Cancer Chemotherapy and Pharmacology

, Volume 36, Issue 1, pp 61–64 | Cite as

A preclinical model for sequential high-dose chemotherapy

  • Sylvia A. Holden
  • Beverly A. Teicher
  • Lois J. Ayash
  • Emil FreiIII
Original Paper Sequential High-Dose Chemotherapy, Antitumor Alkylating Agents, Tumor-Cell Killing


Dose-intensive chemotherapy regimens have entered clinical trial based on the notion that log-linear tumor-cell killing, especially with antitumor alkylating agents, is maintained at higher drug doses. Several clinical trials employing two intensifications are underway. Using the tumor-cell survival assay, animals bearing the FSaII fibrosarcoma were treated with single doses of various chemotherapeutic agents once or twice with a 3-or7-day interval between the drugs. Isobologram methodology was used to determine if the sequential treatment regimens resulted in subadditive, additive or greater-than-additive tumor-cell killing. When melphalan was followed 3 or 7 days later by a second dose of melphalan there was evidence of resistance to the second dose of melphalan as indicated by subadditive tumor-cell killing. Melphalan followed 3 days later by cyclophosphamide (300mg/kg) produced greater-than-additive tumor-cell killing, however, when the interval was 7 days the resulting tumor-cell killing was subadditive. Melphalan followed 3 or 7 days later by thiotepa or carboplatin produced subadditive-to-additive tumor-cell killing. Adriamycin followed 3 days later by melphalan, cyclophosphamide, thiotepa, or carboplatin resulted in subadditive-to-additive tumor-cell killing by the combinations. These results indicate that sequential drug-intensive treatments may not optimize tumor-cell killing in vivo.

Key words

Sequential high-dose chemotherapy Antitumor alkylating agents Tumor-cell killing 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Alvarez Sotomayor E, Teicher BA, Schwartz GN, Holden SA, Meno K, Herman TS, Frei E (1992) Minocycline in combination with chemotherapy or radiation therapy in vitro and in vivo. Cancer Chemother Pharmacol 30:377–384Google Scholar
  2. 2.
    Frei E III (1992) Pharmacologic strategies for high-dose chemotherapy. In: Armitage JO, Antman KH (eds) High-dose cancer therapy: pharmacology, hematopoietins, stem cells. Williams & Wilkins, Baltimore, pp 3–13Google Scholar
  3. 3.
    Frei E III, Antman KH (1993) Combination chemotherapy, dose, and schedule: section XV, principles of chemotherapy. In: Holland JF, Frei E III, Bast RC Jr, Kufe DW, Morton DL, Weichselbaum RR (eds) Cancer medicine Lea & Febiger, Philadelphia, pp 631–639Google Scholar
  4. 4.
    Frei E III, Teicher BA, Holden SA, Cathcart KNS, Wang Y (1988) Preclinical studies and clinical correlation of the effect of alkylating dose. Cancer Res 48:6417–6423Google Scholar
  5. 5.
    Frei E III, Holden SA, Gonin R, Waxman DJ, Teicher BA (1994) Antitumor alkylating agents: in vitro cross-resistance and collateral sensitivity studies. Cancer Chemother Pharmacol (in press)Google Scholar
  6. 6.
    Holden SA, Teicher BA, Frei E III (1993) Stable and transient cross-resistance and collateral sensitivity among antitumor agents (AA). Proceedings 84th Meeting of the American Association for Cancer Research. Orlando, Florida, 34: 268Google Scholar
  7. 7.
    Rice L, Urano M, Suit HD (1980) The radiosensitivity of a murine fibrosarcoma as measured by three cell survival assays. Br J Cancer 41 [Suppl 4]:240–245Google Scholar
  8. 8.
    Schabel FMJ, Trader MW, Laster WRJ, Wheeler GP, Witt MH (1978) Patterns of resistance and therapeutic synergism among alkylating agents. Antibiot Chemother 23:200–215Google Scholar
  9. 9.
    Teicher BA (1992) Preclinical models for high-dose therapy. In: Armitage JO, Antman KH (eds) High-dose cancer therapy: pharmacology, hematopoietins, stem cells. Williams & Wilkins, Baltimore, pp 14–42Google Scholar
  10. 10.
    Teicher BA, Rose CM (1984) Perfluorochemical emulsion can increase tumor radiosensitivity. Science 223:934–936Google Scholar
  11. 11.
    Teicher BA, Holden SA, Jacobs JL (1987) Approaches to defining the mechanism of enhancement by Fluosol-DA 20% with carbogen of melphalan antitumor activity. Cancer Res 47:513–518Google Scholar
  12. 12.
    Teicher BA, Holden SA, Eder JP, Herman TS, Antman KH, Frei E III (1990) Preclinical studies relating to the use of thiotepa in the high-dose setting alone and in combination. Semin Oncol 17:18–32Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Sylvia A. Holden
  • Beverly A. Teicher
  • Lois J. Ayash
  • Emil FreiIII

There are no affiliations available

Personalised recommendations