Pharmacological and toxicological aspects of 4-demethoxy-3′-deamino-3′ -aziridinyl-4′-methylsulphonyl-daunorubicin (PNU-159548)

A novel antineoplastic agent

C. Geroni, M. Ripamonti, C. Arrigoni, F. Fiorentini, L. Capolongo, D. Moneta, S. Marchini, P. Della Torre, C. Albanese, M. G. Lamparelli, M. Ciomei, R. Rossi, M. Caruso

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

4-demethoxy-3′-deamino-3′-aziridinyl-4′-methylsulphonyl- daunorubicin (PNU-159548) belongs to a novel class of antitumor compounds (termed alkycyclines) and is currently undergoing Phase II clinical trial. In the present study, we investigated the in vitro and in vivo antitumor activity, the pharmacokinetics, and the toxicological profile of this compound. PNU-159548 showed good cytotoxic activity in murine and human cancer cells growing in vitro, with an average concentration for 50% growth inhibition of 15.8 ng/ml. The drug showed strong antitumor efficacy in vivo after i.v. and p.o. administration against rapidly proliferating murine leukemias and slowly growing transplantable human xenografts. At nontoxic doses, PNU-159548 produced complete regression and cures in ovarian, breast, and human small cell lung carcinomas. Fourteen of 16 models studied, including colon, pancreatic, gastric, and renal carcinomas, astrocytoma and melanoma, were found to be sensitive to PNU-159548. In addition, PNU-159548 was effective against intracranially implanted tumors. Toxicological studies revealed myelosuppression as the main toxicity in both mice and dogs. The maximum tolerated doses, after a single administration, were 2.5 mg/kg of body weight in mice, 1.6 mg/kg in rats, and 0.3 mg/kg in dogs. In the cyclic studies, the maximum tolerated doses were 0.18 mg/kg/day (cumulative dose/cycle: 0.54 mg/kg) in rats and 0.05 mg/kg/day (cumulative dose/cycle: 0.15 mg/kg) in dogs. PNU-159548 showed minimal cardiotoxicity, when compared with doxorubicin in the chronic rat model at a dose level inducing similar myelotoxicity. Animal pharmacokinetics, carried out in mice, rats, and dogs, was characterized by high volumes of distribution, plasma clearance of the same order of the hepatic blood flow, and short terminal half-life. These findings support the conclusion that PNU-159548 is an excellent candidate for clinical trials in the treatment of cancer.

Original languageEnglish
Pages (from-to)1983-1990
Number of pages8
JournalCancer Research
Volume61
Issue number5
Publication statusPublished - Mar 1 2001

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Daunorubicin
Antineoplastic Agents
Toxicology
Pharmacology
Dogs
Maximum Tolerated Dose
Pharmacokinetics
Neoplasms
Phase II Clinical Trials
Plasma Volume
Astrocytoma
Small Cell Lung Carcinoma
4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulfonyldaunorubicin
Heterografts
Doxorubicin
Half-Life
Melanoma
Stomach
Colon
Leukemia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Geroni, C., Ripamonti, M., Arrigoni, C., Fiorentini, F., Capolongo, L., Moneta, D., ... Caruso, M. (2001). Pharmacological and toxicological aspects of 4-demethoxy-3′-deamino-3′ -aziridinyl-4′-methylsulphonyl-daunorubicin (PNU-159548): A novel antineoplastic agent. Cancer Research, 61(5), 1983-1990.

Pharmacological and toxicological aspects of 4-demethoxy-3′-deamino-3′ -aziridinyl-4′-methylsulphonyl-daunorubicin (PNU-159548) : A novel antineoplastic agent. / Geroni, C.; Ripamonti, M.; Arrigoni, C.; Fiorentini, F.; Capolongo, L.; Moneta, D.; Marchini, S.; Della Torre, P.; Albanese, C.; Lamparelli, M. G.; Ciomei, M.; Rossi, R.; Caruso, M.

In: Cancer Research, Vol. 61, No. 5, 01.03.2001, p. 1983-1990.

Research output: Contribution to journalArticle

Geroni, C, Ripamonti, M, Arrigoni, C, Fiorentini, F, Capolongo, L, Moneta, D, Marchini, S, Della Torre, P, Albanese, C, Lamparelli, MG, Ciomei, M, Rossi, R & Caruso, M 2001, 'Pharmacological and toxicological aspects of 4-demethoxy-3′-deamino-3′ -aziridinyl-4′-methylsulphonyl-daunorubicin (PNU-159548): A novel antineoplastic agent', Cancer Research, vol. 61, no. 5, pp. 1983-1990.
Geroni, C. ; Ripamonti, M. ; Arrigoni, C. ; Fiorentini, F. ; Capolongo, L. ; Moneta, D. ; Marchini, S. ; Della Torre, P. ; Albanese, C. ; Lamparelli, M. G. ; Ciomei, M. ; Rossi, R. ; Caruso, M. / Pharmacological and toxicological aspects of 4-demethoxy-3′-deamino-3′ -aziridinyl-4′-methylsulphonyl-daunorubicin (PNU-159548) : A novel antineoplastic agent. In: Cancer Research. 2001 ; Vol. 61, No. 5. pp. 1983-1990.
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abstract = "4-demethoxy-3′-deamino-3′-aziridinyl-4′-methylsulphonyl- daunorubicin (PNU-159548) belongs to a novel class of antitumor compounds (termed alkycyclines) and is currently undergoing Phase II clinical trial. In the present study, we investigated the in vitro and in vivo antitumor activity, the pharmacokinetics, and the toxicological profile of this compound. PNU-159548 showed good cytotoxic activity in murine and human cancer cells growing in vitro, with an average concentration for 50{\%} growth inhibition of 15.8 ng/ml. The drug showed strong antitumor efficacy in vivo after i.v. and p.o. administration against rapidly proliferating murine leukemias and slowly growing transplantable human xenografts. At nontoxic doses, PNU-159548 produced complete regression and cures in ovarian, breast, and human small cell lung carcinomas. Fourteen of 16 models studied, including colon, pancreatic, gastric, and renal carcinomas, astrocytoma and melanoma, were found to be sensitive to PNU-159548. In addition, PNU-159548 was effective against intracranially implanted tumors. Toxicological studies revealed myelosuppression as the main toxicity in both mice and dogs. The maximum tolerated doses, after a single administration, were 2.5 mg/kg of body weight in mice, 1.6 mg/kg in rats, and 0.3 mg/kg in dogs. In the cyclic studies, the maximum tolerated doses were 0.18 mg/kg/day (cumulative dose/cycle: 0.54 mg/kg) in rats and 0.05 mg/kg/day (cumulative dose/cycle: 0.15 mg/kg) in dogs. PNU-159548 showed minimal cardiotoxicity, when compared with doxorubicin in the chronic rat model at a dose level inducing similar myelotoxicity. Animal pharmacokinetics, carried out in mice, rats, and dogs, was characterized by high volumes of distribution, plasma clearance of the same order of the hepatic blood flow, and short terminal half-life. These findings support the conclusion that PNU-159548 is an excellent candidate for clinical trials in the treatment of cancer.",
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N2 - 4-demethoxy-3′-deamino-3′-aziridinyl-4′-methylsulphonyl- daunorubicin (PNU-159548) belongs to a novel class of antitumor compounds (termed alkycyclines) and is currently undergoing Phase II clinical trial. In the present study, we investigated the in vitro and in vivo antitumor activity, the pharmacokinetics, and the toxicological profile of this compound. PNU-159548 showed good cytotoxic activity in murine and human cancer cells growing in vitro, with an average concentration for 50% growth inhibition of 15.8 ng/ml. The drug showed strong antitumor efficacy in vivo after i.v. and p.o. administration against rapidly proliferating murine leukemias and slowly growing transplantable human xenografts. At nontoxic doses, PNU-159548 produced complete regression and cures in ovarian, breast, and human small cell lung carcinomas. Fourteen of 16 models studied, including colon, pancreatic, gastric, and renal carcinomas, astrocytoma and melanoma, were found to be sensitive to PNU-159548. In addition, PNU-159548 was effective against intracranially implanted tumors. Toxicological studies revealed myelosuppression as the main toxicity in both mice and dogs. The maximum tolerated doses, after a single administration, were 2.5 mg/kg of body weight in mice, 1.6 mg/kg in rats, and 0.3 mg/kg in dogs. In the cyclic studies, the maximum tolerated doses were 0.18 mg/kg/day (cumulative dose/cycle: 0.54 mg/kg) in rats and 0.05 mg/kg/day (cumulative dose/cycle: 0.15 mg/kg) in dogs. PNU-159548 showed minimal cardiotoxicity, when compared with doxorubicin in the chronic rat model at a dose level inducing similar myelotoxicity. Animal pharmacokinetics, carried out in mice, rats, and dogs, was characterized by high volumes of distribution, plasma clearance of the same order of the hepatic blood flow, and short terminal half-life. These findings support the conclusion that PNU-159548 is an excellent candidate for clinical trials in the treatment of cancer.

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