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A preclinical model for sequential high-dose chemotherapy

S A Holden, B A Teicher, L J Ayash

    Cancer Chemotherapy and Pharmacology
    |January 1, 1995
    PubMed
    Summary
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    Sequential chemotherapy may not improve tumor cell killing. Studies show that drug combinations and timing can lead to resistance, reducing treatment effectiveness against fibrosarcoma tumors.

    Area of Science:

    • Oncology
    • Pharmacology
    • Cancer Research

    Background:

    • Dose-intensive chemotherapy aims to maximize tumor cell killing based on log-linear models.
    • Antitumor alkylating agents are key in these regimens, with clinical trials exploring intensified schedules.
    • Optimizing sequential drug administration is critical for enhancing treatment efficacy.

    Purpose of the Study:

    • To evaluate the impact of sequential chemotherapy administration on tumor cell killing in vivo.
    • To determine if specific drug combinations and intervals enhance or reduce cytotoxic effects.
    • To assess the potential for drug resistance following repeated dosing.

    Main Methods:

    • Utilized a tumor-cell survival assay in animals bearing FSaII fibrosarcoma.
    • Administered single doses of various chemotherapeutic agents sequentially with 3- or 7-day intervals.

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  • Employed isobologram methodology to quantify tumor-cell killing interactions (subadditive, additive, supra-additive).

    • Main Results:

    • Melphalan followed by melphalan induced resistance, showing subadditive tumor-cell killing.
    • Melphalan followed by cyclophosphamide demonstrated supra-additive killing at 3 days but subadditive at 7 days.
    • Combinations of melphalan with thiotepa or carboplatin, and adriamycin with other agents, resulted in subadditive-to-additive killing.

    Conclusions:

    • Sequential drug-intensive chemotherapy may not consistently optimize tumor cell killing in vivo.
    • The timing and combination of chemotherapeutic agents significantly influence treatment outcomes and can induce resistance.
    • Further research is needed to refine sequential dosing strategies for improved cancer therapy.