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Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization

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Abstract

Purpose: The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacologic, toxicologic, metabolic and pharmacokinetic developmental potential. Methods: In vitro and in vivo assays were used to assess the compounds for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters. Results: BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin. Both BMS-286309 and −422461 were comparable to irinotecan regarding preclinical antitumor activity assessed in mice bearing distal site murine and human tumors. BMS-422461 was also found to be orally active. Both analogs were >100-fold more potent in vivo than irinotecan and both were superior to irinotecan with respect to toxicological assessment of GI injury in mice. The generation of parent compound from BMS-422461 was qualitatively similar in mouse, rat and human blood and liver S9 fractions. The percentage of BMS-286309 remaining as the active lactone form at equilibrium was comparable in mouse and human plasma. The pharmacokinetic profile in rat blood demonstrated that BMS-422461 was rapidly cleaved to BMS-286309. Conclusions: The favorable in vivo metabolic activation of BMS-422461, and the pharmacokinetic characteristics of BMS-286309, suggest that the good efficacy of BMS-422461 is derived from robust in vivo release of BMS–286309 in rodents and the likelihood that this biotransformation will be preserved in humans. The comparable antitumor activity of BMS-422461 to irinotecan, as well as reduced preclinical GI toxicity, make this novel camptothecin analog attractive for clinical development.

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Abbreviations

AUC:

Area under the blood concentration-time curve

BDC:

Bile duct cannulated

Irinotecan:

7-Ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin

DMSO:

Dimethylsulfoxide

EC50:

Concentration of a compound required to induce topoisomerase I-mediated single-strand breaks in 50% of the DNA substrate

GI:

Gastrointestinal

HSA:

Human serum albumin

HPLC:

High-pressure liquid chromatography

IC50:

Concentration of a compound required to inhibit cell growth by 50% relative to an untreated control

i.a.:

Intraarterial

i.v.:

Intravenous

LCK:

Gross log cell kill

MSA:

Mouse serum albumin

MTD:

Maximum tolerated dose

PBS:

Phosphate buffered saline

p.o.:

Per oral

s.c.:

Subcutaneous

L:

Liters

Vss:

Volume of distribution at steady-state

SD:

Standard deviation

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Authors and Affiliations

  1. Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Inc., Lawrenceville, NJ, USA

    William C. Rose, Punit H. Marathe, Graham R. Jang, Thomas M. Monticello, Balu N. Balasubramanian, Byron Long & Craig R. Fairchild

  2. Experimental Therapeutics Dept, Bristol-Myers Squibb Co, Inc, 4000, Princeton, NJ, 08543, USA

    William C. Rose

  3. Research Triangle Institute, Research Triangle Park, NC, USA

    Monroe E. Wall & Mansukh C. Wani

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  1. William C. Rose
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  2. Punit H. Marathe
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  3. Graham R. Jang
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  4. Thomas M. Monticello
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  5. Balu N. Balasubramanian
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  6. Byron Long
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  7. Craig R. Fairchild
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  8. Monroe E. Wall
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  9. Mansukh C. Wani
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Correspondence to William C. Rose.

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Rose, W.C., Marathe, P.H., Jang, G.R. et al. Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization. Cancer Chemother Pharmacol 58, 73–85 (2006). https://doi.org/10.1007/s00280-005-0128-y

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  • DOI: https://doi.org/10.1007/s00280-005-0128-y

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