5 A phase II study of 9-aminocamptothecin (9-AC) in patients (pts) with non small cell lung cancer (NSCLC)

Vokes, E.; Ansari, Rafat; Minami, H.; Masters, G.; Klepsch, A.; Hoffman, Philip G.; Golomb, Harvey M.; Sciortino, D.; Krauss, Stephen; Lad, Thomas E.; Fishkin, Paul; Ratain, M.

doi:10.1016/s0169-5002(97)89284-7

Cited by 3 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Kirstein et al evaluated the relationship between 9-aminocamptothecin systemic exposure and tumor response in human solid tumor xenografts (29). The systemic exposure of 9-aminocamptothecin required for antitumor effect in the xenograft models was in excess of that achievable in patients, possibly explaining why 9-aminocamptothecin has not produced significant antitumor activity in clinical trials (16,38,39). In our studies, the conversion of 9-nitrocamptothecin to 9-aminocamptothecin in mice and patients was similar, with most of the drug remaining in the 9-nitrocamptothecin form.…”

Section: Discussionmentioning

confidence: 99%

Relationship between Plasma Exposure of 9-Nitrocamptothecin and Its 9-Aminocamptothecin Metabolite and Antitumor Response in Mice Bearing Human Colon Carcinoma Xenografts

Zamboni

Jung

Egorin

et al. 2005

Clinical Cancer Research

View full text Add to dashboard Cite

9-Nitrocamptothecin has completed phase III studies in patients with newly diagnosed and refractory pancreatic cancer; however, the optimal 9-nitrocamptothecin treatment regimenis unclear.We used an intermittent schedule of 9-nitrocamptothecin to evaluate the relationship between plasma exposure of 9-nitrocamptothecinandits 9-aminocamptothecinmetabolite andantitumor response in mice bearing human colon carcinoma xenografts. 9-Nitrocamptothecin was given orally at 0.44, 0.67, or1.0 mg/kg/d qd Â 5d Â 2 weeks repeated q 4 weeks for two cycles to female C.B-17 SCID mice bearing HT29 or ELC2 human colon xenografts. Pharmacokinetic studies were done after oral administration of 0.67 mg/kg Â 1. Serial samples were obtained and 9-nitrocamptothecin and 9-aminocamptothecin lactone concentrations in plasma were determined by high-performance liquid chromatography analysis with fluorescence detection.The areas under plasma concentration versus time curve (AUC) from 0 toinfinity for 9-nitrocamptothecinand 9-aminocamptothecinwere calculated.The antitumor activity of 9-nitrocamptothecin was dose-dependent inboth colonxenografts. At all doses, 9-nitrocamptothecin treatment resulted in significant antitumor activity in both xenografts compared with vehicle-treated and control groups and achieved levels of tumor regression that met criteria (minimum %T/C V 40%) for antitumor activity. In mice bearing HT29 xenografts, the 9-nitrocamptothecin and 9-aminocamptothecin lactone AUCs after administration of 9-nitrocamptothecin at 0.67 mg/kg were 41.3 and 5.7 ng/mL h, respectively. The responses seen in these xenograft models occurred at systemic exposures that are tolerable in adult patients.These results suggest that the intermittent schedule of 9-nitrocamptothecinmay be an active regimenin patients with colorectal carcinoma.

show abstract

Section: Discussionmentioning

confidence: 99%

Relationship between Plasma Exposure of 9-Nitrocamptothecin and Its 9-Aminocamptothecin Metabolite and Antitumor Response in Mice Bearing Human Colon Carcinoma Xenografts

Zamboni

Jung

Egorin

et al. 2005

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Skorašnje studije pokazuju da agresivnija hemio i radioterapija mogu značajno da snize učestalost metastaza u CNS naročito u trimodalitetnom lečenju 16 . Randomizovane studije i metaanalize podržavaju zaključak da kombinovano lečenje koje uključuje hemioterapiju na osnovu preparata platine, poboljšava preživljavanje u poređenju sa samo radioterapijom 17,18 .…”

Section: Diskusijaunclassified

Risk factors for brain metastases after definitive chemoradiation for locally advanced non-small cell lung cancer

Petrović

Tomic²,

Jovanović

2009

VOJNOSANIT PREGL

View full text Add to dashboard Cite

show abstract

“…Despite the impressive preclinical activity of 9-AC in various cancer cell lines and tumor xenograft models, phase I/II studies showed only minor activity in various malignancies, including non-small cell lung cancer (9,10), colorectal cancer (11,12) and breast cancer (13), probably due to limited bioavailability of the drug. In recent years, however, studies have managed to enhance the antitumor activity of 9-AC by using copolymer conjugates for colon specific drug release (14).…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin: Ιmpact on cancer therapy

Maier‐Salamon

Thalhammer

Reznicek

et al. 2014

International Journal of Oncology

View full text Add to dashboard Cite

The metabolism of 9-aminocamptothecin (9-AC) was investigated in human and rat liver microsomes. In both species 9-AC was almost exclusively biotransformed to dihydroxy-9-AC (M1) and monohydroxy-9-AC (M2). The enzymatic efficiencies of the formation of M1 and M2 (V(max)/K(m)) were 1.7- and 2.7‑fold higher in rat than in human liver microsomes indicating species-related differences in 9-AC hydroxylation. Incubation in the presence of human recombinant cytochrome P450 (CYP) enzymes demonstrated that the formation of M1 and M2 is mainly catalyzed by CYP3A4 and only to a minor extent by extrahepatic CYP1A1. The predominant role of CYP3A4 was further supported by a dramatic inhibition of metabolite formation in the presence of the CYP3A4 substrates troleandomycin and ketoconazole. Experiments conducted in isolated perfused rat livers further demonstrated that biliary excretion of 9-AC, M1 and M2 during 60 min of perfusion was pronounced and accounted for 17.7±2.59, 0.05±0.01 and 2.75±0.14% of total 9-AC applied to the liver, respectively. In summary, this study established that CYP3A-dependent hydroxylation is the main metabolic pathway for 9-AC in rat and human liver, which have to be taken into consideration during cancer therapy of patients.

show abstract

5 A phase II study of 9-aminocamptothecin (9-AC) in patients (pts) with non small cell lung cancer (NSCLC)

Cited by 3 publications

References 0 publications

Relationship between Plasma Exposure of 9-Nitrocamptothecin and Its 9-Aminocamptothecin Metabolite and Antitumor Response in Mice Bearing Human Colon Carcinoma Xenografts

Relationship between Plasma Exposure of 9-Nitrocamptothecin and Its 9-Aminocamptothecin Metabolite and Antitumor Response in Mice Bearing Human Colon Carcinoma Xenografts

Risk factors for brain metastases after definitive chemoradiation for locally advanced non-small cell lung cancer

Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin: Ιmpact on cancer therapy

Contact Info

Product

Resources

About