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

Abstract

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 

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Copyright information

© Springer-Verlag 1995

Authors and Affiliations

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

There are no affiliations available

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