DM-CHOC-PEN

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.

The drug discovery programs of the National Cancer Institute and the pharmaceutical industry recently have provided oncologists with a wide array of new chemotherapeutic agents that have considerable potential for breast cancer treatment. Foremost among these new agents are the taxanes, of which paclitaxel and docetaxel, the only members of this class currently in clinical use, have been associated with impressive response rates in patients with metastatic disease. Importantly, they display some evidence clinically of not being cross-resistant with the anthracyclines. Efforts now are being directed toward optimizing dose and schedule in the metastatic setting while integrating these agents into standard adjuvant regimens. Other agents that have undergone Phase II testing in breast cancer include vinorelbine, edatrexate, and losoxantrone. It remains to be determined, however, whether these drugs possess substantial advantages over other members of their class. Newer compounds, such as pyrazoloacridine, ICI D1694, topoisomerase-I inhibitors, temozolomide, penclomidine, fumagillin (TNP-470), and differentiators like the retinoids, hold substantial promise because of their unique mechanisms of action; however, Phase II testing of these agents is just beginning. Although alternative approaches to treatment, such as gene therapies, monoclonal antibodies, and growth factor inhibitors, are likely to have a positive impact, it is probable that progress will best be made by combining these strategies with chemotherapy. Therefore, continuation of the search for more effective chemotherapeutic agents should remain a high priority.