PNU-159548, a novel cytotoxic antitumor agent with a low cardiotoxic potential.

Abstract

PURPOSE:

PNU-159548 (4-demethoxy-3'-deamino-3'aziridinyl-4'-methylsulphonyl-daunorubicin), a derivative of the anticancer idarubicin, has a broad spectrum of antitumoral activity in vitro and in vivo attributable to its DNA intercalating and alkylating properties. The present study was conducted to determine the cardiotoxic activity of PNU-159548 relative to doxorubicin in a chronic rat model sensitive to anthracycline-induced cardiomyopathy.

METHODS:

Young adult male rats were allocated to the following treatment groups: group 1, PNU-159548 vehicle control (colloidal dispersion); group 2, doxorubicin control (saline); groups 3, 4, 5, 6, and 7, PNU-159548 at 0.12, 0.25, 0.50, 0.75, and 1.0 mg/kg, respectively; and group 8, 1.0 mg/kg doxorubicin. Treatments were administered intravenously once weekly for 4 weeks (first sacrifice time) or for 7 weeks (rats killed at weeks 8, 12, 22, 27, or 35). Body weights, organ weights, serum chemistry, hematology, serum troponin-T, and cardiac histopathology were followed throughout the study.

RESULTS:

Doxorubicin caused irreversible cardiomyopathy evident at week 4 in some rats and progressing in severity in all rats by week 8. There were also marked myelotoxicity, increased liver and kidney weights, testicular atrophy, and about 20% mortality by week 27 in doxorubicin-treated rats. The deaths were attributed to cardiomyopathy and/or nephropathy. PNU-159548 caused a dose-dependent myelotoxicity, with the dose of 0.5 mg/kg per week being equimyelotoxic to 1.0 mg/kg per week doxorubicin. PNU-159548 also caused an increase in liver weight that was reversible and a non-reversible testicular atrophy but, unlike doxorubicin, had no effect on kidney weight. At equimyelotoxic doses, the cardiotoxicity caused by PNU-159548, expressed as the mean total score, was less than one-twentieth of that induced by doxorubicin, and much less than that predicted on the basis of its content of idarubicin, which is in turn markedly less cardiotoxic than doxorubicin.

CONCLUSIONS:

The novel cytotoxic antitumor derivative, PNU-159548, is significantly less cardiotoxic than doxorubicin at equimyelosuppressive doses. The combination of intercalating and alkylating activities within the same molecule without the cardiotoxic side effects of anthracyclines makes PNU-159548 an excellent candidate for clinical development in oncology.

• Authors: P Della Torre, A Podestà, A R Imondi, D Moneta, U Sammartini, C Arrigoni, A Terron, M Brughera
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 47 Issue 4 Pg. 355-60 (Apr 2001) ISSN: 0344-5704 [Print] Germany
• PMID: 11345653 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulfonyldaunorubicin
• Antibiotics, Antineoplastic
• Doxorubicin
• Daunorubicin

Topics

• Animals
• Antibiotics, Antineoplastic (toxicity)
• Body Weight (drug effects)
• Bone Marrow Diseases (chemically induced)
• Daunorubicin (analogs & derivatives, toxicity)
• Doxorubicin (toxicity)
• Female
• Heart Diseases (chemically induced)
• Leukocyte Count
• Male
• Organ Size (drug effects)
• Rats
• Rats, Sprague-Dawley