarcinomaActivity in Preclinical Studies Based on Selective Mitochondrial Accumulation

Keizo Koya, Yang Li, Hong Wang, Toshinao Ukai, Noriaki Tatsuta, Masayuki Kawakami, Tadao Shishido,and Lan Bo Chen'

Dana-Farber Cancer Institute. Harvard Medical School. Boston, Massachusetts 02115 (K. K., Y. L, H. W., L B. CI, and Ashigara Research Laboratories, Fuji Photo Film Co..Ltd., Minamiashigara, Kanagawa, 250-01. Japan fT. U.. N. 7'., M. K., T. S.]

on June 5, 2021. © 1996 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

http://cancerres.aacrjournals.org/

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Fig. I . Chemical structure of MKT-077 (formerly FJ-776).

days 1â€”4.On each day, cells were trypsinized, and trypan blue-negative cells

were counted by a hemacytometer.Time-Lapse Videomicroscopy. Cells were seeded at 5 X l0@in a 60-mm

dish, placed on a Leitz inverted microscope equipped with a chamber equilibrated with continuous infusion of 10% CO,. and kept at 37Â°C. Phase-contrast

images were captured by a Newvicon videocamera and recorded on a Panssonic Super VHS time-lapse videorecorder. MKT-077 was added daily at3 j.tg/ml.

LOX i.p. Tumor Model. MaleSwiss nu/nunudemice (about5 weeks old)were obtained from Taconic Farm, Inc. (Germantown, NY). Group housing(5/cage) was provided in polycarbonate cages with wire top and filters. Micewere allowed to acclimate for 1 week prior to experiments. Only normal,healthy mice were used. Human melanoma LOX cells used in this model were

first grown s.c. in nude mice. On the day of i.p. implantation, tumors were

excised, and a single-cell suspension was prepared. RBC were lysed byammonium chloride. Each mouse received 2 X 106 LOX cells (trypan blue

negative) in 0.2 ml of PBS by i.p. injection. MKT-077 was administered i.p.for LOX tumor-bearing mice at 5 mg/kg on days 1â€”5.

A498 and DU145 s.c. Tumor Models. Human prostate carcinoma DU145

and human renal carcinoma A498 xenografts were propagated by s.c. serial

transplantation in male (Taconic Farm) and female (Simonsen Laboratories,

Inc., Gilroy, CA) Ncr-nu nude mice, respectively. On day 0, tumors (about 1cm in diameter) were carefully trimmed to remove all connective tissues, cutinto fragments of 4 mm3, and implanted s.c. with a 12-gauge trocar needle.

MKT-077 was administered iv. for A498 tumor-bearing mice at 7.5 mg/kg ondays 1, 3, 5, 7, 9, 11, and 13 and for DUI45 tumor-bearing mice at I 1.25mg/kg on days 5, 7, 9, 11, 13, 15, 17, 23, and 25. Correspondingly, untreated

tumor-bearing mice serving as controls received 5% dextrose on the same days

as the treated mice. Tumors in excess of 1 g were produced in untreated

controls within 30 days for both A498 and DU145.Laser Scanning Confocal Fluorescence Microscopy. Mixed CX-l and

Cl@ CV-l cellsgrownon12-mmglasscoverslipswereexposedtoMKT-077(3p@g/ml in culture medium) at 37Â°C for the indicated duration, washed, and

mounted on a living cell chamber made of silicon rubber (15). MKT-077fluorescence was detected by a Zeiss LSM inverted confocal microscope(excitation at 488 nm and emission at 543 nm). Digitized fluorescent imageswere stored in a microcomputer driven by Adobe Photoshop 3.1 (AdobeSystem, Inc.) and printed by a Fuji Pictrography 3000 color printer (Fuji PhotoFilm USA, Inc., Elmsford, NY).

Flow Cytometry. CX-l andCV-l cells (106 in 25 ml of culturemedium)were incubated with MKT-077 (3 j@g/ml)at 37Â°Cfor 5 h. During incubation,the cell suspension was shaken gently, and after centrifugation, the cell pelletwas resuspended in 1 ml of fresh medium. Fluorescent intensity was analyzedby a flow cytometer (Becton Dickinson FACScan) with excitation at 488 nm

and emission at 525 nm.Extraction of MKT-077 from Cells for Measurement. CX-l cells

(3 X l0@) or CV-l cells (5 X l0@) in 50 ml of culture medium were treated

with MKT-077 (3 @g/ml)at 37Â°Cfor the indicated time. During incubation,the cell suspension was shaken gently, and after centrifugation, the cell pelletwas resuspended in PBS and recentrifuged. The pellet was then extracted with3 ml of ethanol. After vortexing and further centrifugation, the supematant was

analyzed for the concentration of MKT-077 by a spectrophotometer.

RESULTS

Chemical Structure of MKT-077. Fig. 1 presents the structure ofMKT-077 with chloride as a counter ion, a characteristic that greatlyenhances its water solubility. MKT-077 is a typical lipophilic cornpound with a delocalized positive charge. Such an agent is known toenter cells by membrane potential-driven simple diffusion (1).

Effects of MKT-077, Cisplatin, and Adriamycin in ClonogenicAssays. Fig. 2a shows the effect of MKT-077 on the colony formation of the normal monkey kidney cell line CV-l and five humantumor cell lines, including CX-l (colon), MCF-7 (breast), CRL-l420(pancreas), EJ (bladder), and LOX (melanoma), after 24-h treatments.IC50s of MKT-077 are 0. 15 p.g/ml for LOX and CRL- 1420, [email protected]/mlfor EJ, 0.30 @g/mlfor CX- 1, 0.5 .tg/ml for MCF-7, and 40j@g/rnlfor CV-l. For the most responsive cell lines, LOX and CRL

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Fig. 2. Clonogenic assays comparing the effects of MKT-077 (a) and cisplatin (b) on CV-l, an indicator cell line for normal epithelial cells. and five human cancer cell lines (CX-l,MCF-7, LOX. EJ, and CRL-1420).

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(3 p.g/ml)wasclearlyevident.After24h treatment,themorphologyof MCF-7 cells became abnormal and was accompanied by thecessation of normal ruffling activity. After 48 h, most cells underwentrapid blebbing, followed by cell burst. In contrast, under the sameconditions, CV-! cells grew rapidly, despite the daily addition ofMKT-077.

Antitumor Activity in Nude Mice. Fig. 5 shows that after i.p.implantation of 2 X 106 LOX cells, male nude mice had a mediansurvival of 18 days. In contrast, mice that received i.p. injections ofMKT-077 (5 mg/kg; days 1â€”5)showed a median survival of 62 dayswith T/C = 344%. Two of the five MKT-077-treated mice in thisexperiment were still alive on day 80. Effects of MKT-077 in the LOXi.p. model were examined in an additional 35 trials by varying dosesand schedules. Although efficacy varied, MKT-077 consistently displayed antitumor activity similar to that shown in Fig. 5. In onenotable experiment in which MKT-077 was injected i.p. at 5 mg/kg ondays 1, 5, 8, 11, and 14, the median survival observed was 97 dayswithT/C = 539%.

Fig. 6 shows the response of a human renal carcinoma A-498 s.c.xenograft to i.v. treatment with MKT-077. As indicated by the meantumor size in both control and treated mice, MKT-077 (7.5 mg/kg i.v.on days 1, 3, 5, 7, 9, 11, and 13) exhibited significant antitumoractivity up to 43 days after tumor implantation.

The response of human prostate carcinoma DU- 145 s.c. xenograftsto i.v. treatment with MKT-077 is shown in Fig. 7. MKT-077 administeredi.v.at11.25mg/kgon days5,7,9,11,15,17,23,and25showed marked inhibition of tumor growth.

MKT-077 Uptake Visualized by Confocal Microscopy. To understand the basis for the antitumor activity of MKT-077, confocalfluorescence microscopy was used to localize the fluorescence ofMKT-077. Fig. 8 depicts a coculture of CRL-l420 and CV-l cellsincubated with MKT-077 at 3 pg/ml for 30 mm and examined byconfocal microscopy. MKT-077 fluorescence is localized selectivelyin the mitochondria of CRL-l420 cells. Under this condition, as aresult of its low membrane potential (1â€”13,16â€”24),the mitochondriaof CV-l failed to take up sufficient MKT-077 for visualization. It ispossible to visualize CV-l mitochondria at a much higher concentration of MKT-077 (e.g., 100 @ig/mlfor 30 mm).

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Fig. 3. Selectivity of MKT-077, cisplatin, and Adriamycin between CV-l and fivehuman cancer cell lines by clonogenic assays (CX-l, MCF-7, LOX, E.J, and CRL-l420).

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Fig. 4. Effect of MKT-077 on the growth of CV-1 and human breast carcinoma MCF-7in mass cultures. MKT-077 at 3 @g/mlwas added daily for 4 days.

1420, MKT-077 is 267-fold more effective in inhibiting colony formation than it is for CV-l cells. Fig. 2b shows the effect of cisplatinon the same cell lines under the same conditions. It appears thatcisplatin does not display significant selectivity between CV-! andfive human tumor lines in these assays. Fig. 3 compares the selectivityof cisplatin, Adriamycin, and MKT-077 among five human tumor celllines. Whereas MKT-077 displays high selectivity between CV-l andhuman tumor lines, cisplatin does not.

Effect of MKT-077 on Growth Rate of MCF-7 and CV-!. Fig.4 shows the effect of MKT-077 on the cell growth of MCF-7 andCV-l in mass culture. MKT-077 at 3 @.tg/ml(daily replenishment) hasno effect on the growth of CV- I cells. In contrast, it has a markedeffect on the growth of MCF-7 under the same culture conditions.

Time-Lapse Videomicroscopy. The effect of MKT-077 on cellgrowth was also confirmed by time-lapse videorecording in which theinhibition of MCF-7 cell division soon after the addition of MKT-077

DAYFig. 5. Survival of human melanoma LOX-bearing nude mice treated with MKT-077

i.p. at 5 mg/kg on days 1â€”5.T/C = 344%.

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RHODACYANINES AS ANTICANCER AGENTS

MKT-077 Uptake Monitored by Flow Cytometry. We usedflow cytornetry to compare the uptake of MKT-077 by CX-! andCV-l cells. After a 5-h treatment with MKT-077 at 3 p@g/m1,CX-1cells took up MKT-077 to a significantly higher extent than CV-!cells (Fig. 9).

Quantitation of MKT-077 Uptake and Retention by EthanolExtraction. The uptake of MKT-077 by CX-l and CV-l cells wasalso determined by ethanol extraction followed by spectrophotometricmeasurements. Fig. 10 shows that the uptake of MKT-077 after a 6-hincubation is 65-fold greater by CX-! cells than by CV-! cells. Inaddition, after MKT-077 was removed from the culture medium,CX-l cells continued to retain a significant amount of MKT-077, evenafter 20 h in drug-free medium (Fig. 10). The small amount ofMKT-077 taken up by CV-l cells was rapidly released into the culturemedium once cells were placed in drug-free medium.

DISCUSSION

The results of this study demonstrate that MKT-077 has significantgrowth-inhibitory activity against a variety of keratin-positive humancancer cell lines in culture, as measured by clonogenic assays and cellgrowth inhibition in mass cultures. MKT-077 also displays significantantitumor activity in nude mice implanted with human melanomaLOX, human renal carcinoma A498, and human prostate carcinomaDU145,all of whicharehighlyrefractoryto varioustherapies.

Differences in the mitochondrial membrane potential between carcinoma cells and normal epithelial cells have been noted previously(1â€”7,13, 16â€”27).Dairkee et al. (27) reported recently that primarybreast epithelial cells derived directly from carcinoma explants display increased uptake and retention of rhodamine 123 when comparedwith epithelial cells derived from normal human mammary explants.Earlier studies using normal primary bladder, breast, and kidneyepithelial cells and a variety of epithelial cell lines derived fromnormal tissues have demonstrated that respective mitochondrial membrane potentials, as indicated by rhodamine 123 or tetraphenyiphosphonium uptake, are very similar to that of CV-l cells (1â€”13,16â€”24).For convenience, we have used CV-! as an indicator cell line for cellswith low mitochondrial membrane potentials in this study. CV-1 cells

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used here do not express P-glycoprotein, as examined by immunofluorescence microscopy and immunoelectron microscopy.3 In contrastto cells expressing P-glycoprotein, which render them Adriamycinresistant, the CV-! cells used here are highly sensitive to Adriamycin(Fig.3).

Like other DLCs, MKT-077 is accumulated and retained by themitochondria of carcinoma cells to a much greater extent than bynormal epithelial cells. The mitochondrial membrane potentials ofCV-l and CX-! cells have been estimated previously to be 104 and163 mV, respectively (21). This 60-mV difference (equivalent to120,000 V across 1 cm) may generate a significant difference in theconcentration gradient. Based on the Nernst equation, a 60-mV potential difference would account for a 10-fold difference in the accumulation of MKT-077 (1, 3, 18, 28â€”32).Since the plasma membranepotential is also higher in carcinoma cells, a higher cytoplasmicconcentration of MKT-077 in carcinoma cells relative to normal cellswould result (18, 29, 30). Thus, the increased uptake of MKT-077 bycarcinoma cells could be much higher than the 10-fold differencepredicted by the mitchondrial membrane potentials alone. Indeed,Figs. 9 and 10 show that CX-! cells could take up 20- to 65-fold moreMKT-077 than CV-1 cells.

Thus, the simplest explanation for selective toxicity observed between CV-! cells and carcinoma cells may be the differential uptakeof MKT-077 by these cells. Since MKT-077 is accumulated in mitochondria, one possibility might be that the molecular targets of MKT077 reside in mitochondria. Indeed, in the accompanying manuscripts,we have observed selective mitochondrial toxicity by MKT-077 inseveral different carcinoma cell lines at the cellular, biochemical, andmolecular levels (33, 34).

However, a higher mitochondrial membrane potential in carcinomacells and the resulting increased uptake of MKT-077 may not besufficient for achieving selective cytotoxicity described here. If thiswere the case, cardiac muscle cells, which have high mitochondrialmembrane potential (16), would be especially susceptible to MKT077 toxicity. Significant cardiac toxicity, however, has not yet been

3 Unpublished results.

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Fig. 8. Differential uptake of MKT-077 between CV-l and human pancreatic carcinoma CRL-l420. Cells cocultured on coverslips were exposed to MKT-077 at 3 @.sg/m1for 30 mm.Left. confocal fluorescent micrograph; right, phase-contrast of the same field.

exert any myelotoxicity. Thirty patients with refractory carcinomasCv.-1 havebeentreatedwithMKT-077inPhaseIclinicaltrialsbya30-mm

infusion per day on days 1, 3, and 5, followed by a 3-week rest period.At a dose of 48 mg/rn2, MKT-077 continues to elicit no seriousadverse effects, including cardiac toxicity and myelotoxicity in thesepatients.

There is an urgent need to develop novel selective and effectivet@ [---- â€”--- . - â€˜@â€˜@â€˜@Te'.therapies for human carcinomas, such as those of the lung, breast,

colon, prostate, and pancreas. MKT-077 may represent the first of anew class of antineoplastic agents, based on their mitochondrial

Cx-.1 accumulationandhighdegreeofselectivityforcarcinomaswithoutmajor untoward effects on vital organs such as bone marrow. In thislight, MKT-077 could also be useful in combination therapy forcancer, since mitochondria have never before been exploited as atarget for cancer chemotherapy. Finally, because MKT-077 is accu

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detected in preclinical toxicology studies involving rodents and dogs.3This implicates the involvement of additional cellular factor(s) uniqueto carcinoma cells in the manifestation of the overall cytotoxicityexpressed by MKT-077. Conceivably, these factors could reside outside of mitochondria. Previously, we have shown that mitochondriacan serve not only as a reservoir but also as a slow-release device forDLCs such as MKT-077 (3). The cellular factors unique to carcinomacells may be preferentially affected by MKT-077, which couldaccount for the dramatic selectivity seen in the clonogenic assays.

It is of interest to note that in addition to the lack of cardiac toxicity,MKT-077 also fails to induce myelotoxicity, a serious side effectexperienced by many conventional anticancer drugs. Although bonemarrow cells proliferate very rapidly, their mitochondrial membranepotentials are low and liule MKT-077 is accumulated.3 Preclinicaltoxicology studies in rats and dogs, as well as Phase I clinical trials,have borne out the expectation that DLCs such as MKT-077 do not

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mulated in mitochondria where oxygen is most abundant, it might alsoserve as a sensitizer for hyperthermia, radiation, or photodynamictherapy.

ACKNOWLEDGMENTS

We are indebted to K. Ogawa, K. Aikawa, A. Ikegawa, K. Aoki, M.Hirayama, N. Suzuki, Y. Matsumoto, E. Fujioka, A. Nakazawa, T. Mochizuki,and M. Watanabe of Fuji Photo Film Co., Ltd., for their contributions to the

syntheses and characterizations of more than 1000 MKT-077 analogues. We

are grateful to D. Dykes of Southern Research Institute (Birmingham, AL) forantitumor experiments in nude mice and Cell Sorter Facilities at DFCI for flow

cytometric analysis. We also acknowledge the advice of D. Nishio, N. Furutachi, I. Itoh, M. Sugiyama, and K. Kigasawa of Fuji Photo Film Co., Ltd., J.R. Wong of Cornell University Medical College (New York, NY), D. Kufe andE. Weisberg of Dana-Farber Cancer Institute (Boston, MA), and J. S. ModicaNapolitano of Tufts University (Medford, MA).

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2. Wong, J. R., and Chen. L. B. Recent advances in the study of mitochondria in livingcells. Adv. Cell Biol., 2: 263â€”290,1988.

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1996;56:538-543. Cancer Res Keizo Koya, Yang Li, Hong Wang, et al. Mitochondrial Accumulation

SelectiveAnticarcinoma Activity in Preclinical Studies Based on MKT-077, a Novel Rhodacyanine Dye in Clinical Trials, Exhibits

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