The purpose of this investigation was to synthesize a series of carbonate and carbamate derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma non-toxic metabolite of penclomedine (PEN) seen in patients. DM-PEN has been observed to be an active antitumor agent in mouse human xenograft tumor models and non-neurotoxic in a rat model, however, activity in intracranially implanted human glioma xenograft models have not been reported. The major goal was to identify derivatives that are active in brain tumors.
Derivatives were prepared from DM-PEN and evaluated in vivo against human U251 glioblastoma, D54 glioblastoma and MX-1 breast tumor xenografts and mammary tumor 16/C that were implanted in the mammary fat pad or intracranially (IC).
Carbonate and carbamate derivatives were found to be superior to DM-PEN against IC growing human glioblastoma xenografts.
The activity of the carbonates and carbamates against human tumor xenografts in vivo suggests consideration of these two series of derivatives of DM-PEN for clinical development.
Berlin J, Stewart JA, Storer B, Tutsch KD, Arzoomanian RZ, Alberti D, Feierabend C, Simon K, Wilding G (1998) Phase I clinical and pharmacokinetic trial of penclomedine using a novel, two stage trial design for patients with advanced malignancy. J Clin Oncol 16:1142–1149 PubMed
O’Reilly S, Grochow L, Donehower RC, Bowling K, Chen TL, Hartman N, Struck R, Rowinsky EK (1997) Phase I and pharmacologic studies of penclomedine, a novel alkylating agent in patients with solid tumors. J Clin Oncol 15:1974–1984 PubMed
Jodrell DI, Bowman A, Stewart M, Dunlop N, French R, MacLellan A, Cummings J, Smyth JF (1998) Dose-limiting neurotoxicity in a phase I study of penclomedine (NSC 388720, CRC 88-04), a synthetic alpha-picoline derivative, administered intravenously. Br J Cancer 77:808–811 PubMed
Berlin J, Wahamaki A, Tutsch KD, Alberti D, Feierabend C, Binger K, Arzoomanian RZ, Volkman J, Karca J, Mornocha R, Stewart J, Wilding G (1999) Phase I, pharmacokinetic and bioavailability study of oral penclomedine administered daily × 5 every four weeks. Proc Am Assoc Cancer Res 40:92
Hartman NR, O’Reilly S, Rowinsky EK, Collins JM, Strong JM (1996) Murine and human in vivo penclomedine metabolism. Clin Cancer Res 2:953–962 PubMed
Plowman J, Harrison SD Jr, Dykes DJ, Paull KD, Narayanan VL, Tobol HK, Martin J, Griswold DP Jr (1989) Preclinical antitumor activity of an alpha-picoline derivative, penclomedine (NSC 338720), on human and murine tumors. Cancer Res 49:1909–1915 PubMed
Harrison SD Jr, Plowman J, Dykes DJ, Waud WR, Griswold DP Jr (1991) Preclinical antitumor activity of penclomedine in mice: cross-resistance, schedule-dependence, and oral activity against tumor xenografts in brain. Cancer Res 51:1979–1985 PubMed
O’Reilly S, Hartman NR, Grossman SA, Strong JM, Struck RF, Eller S, Lesser GJ, Donehower RC, Rowinsky EK (1996) Tissue and tumor distribution of 14C-penclomedine in rats. Clin Cancer Res 2:541–548 PubMed
Reid JM, Mathieson DA, Benson LM, Kuffel MJ, Ames MM (1992) Murine pharmacokinetics and metabolism of penclomedine. Cancer Res 52:2830–2834 PubMed
Waud WR, Tiwari A, Schmid SM, Shih T-W, Strong JM, Hartman NR, O’Reilly S, Struck RF (1997) 4-Demethylpenclomedine, an antitumor-active, potentially nonneurotoxic metabolite of penclomedine. Cancer Res 57:815–817 PubMed
O’Reilly S, O’Hearn E, Rowinsky EK, Struck RF, Molliver ME (1996) Neuroanatomic studies of the cerebellar effects of penclomedine. Proc Am Assoc Cancer Res 37:374–375
Friedman H, Keir S, Bigner D, Struck R (1998) Treatment of CNS tumor xenografts with penclomedine (PEN) and 4-demethylpenclomedine (4-DM-PEN). Proc Am Assoc Cancer Res 39:218
Morgan LR, Struck RF, Rodgers AH, Serota DG (2007) Preclinical toxicity of 4-demethylcholesteryloxylcarbonylpenclomedine (DM-CHOC-PEN). Proc Am Assoc Cancer Res 48:5614
Struck RF, Waud WR (2006) Thiolo-, thiono- and dithiocarbonate and thiocarbamate derivatives of 4-demethylpenclomedine as novel anticancer agents. Cancer Chemother Pharmacol 48:180–184 CrossRef
Morgan LR, Struck RF, Waud W, Jursic BS, Serota DG, Papagiannis C, Rodgers AH (2007) Carbonate and carbamate derivatives of 4-demethylpenclomedine as novel anticancer agents. Molecular targets and cancer therapeutics. Am Assoc Cancer Res 49:280
Pletsas D, Wheelhouse RT, Pletsa V, Nicolaou A, Jenkins TC, Bibby MC, Kytopoulas SA (2006) Polar, functionalized guanine-O 6 derivatives resistant to repair by O 6-alkylguanine-DNA alkyltransferase: implications for the design of DNA-modifying drugs, Eur. J Med Chem 11:1–10
Holland WC (1964) Thermodynamics and the concept of free energy. In: Holland WC, Klein RL, Briggs AH (eds) Introduction to molecular pharmacology. Macmillan, New York, pp 119–125
Morgan LR, Struck RF, Waud W, Jursic BS, Serota DG, Papagiannis C, Rodgers AH, Thornton, ME, GS LaHoste. Preclinical pharmacology and toxicity of 4-demethyl-cholesteryloxylcarbonylpenclomedine (DM-CHOC-PEN) (in press)
- Carbonate and carbamate derivatives of 4-demethylpenclomedine as novel anticancer agents
Lee Roy Morgan
Robert F. Struck
William R. Waud
Andrew H. Rodgers
Branko S. Jursic
Neu im Fachgebiet Onkologie
e.Med Kampagnen-Visual, Mail Icon II