Acyl derivatives of demethylpenclomedine, an antitumor-active, non-neurotoxic metabolites of penclomedine.

Abstract

PURPOSE:

The purpose of this investigation was to compare the antitumor activities of a series of acyl derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma metabolite of penclomedine (PEN) observed to be an active antitumor agent in vivo and non-neurotoxic in a rat model with that of DM-PEN.

METHODS:

Acyl derivatives were prepared from DM-PEN and evaluated in vivo against human MX-1 breast tumor xenografts implanted subcutaneously (s.c.) or intracerebrally (i.c.). Several derivatives were also evaluated against other human tumor xenografts and murine P388 leukemia cell lines.

RESULTS:

Several of the acyl derivatives were found to be superior to DM-PEN against MX-1, human ZR-75-1 breast tumor, human U251 CNS tumor and the P388 leukemia parent cell line and lines resistant to cyclophosphamide and carmustine. 4-Demethyl-4-methoxyacetylpenclomedine showed inferior activity to current clinical brain tumor drugs against a glioma cell line, superior activity to temozolomide and procarbazine against the derived mismatch repair-deficient cell line, and superior activity to cyclophosphamide and carmustine but inferior activity to temozolomide against two ependymoma cell lines, all of which were implanted s.c.

CONCLUSION:

Proposed mechanisms of activation and action of DM-PEN and the acyl derivatives support the potential clinical superiority of the acyl derivatives.

• Authors: R F Struck, A Tiwari, H S Friedman, S Keir, L R Morgan, W R Waud
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 48 Issue 1 Pg. 47-52 (Jul 2001) ISSN: 0344-5704 [Print] Germany
• PMID: 11488524 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Picolines
• penclomedine

Topics

• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Brain Neoplasms (drug therapy)
• Humans
• Mice
• Neoplasm Transplantation
• Picolines (metabolism, pharmacology)
• Structure-Activity Relationship
• Transplantation, Heterologous