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Comparative efficacy of DMP 840 against mouse and human solid tumor models

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Summary

Background

DMP 840 is a compound from a class of bis-naphthalimide antitumor agents that recently completed Phase I clinical trials at three North American centers and is currently undergoing Phase II testing. Preclinically, it was shown to have curative activity against a variety of human tumor xenograft models.

Purpose

To test DMP 840 bothin vitro andin vivo for antiproliferative activity against predominantly mouse tumor models.

Methods

A disk diffusion soft agar colony formation assay was used to determine thein vitro growth inhibitory activity against a selection of mouse and human tumor cell lines, and the comparable selective mouse solid tumors were used forin vivo testing.

Result

In vitro DMP 840 exhibited equal cytotoxicity for human tumors (including MX-1 directly cultured from nude mice), mouse tumors and normal cells.In vivo DMP 840 was only modestly active or inactive against the following mouse tumors: Mam 16/C, T/C=30% (T/C=Percent Tumor Growth Inhibition); Mam 16/C/ADR, T/C=33%; Colon 38, T/C=9%; Panc 03, T/C=53%; Colon 51/A, T/C=28%; Pane 02, T/C= 52%; P388/0, 36% ILS (Percent Increased Life Span) and P388/ADR, 14% ILS. Furthermore, the antitumor activity was only observed at the highest non-toxic dose and was associated with a large body weight loss. In contrast, the agent was highly active against the human breast tumor MX-1 implanted subcutaneously in either athymic nude or SCID mice (Nudes: T/C=0%; 1/5 cures; SCIDS: T/C=0%; 5/5 cures).

Conclusions

Although there was no selective cytotoxicity in our clonogenic assay for human versus mouse tumor cell lines, selective activityin vivo for human xenograft tumors was noted. Overall, this compound is rather unique in its differential degree ofin vivo activity for human versus mouse tumors.Implications: Phase II trials, which are ongoing, will help determine if the preclinicalin vivo selective activity of DMP 840 translates to clinical activity in man.

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References

  1. Kirshenbaum MR, Chen SF, Behrens CH, Papp LM, Stafford MP, Sun JH, Beherens DL, Fredericks JR, Polkus SA, Sipple P, Patten AD, Dexter D, Seitz SP, Degan D, VonHoff D, Gross JL: DMP 840, a novel bis-naphthalimide with potent but non-selective tumoricidal activityin vitro. In Press, Cancer Research

  2. Czerniak PM, Dexter DL, Dusak BL, Fredericks JR, Gale KC, Gross JL, Jiang JB, Kirshenbaum MR, McRipley RJ, Papp LM, Patten AD, Perrella FW, Seitz SP, Stafford MP, Sun J-H, Sun T, Wuonola MA, VonHoff DP: XB596, a promising bis-naphthalimide anticancer agent. Anticancer Drugs 4:447–457, 1993

    PubMed  Google Scholar 

  3. Jiang JB, Gross JL, Dusak BA: Bis-naphthalenensul-fonamides. A new series of protein kinase C inhibitors which inhibit tumor cell growth. Proc. of NCI-EORTC symposium on new drugs in cancer therapy 6:45, 1989

    Google Scholar 

  4. McRipley RJ, Burns-Horwitz PE, Czerniak PM, Diamond RJ, Diamond MA, Miller JLD, Page RJ, Dexter DL, Chen SF, Sun J-H, Behrens CH, Seitz SP, Gross JL: Efficacy of DMP 840: A novel bis-naphthalimide cytotoxic agent with human solid tumors xenograft selectivity. Cancer Res 54:159–164, 1994

    PubMed  Google Scholar 

  5. Houghton PJ, Cheshire PJ, Hallman JC III, Gross JL, McRipley RJ, Sun J-H, Behrens CH, Dexter DL, Houghton JA: Evaluation of a novel bis-naphthalimide anticancer agent, DMP 840, against human xenografts derived from adult, juvenile and pediatric cancers. Cancer Chemotherapy Pharmacology 33:265–272, 1994

    Google Scholar 

  6. Corbett TH, Roberts BJ, Leopold WR, Peckham JC, Wilkoff LJ, Griswold Jr DP, Schabel Jr FM: Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57B1/6 mice. Cancer Res 44:717–726, 1984

    PubMed  Google Scholar 

  7. Corbett TH, Griswold Jr DP, Roberts BJ, Peckham JC, Schabel Jr FM: Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure. Cancer Res 35:2434–2439, 1975

    PubMed  Google Scholar 

  8. Corbett TH, Leopold WR, Dykes DJ, Roberts BJ, Griswold Jr DP, Schabel Jr FM: Toxicity and anticancer activity of a new triazine antifolate (NSC127755). Cancer Res 42:1701–1715, 1982

    Google Scholar 

  9. Corbett TH, Griswold Jr DP, Roberts BJ, Peckham JC, Schabel Jr FM: Evaluation of single agents and combinations of chemotherapeutic agents in mouse colon carcinomas. Cancer 40:2660–2680, 1977

    PubMed  Google Scholar 

  10. Corbett TH, Roberts BJ, Trader Jr MW, Laster Jr WR, Griswold Jr DP, Schabel Jr FM: Response of transplantable tumors of mice to anthracenedione derivatives alone and in combination with clinically useful agents. Cancer Treat Rep (5)66:1187–1200, 1982

    PubMed  Google Scholar 

  11. Corbett TH, Griswold Jr DP, Roberts BJ, Peckham JC, Schabel Jr FM: Biology and therapeutic response of a mouse mammary adenocarcinoma (16/C) and its potential as a model for surgical adjuvant chemotherapy. Cancer Treat Rep 62:1741–1488, 1978

    Google Scholar 

  12. Kessel D, Corbett T: Correlations between anthracycline resistance, drug accumulation and membrane glycoprotein patterns in solid tumors of mice. Cancer Letters 28:1870–1893, 1985

    Google Scholar 

  13. Carney DN, Gazdar AF, Bepler G, Guccion JG, Marangos PJ, Moody TW, Zweig MK, Minna JD: Establishment and identification of small cell lung cancer cell lines having classic and variant features. Cancer Res 45:2913–2923, 1985

    PubMed  Google Scholar 

  14. Brattain MG, Fine WD, Khaled FM, Thompson J, Brattain DE: Heterogeneity of malignant cells from a human colonic adenocarcinoma. Cancer Res 41:1751–1756, 1981

    PubMed  Google Scholar 

  15. Corbett TH, Valeriote FA, Polin L,et al.: Discovery of solid tumor active agents using a soft-agar-colony-formation disk-diffusionassay. In: Valeriote FA, Corbett TH, Baker LH (eds) Cytotoxic Anticancer Drugs: Models and Concepts for Drug Discovery and Development. Kluwer Acad Publ, Norwell, Massachusetts, 1992, pp 35–87

    Google Scholar 

  16. LoRusso PM, Polin L, Biernat LA, Valeriote FA, Corbett TH: Activity of datelliptium acetate (NSC311152; SR95156A) against solid tumors of mice. Inv New Drugs 8:253–261, 1990

    Google Scholar 

  17. Corbett TH, Valeriote FA: Rodent models in experimental chemotherapy. In: Kallman RF (ed) The Use of Rodent Tumors in Experimental Cancer Therapy: Conclusions and Recommendations. Pergamon Press, Elmsford, NY, 1987, pp 233–247

    Google Scholar 

  18. Corbett TH, Bissery M, Wozniak A, Plowman J, Polin L, Tapazaglou E, Dieckman J, Valeriote F: Activity of flavone acetic acid (NSC 347512) against solid tumors of mice. Inv New Drugs 4:2027–2040, 1986

    Google Scholar 

  19. Arthaud LE, Springer JK: Preclinical toxicity of the anticancer agent DMP 840 in mice, rats and dogs. Proc Am Soc Clin Oncol 34:2290, 1993

    Google Scholar 

  20. Stafford MM, Kirshenbaum MR, Elliot KJ, Chen SF, Perrella F, Sun T, Trainor GL, Papp LM, Fredericks JR, Sun J-H, Gross JL: DNA binding characteristics of DMP 840, a novel bis-naphthalimide tumor agent. Proc Am Assoc Cancer Res 34:384, 1993

    Google Scholar 

  21. McRipley RJ, Behrens CH, Burns-Horwitz P, Czerniak P, Dexter DL, Diamond M, Diamond R, Miller J, Page, RJ, Sun JH, Gross JL: Evaluation of DMP 840, a novel anti-tumor agent, in murine and human tumor modelsin vivo. Proc Am Assoc Cancer Res 34:384, 1993

    Google Scholar 

  22. Slichenmyer W, Finizio M, Sartorius S, Rowinsky E, Lai C-M, Grochow L, Pieniaszek H, O'Reilly S, Bunitsky K, Brogdon B, Mabring D, Shifflett C, Donehower R: Phase I and pharmacologic study of DMP 840 as a single infusion every three weeks. Proc ASCO 13:364, 1994

    Google Scholar 

  23. Maroun J, Steward D, Goel R, Goss G, Verma S, Yau J, Finizio M, Lai C-M, Bunitsky H, Pieniaszek H, Brodgon B: Phase I pharmacokinetic study of DMP 840 given in a 3 weekly dosage in a 5 weeks schedule. Proc ASCO 13: 400, 1994

    Google Scholar 

  24. Cobb P, Burris H, Finizio M, Lai C-M, Eckardt J, Fields S, Kuhn J, Nelson J, Bunitsky K, Pieniaszek H, Brodgon B, Von Hoff D: Phase I trial and pharmacokinetic study of a new bisnaphthalimide, DMP 840. Proc ASCO 13:429, 1994

    Google Scholar 

  25. O'Reilly S, Rowinsky EK, Grochow L, Adjei A, Bowling K, Slichenmyer W, Sartorius S, Finizio M, Groy JE, Pieniaszek HJ, Peterman VC, Mabring D, Donehower RC: Phase I and pharmacologic study of DMP 840 as a 24 hour infusion in patients with solid tumors. Proc ASCO 14:1529, 1995

    Google Scholar 

  26. Cobb P, Burris H, Drengler R, Fields S, Smith L, White L, Pieniaszek H, Gray J, Peterman V, Finizio M, Von Hoff D: Phase I trial of DMP 840 given as a 120 hour continuous infusion every 28 days. Proc ASCO 14:1577, 1995

    Google Scholar 

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Authors and Affiliations

  1. Division of Hematology/Oncology, Wayne State University, Harper Hospital, Room 530 Hudson Wing, 3990 John R, 48201, Detroit, MI

    Patricia LoRusso, Lisa Demchik, Maria Dan, Lisa Polin, Janet L. Gross & Thomas H. Corbett

  2. 499 Ramblewood Dr., 19010, Bryn Mawr, PA, USA

    Patricia LoRusso, Lisa Demchik, Maria Dan, Lisa Polin, Janet L. Gross & Thomas H. Corbett

Authors
  1. Patricia LoRusso
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  2. Lisa Demchik
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  3. Maria Dan
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  4. Lisa Polin
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  5. Janet L. Gross
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  6. Thomas H. Corbett
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LoRusso, P., Demchik, L., Dan, M. et al. Comparative efficacy of DMP 840 against mouse and human solid tumor models. Invest New Drugs 13, 195–203 (1995). https://doi.org/10.1007/BF00873800

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