Sustained delivery of a camptothecin prodrug - CZ48 by nanosuspensions with improved pharmacokinetics and enhanced anticancer activity.

We have synthesized a novel lactone-stabilized camptothecin (CPT) analog named CZ48 and demonstrated its potent anticancer effects via bioconversion to the active CPT in earlier studies. Herein, we aimed to develop, optimize and characterize CZ48 nanosuspensions, for a sustained delivery of this drug in humans with an intravenous (i.v.

Correlation between the sensitivity of tumors to treatment with CZ48 and local concentrations of the active metabolite CPT within the tumors.

Crystalline camptothecin-20-O-propionate hydrate (CZ48) is an esterification product from the reaction of natural camptothecin with propionic anhydride. CZ48 has been tested against 29 human tumor lines grown in nude mice as xenografts. Of the tested tumor lines, 28 were found to be responsive to CZ48, by regression or significant inhibition.

Enhanced lactone stability of CZ48 in blood correlates to its lack of toxicity in mice.

Purpose: The aim of this study was to correlate the relationship between the pharmacokinetic behaviors and the toxicity of a new investigational anticancer agent CZ48, a C20-propionate ester of camptothecin (CPT) in mice.

Methods: In this study, the safety and pharmacokinetics of oral doses of CZ48 were compared with the oral doses of CPT. Mice were administered orally one of three single doses of CZ48 (50, 200 and 1000 mg/kg) and two single doses of CPT (1.

TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.

Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types.

Metabolic difference of CZ48 in human and mouse liver microsomes.

CZ48, chemically camptothecin-20-O-propionate hydrate, is currently under clinical investigation. The kinetics of the metabolite camptothecin (CPT) formation and of CZ48 depletion in mouse and human liver microsomes in the presence or absence of NADPH was examined. The formation rate of camptothecin in human liver microsomes was significantly higher than that in mouse with mean K(m)s of 1.

Anticancer activity of new haloalkyl camptothecin esters against human cancer cell lines and human tumor xenografts grown in nude mice.

All chemotherapeutic agents currently in use have a narrow window of therapeutic index of 1 to 1.2. Camptothecin ester compounds are reported to have a wider therapeutic index when being used to treat human xenografts in nude mice.

Crystalline camptothecin-20(S)-O-propionate hydrate: a novel anticancer agent with strong activity against 19 human tumor xenografts.

To find a more effective and less toxic chemotherapeutic agent, we have successfully prepared crystalline camptothecin-20(S)-O-propionate hydrate (CZ48) by reacting camptothecin with propionic anhydride using concentrated sulfuric acid as catalyst. The biological effectiveness of this new anticancer agent was evaluated by using xenografts of human cancers in nude mice as the testing models. The extensive treatment of 21 human tumors with various dose levels of CZ48 has shown that this agent is highly effective against many different human tumors tested with a striking lack of toxicity.

ISG15 as a novel tumor biomarker for drug sensitivity.

Tumor cells are known to exhibit highly varied sensitivity to camptothecins (CPT; e.g., irinotecan and topotecan).

Development and validation of a reverse-phase HPLC with fluorescence detector method for simultaneous determination of CZ48 and its active metabolite camptothecin in mouse plasma.

A simple and sensitive high-performance liquid chromatography (HPLC) assay for the analysis of CZ48, a potent anticancer candidate, and its active metabolite camptothecin (CPT) in mouse plasma was developed and validated. CZ44 was used as an internal standard (IS). The samples were injected onto a C18 Synergi Polar-RP column (4 microm, 150 mm x 4.

Synthesis and antitumor activity of aromatic camptothecin esters.

Twenty-eight new aromatic esters of camptothecins 2-29 were prepared in yields of 5 to 96% by straight acylation of camptothecin (1a) and 9-nitrocamptothecin (1b) with various aromatic acids as acylating agents. All of these esters were tested against 14 different human cancer cell lines. The antitumor activity of these compounds was related to the nature of the substituting groups of their side aromatic chains.

Synthesis and anti-tumor activity of alkenyl camptothecin esters.

Aim: To study the degrees of influence of changing side ester chains at position C20 of camptothecin on the anti-tumor activity of the molecules.

Methods: The esterification reaction of camptothecin 1 and 9-nitrocamptothecin 2 with crotonic anhydride in pyridine gave the corresponding esters 3 and 4, respectively. The acylation of 1 and 2 with cinnamoyl chloride gave products 7 and 8.

Establishment and characterization of cancer cell cultures and xenografts derived from primary or metastatic Mullerian cancers.

Purpose: The purpose of this study was to characterize cell cultures and xenografts derived from patients with ovarian cancer.

Experimental Design: Ninety specimens from 67 patients were plated in RPMI 1640 or inoculated in nude mice. Growth characteristics of cell cultures and xenografts were determined.

Structure-activity relationship of alkyl 9-nitrocamptothecin esters.

Aim: To study the structure-activity relationship of alkyl 9-nitrocamptothecin esters.

Methods: Two alkyl 9-nitrocamptothecin (9NC) esters 5g and 5h were prepared by esterification reactions of 9NC with valeric anhydride and heptanoic anhydride, respectively. Eight 9NC esters 5a-5h were tested for cytotoxicity against human leukemia cell lines HL-60 and U-937.

Preclinical evaluation of the anticancer activity and toxicity of 9-nitro-20(S)-camptothecin (Rubitecan).

The purpose of this study is to establish the maximum tolerated dose of rubitecan in mice, dogs and men and to establish the anticancer activity of such dose against human tumors xenografted in nude mice. Nude mice received increasing doses of Rubitecan by intrastomach injection until the maximum tolerated dose (MTD) had been established for both the single dose and the multiple doses at the schedule of 5 days on, 2 days off. Extrapolating from the mouse data, MTD was determined for oral administration in dogs and man.