Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 4/2009

Open Access 01-09-2009 | Original Article

Carbonate and carbamate derivatives of 4-demethylpenclomedine as novel anticancer agents

Authors: Lee Roy Morgan, Robert F. Struck, William R. Waud, Blaise LeBlanc, Andrew H. Rodgers, Branko S. Jursic

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2009

Login to get access

Abstract

Purpose

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.

Methods

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).

Results

Carbonate and carbamate derivatives were found to be superior to DM-PEN against IC growing human glioblastoma xenografts.

Conclusion

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.
Literature
1.
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 16:1142–1149PubMed
2.
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 15:1974–1984PubMed
3.
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 77:808–811PubMed
4.
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
5.
Hartman NR, O’Reilly S, Rowinsky EK, Collins JM, Strong JM (1996) Murine and human in vivo penclomedine metabolism. Clin Cancer Res 2:953–962PubMed
6.
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 49:1909–1915PubMed
7.
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 51:1979–1985PubMed
8.
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 2:541–548PubMed
9.
Reid JM, Mathieson DA, Benson LM, Kuffel MJ, Ames MM (1992) Murine pharmacokinetics and metabolism of penclomedine. Cancer Res 52:2830–2834PubMed
10.
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 57:815–817PubMed
11.
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
12.
O’Reilly S, O’ Hearn E, Struck RF, Rowinsky EK, Molliver ME (2003) The alkylating agent penclomedine induces degeneration of purkinje cells in the rat cerebellum. Invest New Drugs 21:269PubMedCrossRef
13.
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
14.
Morgan LR, Struck RF, Rodgers AH, Serota DG (2007) Preclinical toxicity of 4-demethylcholesteryloxylcarbonylpenclomedine (DM-CHOC-PEN). Proc Am Assoc Cancer Res 48:5614
15.
Struck RF, Tiwari A, Friedman HS, Keir S, Morgan LR, Waud WR (2001) Acyl derivatives of demethylpenclomedine, an antitumor active, non-neurotoxic metabolite of penclomedine. Cancer Chemother Pharmacol 48:47–52PubMedCrossRef
16.
Struck RF, Waud WR (2006) Thiolo-, thiono- and dithiocarbonate and thiocarbamate derivatives of 4-demethylpenclomedine as novel anticancer agents. Cancer Chemother Pharmacol 48:180–184CrossRef
17.
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
18.
Pletsas D, Wheelhouse RT, Pletsa V, Nicolaou A, Jenkins TC, Bibby MC, Kytopoulas SA (2006) Polar, functionalized guanine-O6 derivatives resistant to repair by O6-alkylguanine-DNA alkyltransferase: implications for the design of DNA-modifying drugs, Eur. J Med Chem 11:1–10
19.
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
20.
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)
Metadata
Title
Carbonate and carbamate derivatives of 4-demethylpenclomedine as novel anticancer agents
Authors
Lee Roy Morgan
Robert F. Struck
William R. Waud
Blaise LeBlanc
Andrew H. Rodgers
Branko S. Jursic
Publication date
01-09-2009
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 4/2009
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-009-0933-9

Other articles of this Issue 4/2009

Cancer Chemotherapy and Pharmacology 4/2009 Go to the issue

Original Article

A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer

Original Article

Pro-apoptotic and cytostatic activity of naturally occurring cardenolides

Original Article

Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors

Original Article

Single- and multiple-dose disposition kinetics of sunitinib malate, a multitargeted receptor tyrosine kinase inhibitor: comparative plasma kinetics in non-clinical species

Original Article

Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: results from an open-label, multicentre Phase I study

Short Communication

Intestinal perforation associated with rituximab therapy for post-transplant lymphoproliferative disorder after liver transplantation
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits