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Clinical Cancer Research Vol. 5, 4295-4300, December 1999
© 1999 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

MST-16, a Novel Bis-dioxopiperazine Anticancer Agent, Ameliorates Doxorubicin-induced Acute Toxicity While Maintaining Antitumor Efficacy

Motofumi Yoshida, Yoshihiko Maehara1 and Keizo Sugimachi

Department of Surgery II, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
MST-16 [4,4-1,2-(ethanediyl)bis(1-isobutoxycarbonyloxy-methyl-2,6-piperazinedione)], recently approved as an oral anticancer drug for clinical use in Japan, was evaluated as a chemotherapeutic agent in combination with doxorubicin (DOX) in vitro and in vivo. Cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and murine Colon 26 and human KATO III adenocarcinoma cells were used. The combination index derived from these cytotoxic values indicated a synergistic interaction between DOX and MST-16 or its active metabolite, ICRF-154 (1,1'-ethylenedi-3,5-dioxopiperazine). A maximal tolerated dose of DOX administered to female BALB/c mice bearing a solid Colon 26 tumor resulted in severe body weight loss and diarrhea, but a limited tumor growth delay (1.8 days). However, when combined with an oral dose of MST-16, DOX-induced body weight loss and diarrhea were significantly ameliorated, and an additive tumor growth delay (8.7 days) was obtained. The LD50 of DOX administered i.p. to control female BALB/c mice increased more than 1.5-fold when combined with MST-16. Thus, MST-16 ameliorates DOX-induced acute toxicity while maintaining antitumor efficacy. These results indicate that MST-16 may be effective chemotherapy for cancer patients when combined with DOX.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
MST-16 (Fig. 1)Citation is a newly developed oral bis-dioxopiperazine anticancer agent (1 , 2) recently approved for clinical use in Japan. Clinical trials have shown its efficacy against malignant lymphoma, breast cancer, and lung cancer (3, 4, 5, 6) . This compound is an analogue belonging to the class bis-piperazine and was developed to improve the bioavailability and/or antitumor activity over other agents, such as ICRF-154, -159, and -187 (2 , 7, 8, 9) . MST-16 seems to be a prodrug because it is immediately converted to ICRF-154 in vivo (2) , whereas ICRF-154 is not absorbed from the gastrointestinal tract and is insoluble in water.



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  		Fig. 1. Structures of MST-16, ICRF-154, and ICRF-187.

 
Although bis-dioxopiperazine derivatives, such as ICRF-159 and -187, were developed primarily as antitumor agents, they have also demonstrated significant protective effects against side effects manifested by anthracyclines, in particular, DOX2 and epirubicin, in preclinical and clinical investigations (10, 11, 12, 13, 14, 15, 16, 17, 18) . More importantly, these compounds had no adverse effects on antitumor activity (15, 16, 17) .

ICRF-154, the active metabolite of MST-16, resembles ICRF-159 and -187 with regard to chemical structure, but its potential to protect against anthracycline-induced side effects has heretofore not been demonstrated. This finding, together with the report that ICRF-154 has synergistic cytotoxicity with DOX in an in vitro model system (19) , makes it very likely that MST-16, as a prodrug for ICRF-154, will be combined with an anthracycline in clinical trials. In anticipation of such a trial, we selected DOX as a representative anthracycline to evaluate interactions between DOX and ICRF-154 or MST-16 in vitro and in vivo.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Drugs.
MST-16 and ICRF-154, provided by Zenyaku Kogyo Co., Ltd. (Tokyo, Japan), were dissolved in DMSO for use in the cytotoxic assays. MST-16 was suspended in a 0.5% HPMC (Shin-Etsu Chemical Co., Ltd., Tokyo, Japan) solution for oral administration to mice. DOX was obtained from Kyowa Hakko Co. (Tokyo, Japan). MTT was purchased from Sigma (St. Louis, MO).

Animals.
Female BALB/c mice (5 weeks of age) were purchased from Charles River Japan Inc. (Kanagawa, Japan), housed in plastic cages, and provided a laboratory diet and tap water ad libitum.

Cell Lines.
Murine Colon 26 adenocarcinoma cells (20) and human KATO III gastric adenocarcinoma cells (21) were maintained in plastic culture flasks containing RPMI 1640 (Nissui Pharmaceutical Co., Tokyo, Japan) supplemented with penicillin (200 units/ml), gentamycin (0.04 mg/ml), streptomycin (0.1 mg/ml), and 10% heat-inactivated FCS (Cell Culture Laboratories, Cleveland, OH).

Cytotoxic Assay in Vitro.
The cytotoxic activity of drugs was measured using a MTT assay (22 , 23) . Exponentially growing cells were harvested from flasks, counted by trypan blue exclusion, and resuspended to an appropriate concentration (Colon 26, 7 x 103 cells/ml; KATO III, 1 x 105 cells/ml). Cell suspensions (0.1 ml) were dispensed within a replicate 96-well culture plate with a lid (Corning 25860) in which 0.1 ml of culture medium with the drug at a chosen concentration or with the drug vehicle was added (vehicle control group, n = 11; examined group, n = 4) using a multichannel pipette. After several days of incubation (Colon 26, 5 days; KATO III, 7 days), 0.01 ml of 0.4% MTT solution in PBS and the same volume of sodium succinate solution (0.1 M in PBS) were dispensed in each well after the removal of culture medium. The culture plate was incubated for 3 h before the addition of 0.15 ml of DMSO. The absorbance was measured using a microtiter culture plate reader (SLT-LABINSTRUMENTS, EAR 340) soon after shaking the plate for 5 min with a plate mixer (Sanko Junyaku Co., Ltd.; MICRO MIXER model MX-4).

Analysis of Cytotoxic Interaction between Two Drugs.
Data for additive, antagonistic, or synergistic cytotoxicity was analyzed by the median effect principle (24 , 25) . Fraction affected (fa) was defined as:

where A represents absorbance.

The median-effect plot was graphed, and the correlative coefficient (r), the Hill-type coefficient that signifies the sigmoidicity of the dose-response curve (m), and the median dose concentration (Dm), i.e. ED50, LD50, and IC50, of the respective drug and their mixture were measured. Combination index (CI) was obtained using the formula:

where (D)1 and (D)2 are the contribution of drugs 1 and 2 in the mixture (Dx)1,2 from the known dose ratio of two drugs, and (Dx) was defined as follows:

Tumor, Body Weight Change, and Survival Study.
The effect on tumor growth of MST-16, either alone or in combination with DOX, was investigated using mice bearing s.c. Colon 26 adenocarcinoma. A suspension of viable tumor cells (106 cells in 0.05 ml of HBSS) was prepared from exponentially growing tumor cells and injected into the right flank of each mouse. The tumor grew in 96% of the mice. The sizes of those tumors were measured daily from day 5 (when the tumors became palpable), using a slide caliper. Because Colon 26 tumor induced cancer cachexia (20) , which resulted in a 16.8-day survival time in the control group before the tumors grew to be more than 20% of body weight, the survival time of individual mice was recorded. Treatments were administered when tumors reached an estimated weight of 70–100 mg. The 34 tumor-bearing animals were separated into four groups of eight to nine mice each. The animals were given oral HPMC (0.1 ml/10 g) in the control and DOX alone groups or given MST-16 (750 mg/kg) in the MST-16 alone and combination treatment groups, followed 60 min later by an i.p. injection of saline (0.1 ml/10 g) in the control and MST-16 alone groups or a maximal tolerated dose (7.5 mg/kg) of DOX in the DOX alone and combination treatment groups. The dose ratio of MST-16:DOX (100:1) that we used previously showed a significant protective effect against DOX-induced cardiotoxicity or nephrotoxicity in another experiment using a long-lasting administration schedule in normal rats.3

An estimated TW was calculated by the formula:

where a and b represent maximal and minimal diameter of a tumor, respectively.

where TW0 is pretreatment TW. The parameter of TGT was calculated as time for relative TW to increase 2.5-fold. The parameter of TGD, defined as the difference of the TGT between the treatment group and the control group, was used to evaluate the response of the tumor to treatments.

A relative CW, measured daily as an index of general toxicity induced by drug and cachexia, was calculated by the formula:

where

and CW0 is a pretreatment CW.

Acute Lethal Toxicity of DOX.
The normal animals were allocated to five groups, each of which included seven mice. Either HPMC or MST-16 (375, 750, or 1500 mg/kg) was administered orally before i.p. injection of DOX (0, 7.9, 12, 18, 27, or 40 mg/kg) on day 0. The mortality rates were then monitored for 14 days. The LD10, LD50, and LD90 values were calculated by the probit method. The highest dose of MST-16 was selected based on previous data that shows that oral MST-16, even at 2000 mg/kg, does not have lethality in mice.4

Statistics.
Differences in TGT and CW change among the four groups were evaluated by the Wilcoxon rank-sum test after the Kruskal-Wallis test, a nonparametric variance analysis. Difference in survival was evaluated by the log-rank test. For multiple comparison, Ps were multiplied by k(k - 1)/2 to be corrected, where k is the number of groups being compared (Bonferoni’s procedure). The difference was significant when the corrected P was less than 0.05.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Cytotoxic Interaction between DOX and ICRF-154 or MST-16 in Vitro.
The maximal synergism was obtained when the concentration ratio (ICRF or MST-16:DOX) was 80:1 against Colon 26 cells or 40:1 against KATO III cells. At these concentration ratios, combination indices (in the 0.1–0.9 fraction affected) were less than 1.0 against both Colon 26 and KATO III cells. This means that the cytotoxic interactions between DOX and ICRF-154 or MST-16 are synergistic at this cytotoxic level (Fig. 2)Citation .



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  		Fig. 2. Combination indices indicating the cytotoxic interaction between DOX and MST-16 ( –) or ICRF-154 () against Colon 26 (A) and KATO III (B) cells at each cytotoxic level (fa) shown on the horizontal axis. The combination index indicates the synergistic, additive, and antagonistic interactions when the value is less than 1, equal to 1, and more than 1, respectively.

 
TGD Assay.
The mean tumor doubling time of s.c. Colon 26 adenocarcinoma in the mouse was 2.1 days through the exponential growth phase. As shown in Table 1Citation , treatment with a maximal tolerated dose of DOX alone produced a limited TGD against Colon 26 s.c. tumor, whereas MST-16 alone showed a TGD of 5.3 days. The combination treatment of DOX and MST-16 produced significantly greater antitumor efficacy.


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  		Table 1 TGTa and TGD

 
CW Change and Gastrointestinal Toxicity.
The effect of drugs on the CW of Colon 26 tumor-bearing mice is shown in Fig. 3.Citation The control group showed a temporary weight gain before weight loss due to Colon 26 tumor-induced cachexia became apparent. The first animal to die was in the control group on day 12. In the DOX alone group, there was a decrease in CW. On the other hand, treatment with MST-16 alone and MST-16 plus DOX led to a weight gain after a temporary weight loss before death, and the first animals died on day 18 and day 19, respectively. In the DOX alone group, all mice had severe diarrhea from day 9 until death. However, no incidence of diarrhea was seen in the other three groups.



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  		Fig. 3. Temporal change of mean CW of tumor-bearing mice after treatment day. The mean value ± SD of starting body weight for the animals was 20.6 ± 0.8 g on day 0. Mice were given oral HPMC in the control and DOX alone group or MST-16 (750 mg/kg) in the MST-16 and DOX + MST-16 (combination treatment) groups, followed by i.p. injection of saline (control and DOX alone groups) or 7.5 mg/kg of DOX (DOX and DOX + MST-16 groups). Significance was given when P < 0.01 (*) and P < 0.001 (**). Error bars, SE; n = 8–9.

 
Effects on Survival.
The survival curve in the DOX alone (mean survival time, 16.6 days) and the MST-16 alone (20.8 days) groups showed no significance compared with that of control group (16.8 days). In the combination treatment group (24.8 days), the survival curve was significantly greater than that of both the control and the DOX alone groups (Fig. 4)Citation .



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  		Fig. 4. Survival curves of tumor-bearing mice after treatment day in the control (), DOX alone (– – –), MST-16 alone ( –), and DOX + MST-16 () groups. See Fig. 3Citation for an explanation of the treatment given to each group. The survival curve of the DOX + MST-16 group was significantly greater than that of the control and DOX alone group; P < 0.05.

 
Effects on Acute Lethal Toxicity of DOX.
MST-16 at 375 and 750 mg/kg increased the LD10, LD50, and LD90 values of DOX by 35–107%, whereas 1500 mg/kg MST-16 did not increase the LD values of DOX (Table 2)Citation . The diarrhea that occurred in tumor-bearing mice did not occur in normal mice. The animals given MST-16 alone did not die or show physical signs of side effects.


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  		Table 2 Lethal doses of DOX i.p. with or without MST-16 p.o.a by the probit method

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
MST-16 is a newly developed bis-dioxopiperazine anticancer drug currently under Phase II clinical trial in Japan. In this preclinical study, we evaluated MST-16 in combination with DOX to determine the efficacy and toxicity of the combined treatment.

The combination index derived from in vitro antitumor interaction between DOX and MST-16 or ICRF-154 showed synergistic cytotoxicity against both Colon 26 murine adenocarcinoma and KATO III human gastric cancer cell lines. Wadler et al. (26) noted a synergistic interaction between DOX and ICRF-187, closely resembling ICRF-154, against a murine sarcoma 180 cell line, and Monti et al. (27) reported a similar synergism against a HL-60 human leukemia cell line. Kano et al. (19) found a synergistic interaction between DOX and ICRF-154 against four in vitro human leukemia cell lines. Our results support these previous findings and further demonstrate that MST-16 is also effective, even in gastrointestinal cell lines. Whether, in vitro, MST-16 is active itself or via the generation of ICRF-154 is unknown. The enhancement DOX-induced G2-M-phase arrest by ICRF-187 has been reported to be a mechanism of synergistic interaction (28) . An identical mechanism can be expected for MST-16 or ICRF-154. Because ICRF-154 has recently been identified as a new class of topoisomerase II inhibitors that does not produce a cleavable complex (29 , 30) , studies on interactions between DOX and MST-16 or ICRF-154 are expected.

In terms of the animal study using the Colon 26 tumor model, mice given the maximal tolerated dose of DOX showed significant body weight loss and diarrhea in comparison to the control group and had almost the same survival time as nontreated animals, although they showed a limited but certain TGD. On the other hand, MST-16 showed a greater TGD in this study. Although the reason for this is unknown, it may be because of a poor pharmacokinetic profile of DOX compared to MST-16 with this schedule or route of drug administration. The concomitant administration of MST-16 significantly ameliorated DOX-induced toxicities and prolonged both TGD and survival time.

To confirm this protective effect of MST-16 against DOX-induced acute toxicity, we determined the LD values for 14 days of i.p. injected DOX, with or without oral MST-16, in normal mice. Doses of 375 and 750 mg/kg MST-16 reduced the incidence of DOX-induced lethality, findings in good agreement with a report that ICRF-159 structurally resembles ICRF-154 (31) . Woodman et al. (31) found that concomitant administration of ICRF-159 reduced DOX-induced acute lethality and allowed for an increase in the dose of DOX, which resulted in an enhancement of antitumor efficacy in a murine L1210 leukemia model. Protective effects were limited when the highest dose of MST-16, 1500 mg/kg, was administered. The normal mice had no diarrhea, even though they were given lethal doses of DOX. This apparent difference from animals bearing a Colon 26 tumor may be explained by tumor-induced changes in the pharmacokinetics of the antitumor agents in the host, as described by Teicher et al. (32) .

DOX-induced acute lethality after a single injection of DOX is related to such multiple toxic effects as gastrointestinal lesions, myelotoxicity, and atrophy of hematopoietic organs and subacute cardiomyopathy (33 , 34) . ICRF-159 and -187 are reported to enhance but not diminish the anthracycline-induced antitumor efficacy and to reduce lethality and cardiomyopathy induced by anthracyclines in an acute phase (31 , 35 , 36) .

With regard to a possible mechanism for this protective effect, ICRF-187 has the potential to chelate free metal cations, iron or copper, and to reverse the metal-anthracycline complex that facilitates free radical generation and causes cardiomyopathy (37 , 38) . There may be a similar mechanism of action, because MST-16 and ICRF-154 are similar in structure. Details on toxic interaction in a specific organ between DOX and MST-16 remain to be investigated, especially in the heart and bone marrow, because DOX-induced cardiomyopathy is life-threatening (39 , 40) , and both MST-16 (3) and DOX (34) may induce myelosuppression.

In summary, we found that MST-16 ameliorates DOX-induced acute toxicity while maintaining antitumor activity.


   ACKNOWLEDGMENTS
 
We thank Dr. Z. H. Siddik (The University of Texas M. D. Anderson Cancer Center, Houston, TX) for critical comments and helpful discussions.


   FOOTNOTES
 
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 with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Department of Surgery II, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Phone: 81-92-642-5462; Fax: 81-92-642-5482. Back

2 The abbreviations used are: DOX, doxorubicin; TW, tumor weight; CW, carcass body weight; TGT, tumor growth time; TGD, tumor growth delay; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; HPMC, hydroxypropylmethylcellulose 2910. Back

3 M. Yoshida, unpublished observations. Back

4 T. Narita, personal communication. Back

Received 1/ 5/99; revised 9/13/99; accepted 9/13/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Narita T., Yaguchi S., Komatsu T., Takase M., Hoshino A. Antitumor activity of MST-16, a novel derivative of bis(2, 6-dioxopiperazine), in murine tumor models. Cancer Chemother. Pharmacol., 26: 193-197, 1990.[Medline]
  2. Narita T., Koide Y., Yaguchi S., Kimura S., Izumisawa Y., Takase M., Inaba M., Tsukagoshi S. Antitumor activities and schedule dependence of orally administered MST-16, a novel derivative of bis(2, 6-dioxopiperazine), in murine tumor models. Cancer Chemother. Pharmacol., 28: 235-240, 1991.[Medline]
  3. Furue H., Niitani H., Nakao I., Hoshino A., Hasegawa K., Tsukagoshi S., Fujita H. Phase I study of MST-16. Jpn. J. Cancer Chemother., 17: 1287-1294, 1990.
  4. Masaoka T., Furue H. MST-16 for the treatment of lymphoma. J. Cancer Res. Clin. Oncol., 116 (Suppl. Part I): 607 1990.
  5. Ohno R., Yamada K., Hirano M., Shirakawa S., Tanaka M., Oguri T., Kodera Y., Mitomo Y., Ikeda Y., Yokomaku S., Kamiya O., Kobayashi M., Saito H., Kimura K. Phase II Study: treatment of non-Hodgkin’s lymphoma with an oral antitumor derivative of bis(2, 6-dioxopiperazine). J. Natl. Cancer Inst., 84: 435-438, 1992.[Abstract/Free Full Text]
  6. Ohno R., Masaoka T., Shirakawa S., Sakamoto S., Hirano M., Hanada S., Yasunaga K., Yokomaku S., Kitomo Y., Nagai K., Yamada K., Furu H. Treatment of adult T-cell leukemia/lymphoma with MST-16, a new oral antitumor drug and a derivative of bis(2, 6-dioxopiperazine). Cancer (Phila.), 71: 2217-2221, 1993.[Medline]
  7. Brubaker L. H., Vogel C., Einhorn L. H., Birch R. Treatment of advanced adenocarcinoma of kidney with ICRF-187: a Southeastern Cancer Study Group trial. Cancer Treat. Rep., 70: 915-916, 1986.[Medline]
  8. Creaven P. J., Allen L. M., Alford D. A. The bioavailability in man of ICRF-159, a new oral antineoplastic agent. J. Pharm. Pharmacol., 27: 914-918, 1975.[Medline]
  9. Wheeler R. H., Bricker L. J., Natale R. B., Baker S. R. Phase II trial of ICRF-187 in squamous cell carcinoma of the head and neck. Cancer Treat. Rep., 68: 427-428, 1984.[Medline]
  10. Alderton P. M., Gross J., Green M. D. Comparative study of doxorubicin, mitoxantron, and epirubicin in combination with ICRF-187 (ADR-529) in a chronic cardiotoxicity animal model. Cancer Res., 52: 194-201, 1992.[Abstract/Free Full Text]
  11. Dardir M., Herman E. H., Ferrans V. J. Effects of ICRF-187 on the cardiac and renal toxicity of epirubicin in spontaneously hypertensive rats. Cancer Chemother. Pharmacol., 23: 269-275, 1989.[Medline]
  12. Herman E. H., Ferrans V. J. Pretreatment with ICRF-187 provides long-lasting protection against chronic daunorubicin toxicity in rabbits. Cancer Chemother. Pharmacol., 16: 102-106, 1986.[Medline]
  13. Herman E. H., Ferrans V. J., Young R. S. K., Hamlin R. L. Effect of pretreatment with ICRF-187 on the total cumulative dose of doxorubicin tolerated by beagle dogs. Cancer Res., 48: 6918-6925, 1988.[Abstract/Free Full Text]
  14. Perkins W. E., Schroeder R. L., Carrano R. A., Imondi A. R. Effect of ICRF-187 on doxorubicin-induced myocardial effects in the mouse and guinea pig. Br. J. Cancer, 46: 662-667, 1982.[Medline]
  15. Speyer J. L., Green M. D., Kramer E., Rey M., Sanger J., Ward C., Dubin N., Ferrans V., Stecy P., Zeleniuch-Jacquotte A., Wernz J., Feit F., Slater W., Blum R., Muggia F. M. Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N. Engl. J. Med., 319: 745-752, 1988.[Abstract]
  16. Speyer J. L., Green M. D., Sanger J., Zeleniuch-Jacquotte A., Kramer E., Rey M., Wernz J. C., Blum R. H., Hochster H., Meyers M., Muggia F. M. A prospective randomized trial of ICRF-187 for prevention of cumulative doxorubicin-induced cardiac toxicity in women with breast cancer. Cancer Treat. Rev., 17: 161-163, 1990.[Medline]
  17. Speyer J. L., Green M. D., Zeleniuch-Jacquotte A., Wernz J. C., Rey M., Sanger J., Kramer E., Ferrans V., Hochster H., Meyers M., Blum R. H., Feit F., Attubato M., Burrows W., Muggia F. M. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J. Clin. Oncol., 10: 117-127, 1992.[Abstract]
  18. Von Hoff D. D., Layard M. W., Basa P., Davis H. L., Jr., Von Hoff A. L., Rosencweig M., Muggia F. M. Risk factors for doxorubicin-induced congestive heart failure. Ann. Int. Med., 91: 710-717, 1979.
  19. Kano Y., Narita T., Suzuki K., Akutsu M., Suda K., Sakamoto S., Miura Y. The effects of ICRF-154 in combination with other anticancer agents in vitro. Br. J. Cancer, 66: 281-286, 1992.[Medline]
  20. Tanaka Y., Eda H., Fujimoto K., Tanaka T., Ishikawa T., Ishitsuka H. Anticachectic activity of 5'-deoxy-5-fluorouridine in a murine tumor cachexia model, colon 26 adenocarcinoma. Cancer Res., 50: 4528-4532, 1990.[Abstract/Free Full Text]
  21. Yamada Y., Yoshida T., Hayashi K., Sekiya T., Yokota J., Hirohashi S., Nakatani K., Nakano H., Sugimura T., Terada M. p53gene mutations in gastric cancer metastases and in gastric cancer cell lines derived from metastases. Cancer Res., 51: 5800-5805, 1991.[Abstract/Free Full Text]
  22. Alley M. C., Scudiero D. A., Monks A., Hursey M. L., Czerwinski M. J., Fine D. L., Abbott B. J., Mayo J. G., Shoemaker R. H., Boyd M. R. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res., 52: 589-601, 1988.
  23. Maehara Y., Anai H., Kusumoto H., Sugimachi K. Poorly differentiated human gastric carcinoma is more sensitive to antitumor drugs than is well differentiated carcinoma. Eur. J. Surg. Oncol., 13: 203-206, 1987.[Medline]
  24. Chou T-C., Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul., 22: 27-55, 1984.[Medline]
  25. Chou T-C., Talalay P. Applications of the median effect principle for the assessment of low-dose risk carcinogens and the quantitation of synergism and antagonism of chemotherapeutic agents Harrap K. R. Connors T. A. eds. . New Avenues in Developmental Cancer Chemotherapy, : 37-64, Academic New York 1987.
  26. Wadler S., Green M. D., Muggia F. M. Synergistic activity of doxorubicin and the bisdioxopiperazine (+)-1, 2-bis(3, 5-dioxopiperazinyl-1-yl)propane (ICRF-187) against the murine sarcoma S180 cell line. Cancer Res., 46: 1176-1181, 1986.[Abstract/Free Full Text]
  27. Monti E., Sinha B. K. Potenciation of doxorubicin cytotoxicity by (+)-1, 2-bis-3, 5-dioxopiperazine-1-yl)propane (ICRF-187) in human leukemic HL-60 cells. Cancer Commun., 2: 145-149, 1990.[Medline]
  28. Wadler S., Green M. D., Basch R., Muggia F. M. Lethal and sublethal effects of the bisdioxopiperazine, (+)-1, 2-bis(3, 5-dioxopiperazinyl-1-yl)propane (ICRF-187), on murine sarcoma S180 in vitro. Biochem. Pharmacol., 36: 1495-1501, 1987.[Medline]
  29. Ishida Y., Miki T., Narita T., Yui R., Sato M., Utsumi R. K., Tanabe K., Andoh T. Inhibition of topoisomerase II by antitumor bis(2, 6-dioxopiperazine) derivatives: mode of cell growth inhibition distinct from that of cleavable complex-forming type inhibitors. Cancer Res., 51: 4909-4916, 1991.[Abstract/Free Full Text]
  30. Tanabe K., Ikegami Y., Andoh T. Inhibition of topoisomerase II by antitumor agents bis(2, 6-piperazine) derivatives. Cancer Res., 51: 4903-4908, 1991.[Abstract/Free Full Text]
  31. Woodman R. J., Cysyk R. L., Gang M., Venditti J. M. Enhancement of the effect of daunorubicin (NSC-82151) or Adriamycin (NSC-123127) against early mouse L1210 leukemia with ICRF-159 (NSC-129943). Cancer Chemother. Rep., 59: 689-695, 1975.[Medline]
  32. Teicher B. A., Herman T. S., Holden S. A., Wang Y. Y., Pfeffer M. R., Crawford J. W., Frei E. Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science (Washington DC), 247: 1457-1461, 1990.[Abstract/Free Full Text]
  33. Balazsovits J. A. E., Mayer L. D., Bally M. B., Cullis P. R., McDonell M., Ginsberg R. S., Falk R. E. Analysis of the effect of liposome encapsulation on the vesicant properties, acute and cardiac toxicities, and antitumor efficacy of doxorubicin. Cancer Chemother. Pharmacol., 23: 81-86, 1989.[Medline]
  34. Villani F., Manzotti C., Mella M., Monti E., Savi G., Zunnino F. Effect of amrinone on anthracycline-induced lethal and cardiac toxicity in mice and rats. Med. Oncol. Tumor Pharmacother., 7: 227-232, 1990.[Medline]
  35. Baba H., Stephens L. C., Strebel F. R., Siddik Z. H., Newman R. A., Ohno S., Bull J. M. C. Protective effect of ICRF-187 against normal tissue injury induced by Adriamycin in combination with whole body hyperthermia. Cancer Res., 51: 3568-3577, 1991.[Abstract/Free Full Text]
  36. Herman E., Ardalan B., Bier C., Waravdekar V., Krop S. Reduction of daunorubicin lethality and myocardial cellular alterations by pretreatment with ICRF-187 in Syrian golden hamsters. Cancer Treat. Rep., 63: 89-92, 1979.[Medline]
  37. Hashinoff B. B. The interaction of the cardioprotective agent ICRF-187 ((+)-1, 2-bis(3, 5-dioxopiperazinyl-1-yl)propane) its hydrolysis product (ICRF-198) and other chelating agents with the Fe(III) and Cu(II) complexes of Adriamycin. Agents Actions, 26: 378-385, 1989.[Medline]
  38. Sobol M. M., Amiet R. G., Green M. D. In vitro evidence for direct complexation of ADR-529/ICRF-187'(+)-1, 2-bis-(3, 5-dioxo-piperazine-1-yl)propane onto an existing ferric-anthracycline complex. Mol. Pharmacol., 41: 8-17, 1992.[Abstract]
  39. Bristow M. R., Billingham M. E., Masson J. W., Daniels J. R. Clinical spectrum of anthracycline antibiotic cardiotoxicity. Cancer Treat. Rep., 62: 873-878, 1978.[Medline]
  40. Lefrak E. A., Pitha J., Rosenheim S., O’Bryan R. M., Burgess M. A., Gottlieb J. A. Adriamycin (NSC123127) cardiomyopathy. Cancer Chemother. Rep., 6: 203-208, 1975.




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