Antitumor activity and murine pharmacokinetics of parenteral acronycine

Robert T Dorr, J. D. Liddil, D. D. Von Hoff, M. Soble, C. K. Osborne

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Abstract

The lipophilic antitumor alkaloid acronycine (ACRO) was solubilized in the cosolvent system used for etoposide. ACRO in this etoposide diluent (VPD) was found to be cytotoxic (≤ 50% colony formation in soft agar) in fresh human tumors from patients with renal cell cancer, ovarian cancer, uterine cancer, and metastatic tumors of unknown primary. In P-glycoprotein-positive, multidrug-resistant (MDR) cell lines, ACRO in VPD was active in MDR Chinese hamster ovary cells but not against MDR L1210 murine leukemia cells, 8226 human myeloma cells, or human CCRF-CEM lymphoblasts. In mice, ACRO in VPD was active in two solid tumor models and an i.p. MOPC-315 plasmacytoma model. ACRO i.p. in 10% VPD (v/v%) produced significant tumor growth delays in (a) nude mice bearing human MCF-7 breast cancer xenografts and (b) C57BL mice bearing colon 38 tumor. In MOPC-315-bearing mice, a single i.p. ACRO dose of 25 mg/kg was as effective as melphalan (15 mg/kg) at prolonging life span. Finally, ACRO pharmacokinetics was evaluated in mice given single 25-mg/kg doses i.p. or p.o. The oral bioavailability of an ACRO solution in VPD was only 50% but both i.p. and p.o. regimens achieved plasma levels > 1.0 μg/ml. The plasma half-life was just under 2 h. These results show that parenteral ACRO in VPD comprises a cytotoxic antitumor agent with improved bioavailability over p.o. administration. ACRO is active in vitro against several human solid tumors but is cross-resistant in 3 of 4 MDR tumor cell lines. The prior clinical activity of p.o. ACRO in myeloma and the new results in MOPC-315 plasmacytomas in mice suggest that ACRO in VPD could have activity against human multiple myeloma.

Original languageEnglish (US)
Pages (from-to)340-344
Number of pages5
JournalCancer Research
Volume49
Issue number2
StatePublished - 1989

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Acronine
Pharmacokinetics
Plasmacytoma
Etoposide
Neoplasms
Biological Availability
Unknown Primary Neoplasms
Leukemia L1210
Uterine Neoplasms
Melphalan
Cytotoxins
P-Glycoprotein

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dorr, R. T., Liddil, J. D., Von Hoff, D. D., Soble, M., & Osborne, C. K. (1989). Antitumor activity and murine pharmacokinetics of parenteral acronycine. Cancer Research, 49(2), 340-344.

Antitumor activity and murine pharmacokinetics of parenteral acronycine. / Dorr, Robert T; Liddil, J. D.; Von Hoff, D. D.; Soble, M.; Osborne, C. K.

In: Cancer Research, Vol. 49, No. 2, 1989, p. 340-344.

Research output: Contribution to journalArticle

Dorr, RT, Liddil, JD, Von Hoff, DD, Soble, M & Osborne, CK 1989, 'Antitumor activity and murine pharmacokinetics of parenteral acronycine', Cancer Research, vol. 49, no. 2, pp. 340-344.
Dorr RT, Liddil JD, Von Hoff DD, Soble M, Osborne CK. Antitumor activity and murine pharmacokinetics of parenteral acronycine. Cancer Research. 1989;49(2):340-344.
Dorr, Robert T ; Liddil, J. D. ; Von Hoff, D. D. ; Soble, M. ; Osborne, C. K. / Antitumor activity and murine pharmacokinetics of parenteral acronycine. In: Cancer Research. 1989 ; Vol. 49, No. 2. pp. 340-344.
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abstract = "The lipophilic antitumor alkaloid acronycine (ACRO) was solubilized in the cosolvent system used for etoposide. ACRO in this etoposide diluent (VPD) was found to be cytotoxic (≤ 50{\%} colony formation in soft agar) in fresh human tumors from patients with renal cell cancer, ovarian cancer, uterine cancer, and metastatic tumors of unknown primary. In P-glycoprotein-positive, multidrug-resistant (MDR) cell lines, ACRO in VPD was active in MDR Chinese hamster ovary cells but not against MDR L1210 murine leukemia cells, 8226 human myeloma cells, or human CCRF-CEM lymphoblasts. In mice, ACRO in VPD was active in two solid tumor models and an i.p. MOPC-315 plasmacytoma model. ACRO i.p. in 10{\%} VPD (v/v{\%}) produced significant tumor growth delays in (a) nude mice bearing human MCF-7 breast cancer xenografts and (b) C57BL mice bearing colon 38 tumor. In MOPC-315-bearing mice, a single i.p. ACRO dose of 25 mg/kg was as effective as melphalan (15 mg/kg) at prolonging life span. Finally, ACRO pharmacokinetics was evaluated in mice given single 25-mg/kg doses i.p. or p.o. The oral bioavailability of an ACRO solution in VPD was only 50{\%} but both i.p. and p.o. regimens achieved plasma levels > 1.0 μg/ml. The plasma half-life was just under 2 h. These results show that parenteral ACRO in VPD comprises a cytotoxic antitumor agent with improved bioavailability over p.o. administration. ACRO is active in vitro against several human solid tumors but is cross-resistant in 3 of 4 MDR tumor cell lines. The prior clinical activity of p.o. ACRO in myeloma and the new results in MOPC-315 plasmacytomas in mice suggest that ACRO in VPD could have activity against human multiple myeloma.",
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