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Intraperitoneal 5-fluoro-2′-deoxyuridine with escalating doses of leucovorin: Pharmacology and clinical tolerance

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Summary

In a preceding study, we established the tolerance and pharmacokinetic behavior of 5-fluoro-2′-deoxyuridine (FdUrd) given by the intraperitoneal (IP) route. A dose of 3 g daily × 3 days was found satisfactory for Phase II study and exploration of biochemical modulation. Therefore, the current study was conducted to study the tolerance and pharmacokinetics of such a dose-schedule and route of FdUrd combined with escalating doses of leucovorin (LV). Fourteen patients were entered and 13 were evaluable for tolerance determination. Pharmacologic determinations of IP FdUrd and 5-Fluorouracil (FUra) derived from it and LV were obtained by HPLC methods on 11 occasions. Findings were compared with the preceding study of FdUrd alone. LV did not appear to alter the tolerance of IP FdUrd even in the four patients receiving the highest dose of LV (640 mg). Toxicities included nausea, vomiting, and rarely neutropenia and diarrhea. Pharmacokinetic parameters indicate a parallel rate of egress of FdUrd and LV from the peritoneal cavity. The pharmacologie advantage for FdUrd is at least 3 logs as previously reported and one log for LV. Evidence of antitumor effect was noted particularly among untreated patients with gastrointestinal primaries. We conclude that IP FdUrd 3 g and LV in doses of up to 640 mg x 3 days are well tolerated. Since FdUrd is more potent, has an even greater hepatic clearance and shows greater potential for modulation with LV than FUra, it may be the preferred fluoropyrimidine for subsequent studies via the IP route in the treatment of carcinomas with prominent peritoneal spread. The pharmacologie advantage for leucovorin is limited but it is a good marker for peritoneal clearance since it parallels FdUrd clearance.

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Abbreviations

FdUrd:

5-fluoro-2′-deoxyuridine

FUra:

5-fluorouracil

LV:

leucovorin or 6(R,S)-5-formyl tetrahydrofolate

IP:

intraperitoneal therapy

CHexUP:

cyclophosphamide

Hexalen® :

5-fiuorouracil, Platinol® (cisplatin)

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Author notes

  1. Kenneth K. Chan

    Present address: Ohio State University Comprehensive Cancer Center, 43210, Columbus, Ohio, USA

Authors and Affiliations

  1. Department of Medicine and the Kenneth Morris Jr. Cancer Center, USA

    Franco M. Muggia, Anil Tulpule, Susan Jeffers, C. Gail Leichman, Lawrence Leichman & C. Paul Spears

  2. School of Pharmacy at the University of Southern California, 90033, Los Angeles, California, USA

    Anastassios Retzios, Fei Chen & Kenneth K. Chan

Authors
  1. Franco M. Muggia
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  2. Anil Tulpule
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  3. Anastassios Retzios
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  4. Fei Chen
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  5. Susan Jeffers
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  6. C. Gail Leichman
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  8. C. Paul Spears
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  9. Kenneth K. Chan
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Muggia, F.M., Tulpule, A., Retzios, A. et al. Intraperitoneal 5-fluoro-2′-deoxyuridine with escalating doses of leucovorin: Pharmacology and clinical tolerance. Invest New Drugs 12, 197–206 (1994). https://doi.org/10.1007/BF00873960

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