ledoxantrone and Prostatic-Neoplasms

A phase II trial of CI-958 (NSC #635371), a new benzothiopyranoindazole was performed in patients with hormone refractory prostate carcinoma using prostate specific antigen (PSA) levels for response assessment. Twenty-two patients were entered on this study and twenty one were eligible. Toxicity consisted mainly of granulocytopenia (71% grade 3 or 4), but there were no significant infections. Two patients were removed from study due to asymptomatic decreases in cardiac ejection fraction. Of 21 evaluable patients, there were four responders (19%, CI 0-35%).

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Drug Resistance, Neoplasm; Drugs, Investigational; Humans; Indazoles; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms

To assess the antitumor activity of the benzothiopyranoindazole CI-958 ¿5-[(2-aminomethyl)amino]-2-[2-(diethylamino)ethyl]-2H- [l]benzothiopyrano[4,3,2-cd]-indazol-8-ol trihydrochloride¿ in hormone-resistant prostate carcinoma, using an intravenous dose of 700 mg/m(2) every 3 weeks.. Patients eligible for this study had advanced prostate carcinoma that had failed hormonal treatment. Changes in an initially elevated prostate-specific antigen (PSA) level and regression of objectively measurable disease were used as response criteria.. All 33 patients enrolled were evaluated. Of 30 with elevated PSA levels, 6 had a >50% decline maintained for >30 days; response durations ranged from 105 to 623 days. Eleven patients had objectively measurable disease; two had partial responses (lasting 316 and 461 days) consisting of shrinkage of retroperitoneal nodes and of masses surrounding the rectum and bladder. The survival of all responding patients ranged from 366 days to 709 days and the median survival of all patients was 12 months (range 1-23 + months). Neutropenia was common, but thrombocytopenia was not. Nonhematologic side effects included nausea, vomiting, anorexia, asthenia, and chills, but were usually mild. The drug caused phlebitis when given into peripheral veins and central venous administration is recommended. No consistent reductions in cardiac function were documented by sequential assessment of left ventricular ejection fractions.. CI-958 has modest but definite antitumor activity in hormone-resistant prostate carcinoma. Its toxicities include neutropenia, nausea, vomiting, anorexia, asthenia, chills and phlebitis.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Humans; Indazoles; Male; Middle Aged; Neoplasm Staging; Patient Selection; Prostate-Specific Antigen; Prostatic Neoplasms; Tomography, X-Ray Computed; Treatment Failure

CI-958, a new DNA-intercalating drug derived from a series of substituted 2H-[1] benzothiopyrano[4,3,2-cd]indazoles, is being tested in clinical trails because of its curative properties against murine solid tumor models and because it has demonstrated activity in a pilot phase II study of patients with hormone-refractory prostate cancer. However, the mechanism of anticancer action of CI-958 has not been established. Because CI-958 binds to DNA and DNA helicases are profoundly affected by DNA-binding drugs, we examined the effects of CI-958 on human DNA helicase action. DNA helicase activity was measured by strand dissociation of double-stranded (ds) DNA with a gel electrophoresis assay, and ATPase activities were determined on thin-layer chromatography by measurement of the conversion of ATP to ADP. For human helicase blockade, CI-958 is slightly more potent than doxorubicin (EC50 values 0.17 and 0.26 microM, respectively). We observed no difference in helicase-blockade EC50 values recorded for three helicase substrates containing A-T rich, G-C rich, and both types of oligonucleotide sequences. The effects of CI-958 helicase blockade and DNA-dependent ATPase activities were similar for the two reactions. The kinetics of the blockade by CI-958 of the human DNA helicase indicates that it involves a reversible ternary complex of helicase-drug-dsDNA. CI-958 produces potent blockade of human DNA helicases with no apparent strong DNA sequence-binding preference. Similar potency against helicase strand dissociation and DNA-dependent ATPase suggests that the mechanism against these reactions is the same. The blockade of DNA helicases by CI-958 may be central in its mechanism of action as an anticancer drug.

Topics: Antineoplastic Agents; Base Sequence; DNA Helicases; DNA Primers; Enzyme Inhibitors; Humans; Indazoles; Kinetics; Male; Prostatic Neoplasms