Preclinical activity of an i.v. formulation of rubitecan in IDD-P™ against human solid tumor xenografts

An i.v. formulation of rubitecan (9-nitrocamptothecin) was evaluated in five human solid tumor xenograft models. Rubitecan in IDD-P™, a particulate suspension of the insoluble analog, produced significant tumor growth delay in athymic nude mice bearing A375 melanoma, and MX-1 breast, SKMES non-small-cell lung, Panc-1 pancreatic and HT29 colon carcinomas. The activity of i.v. rubitecan was similar or somewhat superior to those of i.p. regimens with the reference drugs, irinotecan and topotecan. Tumor sensitivity to rubitecan in IDD-P was MX-1>A375>SKMES >Panc-1>HT29. Some complete regression responses were seen with MX-1, A375 and SKMES tumors treated with 2.5 mg/kg on a schedule of two 5-day dosing cycles separated by 2 drug-free days. In nude mice, the MTD of rubitecan in IDD-P lies between 2 and 2.5 mg/kg on this schedule; antitumor efficacy was achieved with doses between 2.5 and 1.25 mg/kg. Dosing with 6.6 mg/kg rubitecan in IDD-P on intermittent schedules (4- or 7-day intervals) was tolerated, but less efficacious, when tested in the A375 model. The good responses obtained with rubitecan in IDD-P suggest it could be used clinically in circumstances where an i.v. formulation offers advantages to oral or aerosol formulations.

[1]  B. Giovanella,et al.  Preclinical evaluation of the anticancer activity and toxicity of 9-nitro-20(S)-camptothecin (Rubitecan). , 2002, International journal of oncology.

[2]  C. Verschraegen,et al.  A phase I clinical and pharmacological study of oral 9-nitrocamptothecin, a novel water-insoluble topoisomerase I inhibitor , 1998, Anti-cancer drugs.

[3]  S. Arbuck,et al.  Pharmacodynamics and pharmacokinetics of a 72-hour infusion of 9-aminocamptothecin in adult cancer patients. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  P. Houghton,et al.  Schedule‐dependent Efficacy of Camptothecins in Models of Human Cancer a , 1996, Annals of the New York Academy of Sciences.

[5]  B. Giovanella,et al.  Protocols for the Treatment of Human Tumor Xenografts with Camptothecins , 1996, Annals of the New York Academy of Sciences.

[6]  B. Giovanella,et al.  Pharmacokinetics of the in vivo and in vitro conversion of 9-nitro-20(S)-camptothecin to 9-amino-20(S)-camptothecin in humans, dogs, and mice. , 1994, Cancer research.

[7]  D. Kufe,et al.  Identification of a mutant human topoisomerase I with intact catalytic activity and resistance to 9-nitro-camptothecin. , 1994, The Journal of biological chemistry.

[8]  Y. Pommier,et al.  Cloning of Chinese hamster DNA topoisomerase I cDNA and identification of a single point mutation responsible for camptothecin resistance. , 1993, The Journal of biological chemistry.

[9]  L. Liu,et al.  DNA topoisomerase I--targeted chemotherapy of human colon cancer in xenografts. , 1989, Science.

[10]  L. Liu,et al.  Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. , 1989, Cancer research.

[11]  K. Kohn,et al.  Structure-activity study of the actions of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity. , 1989, Cancer research.

[12]  M. Wani,et al.  Plant antitumor agents. 23. Synthesis and antileukemic activity of camptothecin analogues. , 1986, Journal of medicinal chemistry.

[13]  R. Hertzberg,et al.  Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. , 1985, The Journal of biological chemistry.

[14]  A. McPhail,et al.  Plant Antitumor Agents. I. The Isolation and Structure of Camptothecin, a Novel Alkaloidal Leukemia and Tumor Inhibitor from Camptotheca acuminata1,2 , 1966 .