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PurposeThe 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.MethodsDerivatives 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).ResultsCarbonate and carbamate derivatives were found to be superior to DM-PEN against IC growing human glioblastoma xenografts.ConclusionThe 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.

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4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) has recently completed a phase I clinical trial in advanced cancer with minimal toxicity, and impressive objective responses were noted. A-007 possesses three moieties that appear to have an influence on its anticancer activities: diphenylmethane, hydrazone, and dinitrophenyl. The goals of this study were to modify A-007's chemical moieties with the ultimate goal of maximizing its anticancer activity through increased planarity and introduction of functional groups. Thirty-five phenylhydrazone analogues of A-007 were synthesized and evaluated in vitro in a human primary cancer explant assay. Anticancer activities for selected analogues were also assayed for activity vs established human/murine cell lines. One-hundred-eighty-six fresh human solid tumors were used to screen for anticancer activity. Selected analogues were assayed for therapeutic indices (vs GM-CFC from bone marrow) in preparation for preclinical studies. Several polyaryl phenylhydrazones demonstrated improved cytotoxic activities by factors of 10(2)-10(3) when compared with A-007. However, the polyaryl quinone moieties of the latter analogues introduced potential toxic properties (cardiac, hematological) that do not exist with A-007.

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Charge is an important characteristic of drug molecules, since ionization sites determine the pKa at a particular pH. The pKa in turn can affect many parameters, including solubility, dissolution rate, reaction kinetics, formulation, cell permeability, tissue distribution, renal elimination, metabolism, protein binding and receptor interactions. The impact of charge dynamics is amplified in human solid tumors that exhibit the glycolytic phenotype and associated acidic extracellular microenvironment. This phenotype is driven by hypoxia and creates a pH gradient in tumors that favors uptake of weak acids and exclusion of weak bases. Established anticancer drugs exhibit a range of pKa’s and thus variable ability to exploit the tumor pH gradient. The camptothecins are a prime example as they represent a diverse class of approved anticancer drugs and drug candidates whose charge distribution varies with pH. An in silico method was used to predict charge distribution of camptothecins at physiological versus acidic pH in both the lactone and carboxylate forms. A significant amount of uncharged carboxylate was predicted at acidic pH that could enter tumor cells and accumulate in mitochondria to inhibit mitochondrial topoisomerase I. A model is presented to describe the charge dynamics of a new camptothecin analog and the impact on nuclear and mitochondrial mechanism(s) of action. This example illustrates the importance of integrating tumor physiology and charge dynamics into anticancer drug development.

The incidence of EGFR mutation may be higher in Australian populations than in other populations of predominantly European origin. Rare and compound EGFR mutations may occur and may have implications for treatment that differ from classically activating mutations.

4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a polychlorinated pyridine cholesteryl carbonate, which is active vs. intracranially (IC) implanted human xenograft models - U251 and D54 glioblastoma and MX-1 breast cancer (%LTS/CR): +29/25 and +20/17, resp. and has a MOA via alkylation of DNA @ N7 - guanine (CCP, 64, 829, 2009). DM-CHOC-PEN's preclinical rodent single IV dose toxicity studies documented the following landmark values: for mice - LD10/50 136/385 mg/kg; & for rats - LD10 100 mg/kg. DM-CHOC-PEN is metabolized to 4-demethyl-PEN (DM-PEN) and cholesterol. The DLT in rats was hypercholesteremia - 2nd to release of cholesterol from the oxycarbonate moiety. The LDL-cholesterol was increased 30 fold at doses of 200 and 300 mg/kg, which returned to normal values - predominantly as the HDL-cholesterol by Day 15. Plasma and erythrocyte DM-CHOC-PEN and metabolites DM-PEN/cholesterol were assayed vs. time by HPLC. Overall, PK values in rats revealed the following profile for DM-CHOC-PEN @ 100 mg/kg: AUC o-t = 1.05 mg (h/L), T1/2β = 0.51 (h), T1/2β = 2.48 (h) & CL = 3.04 (L/h) [a two compartment model]. The AUC was linear for 100, 200, 300 mg/kg doses. There were no differences between males and females. For the Phase I clinical trial (IND 68,876), the calculated (from mice) initial single dose for DM-CHOC-PEN was 39 mg/m2 administrated IV q 21-days with 40% dose escalations q 3-cycles until SLTs were identified. To date, doses of 39, 55, 70 mg/m2 have been administered to patients without toxicity. DM-CHOC-PEN PK modeling revealed a central compartment (cpt) which released the drug into a peripheral compartment (pct) with CL - 0.141L/h, T1/2 α - 0.63 h & Tα - 24.1 h. DM-CHOC-PEN & DM-PEN showed an important rebound phenomenon @ ∼ 50 hours post-infusion with Trelease 26.7h (for both).Same phenomenon is observed in rbcs (estimation using Monolix 3.2). DM-CHOC-PEN and DM-PEN were detected for 3 and 15 days, resp., bound to rbcs (after 70 mg/m2); DM-CHOC-PEN was also detected in the urine (Cmax=17.5 µg/mL) until day 15. Similar to rats, the total lipid profiles (cholesterol and triglycerides) for the patients were erratic during the 3-h IV infusion period (2o to the lipid emulsion vehicle) and then returned to pre-treatment values after 24 h; triglycerides most significantly affected. In 1-patient, DM-CHOC-PEN could be identified in sarcoma tissue metastatic to the spine in 190 ng/g quantities, which was obtained 21-days post IV infusion with 39 mg/m2. Five (5) patients have been treated to date; no hematological, neurotoxic or psychological alterations have been identified. Thus, DM-CHOC-PEN is well tolerated with manageable toxicities to date; the trial continues. An update on patient responses/toxicities will be presented. Comparative PK profiles of DM-CHOC PEN and metabolite in plasma, RBC and urine are analyzed and will be presented here. Supported by NCI/SBIR grant - 1R43CA132257. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 758. doi:1538-7445.AM2012-758