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Current status of pyrazoloacridine as an anticancer agent

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Abstract

Pyrazoloacridine (PZA) is the first of a new class of rationally synthesized acridine derivatives to undergo clinical testing as an anticancer agent. Recent studies suggest that PZA might be a dual inhibitor of DNA topoisomerase I and DNA topoisomerase II that exerts its effects by diminishing the formation of topoisomerase-DNA adducts. Consistent with this unique mechanism of action, PZA exhibits broad spectrum antitumor activity in preclinical models in vivo. In addition, this agent displays several unique properties including solid tumor selectivity, activity against hypoxic cells, and cytotoxicity in noncycling cells. PZA also retains full activity against cells that are resistant to other agents on the basis of overexpression of P-glycoprotein or the multidrug resistance-associated protein (MRP). PZA has been studied in phase I trials in adults and children, and is currently undergoing broad phase II trials in a number of tumor types. No significant anti-tumor activity has been seen in gastrointestinal malignancies and prostate cancer. Results from ongoing or recently completed trials are awaited before the utility of this agent in our current armamentarium can be defined. Because of its unique properties, combination studies with other antineoplastic agents are warranted.

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References

  1. Jackson R, Sebolt J, Shillis J: The pyrazoloacridines: approaches to the development of a carcinoma-selective cytotoxic agent. Cancer Inv 8: 39–47, 1990

    Google Scholar 

  2. Capps D, Ross-Kesten S, Shillis J, Plowman J: 2-aminoalkyl-5-nitropyrazolo[3,4,5-k] acridines, a new class of anticancer agents (abstract). Proc Am Assoc Cancer Res 27: 277, 1986

    Google Scholar 

  3. Sebolt J, Scavone S, Pinter C: Pyrazoloacridines, a new class of antitumor agents with selectivity against solid tumors in vitro. Cancer Res 47: 4299–4304, 1987

    Google Scholar 

  4. LoRusso P, Wozniak AJ, Polin L: Antitumor efficacy of PD 115932 (NSC 366140) against solid tumors of mice. Cancer Res 50: 4900–4905, 1990

    Google Scholar 

  5. Sebolt J, Havlick M, Hamelehle K: Activity of the pyrazoloacridines against multidrug-resistant tumor cells. Cancer Chemother Pharmacol 24: 219–224, 1989

    Google Scholar 

  6. Cole SPC: Patterns of cross-resistance in a multidrugresistance small cell lung carcinoma line. Cancer Chemother Pharmacol 26: 250–256, 1990

    Google Scholar 

  7. Sebolt-Leopold JS, Scavone SV: Biochemistry of the interactions between DNA and the pyrazoloacridines, a series of 48 biologically novel anticancer agents. Proc Am Assoc Cancer Res 32: 334, 1991

    Google Scholar 

  8. Grem JL, Politi PM, Berg SL, Benchekroun NM, Patel M, Balis FM, Sinha BK, Dahut W, Allegra CJ: Cytotoxicity and DNA damage associated with pyrazolaacridine in MCF-7 breast cancer cells. Biochem Pharmacol 51(12): 1648–1659, 1996

    Google Scholar 

  9. Adjei AA, Charron M, Rowinsky EK, Svingen PA, Miller J, Reid JM, Sebolt-Leopold J, Ames MM, Kaufmann SH: Effect of pyrazoloacridine (NSC 366140) on DNA topoisomerases I and II. Clin Cancer Res 4(3): 683–691, 1998

    Google Scholar 

  10. Berg SL, Balis FM, McCully CL, Godwin KS, Poplack DG: Pharmacokinetics of pyrazoloacridine in the rhesus monkey. Cancer Res 51(20): 5467–5470, 1991

    Google Scholar 

  11. Rowinsky EK, Noe DA, Grochow LB, Sartorious SE, Bowling MK, Chen T-L, Lubejko BG, Kaufmann SH, Donehower RC: Phase I and pharmacologic studies of pyrazoloacridine, a novel DNA intercalating agent, on single and multiple dosing schedules. J Clin Oncol 13: 1975–1984, 1995

    Google Scholar 

  12. LoRusso P, Foster BJ, Poplin E, McCormick J, Kraut M, Flaherty L, Heilbrun LK, Valdivieso M, Baker L: Phase I clinical trial of pyrazoloacridine NSC 366140 (PD 115934). Clin Cancer Res 1: 1487–1493, 1995

    Google Scholar 

  13. Monahan B, Quinn M, Takimoto C et al.: Phase I trial of pyrazoloacridine (PZA), a potent DNA binding agent, given as a weekly 24 hour continuous intravenous infusion in adult patients with refractory solid tumors. Proc Amer Soc Clin Oncol 17: 736, 1998

    Google Scholar 

  14. Berg SL, Blaney SM, Adamson PC, O'Brien M, Poplack DG, Arndt C, Blatt J, Balis FM: Phase I trial and pharmacokinetic study of pyrazoloacridine in children and young adults with refractory cancers. J Clin Oncol 16(1): 181–186, 1998

    Google Scholar 

  15. Murgo AJ, Cannon D, Christian MC, Cheson B, Nelson AP: Clinical trials referral resource. Clinical trials with pyrazoloacridine. Oncology 11(7): 991–994, 1997

    Google Scholar 

  16. Zalupski MM, Shields AF, Philip PA, Kraut M, LoRusso P, Heilbrun LK, Vaitkevicius V: Evaluation of pyrazoloacridine in patients with advanced pancreatic carcinoma. Invest New Drugs (16(1): 93–96, 1998

    Google Scholar 

  17. Small EJ, Fippin LJ, Whisenant SP: Pyrazoloacridine for the treatment of hormone-refractory prostate cancer. Cancer Invest 16(7): 456–461, 1998

    Google Scholar 

  18. Zalupski MM, Philip PA, LoRusso P, Shields AF: Phase II study of pyrazoloacridine in patients with advanced colorectal carcinoma. Cancer Chemother & Pharmacol 40(3): 225–227, 1997

    Google Scholar 

  19. Mani S, Gerstner JB, Wade JL, Kugler JW et al.: Phase II trials of pyrazoloacridine (NSC 366140) in patients with advanced hepatobiliary and pancreatic cancer. Cancer Therapeutics 1: 313–317, 1998

    Google Scholar 

  20. Adjei AA, Budihardjo I, Rowinsky EK et al.: Cytotoxic synergy between pyrazoloacridine (NSC 366140) and cisplatin in vitro: Inhibition of platinum-DNA adduct removal. Clin Cancer Res 4: 683–691, 1998

    Google Scholar 

  21. Adjei AA, Kaufman SH, Reid J, Sloan JA, Alberts SR, Goldberg RM, Erlichman C: A phase I study of pyrazoloacridine (PZA) and carboplatin (CBDCA) in patients with advanced solid tumors. Proc Amer Assoc Cancer Res 39: 2206, 1998

    Google Scholar 

  22. Jackson RC: The problem of the quiescent cancer cell. Adv Enzyme Reg 29: 27–46, 1989

    Google Scholar 

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Adjei, A.A. Current status of pyrazoloacridine as an anticancer agent. Invest New Drugs 17, 43–48 (1999). https://doi.org/10.1023/A:1006242321596

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  • DOI: https://doi.org/10.1023/A:1006242321596

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