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Updated: Aug 16, 2026
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Use of a human tumor cloning system to evaluate analogs of methotrexate and mitoxantrone
Abstract:
We have utilized a human tumor cloning system to compare the antitumor activity of trimetrexate ( TMQ ), a new dihydrofolate reductase inhibitor, and ametantrone , a new anthracenedione, with that of analogs already in clinical trial (methotrexate and mitoxantrone). Sixty-nine of 136 tumors plated for the TMQ study and 84 of 228 tumors plated for the ametantrone study were evaluable for drug-sensitivity assays. The overall in vitro response rates (defined as a less than or equal to 50% survival of tumor colony-forming units) for TMQ were 20% and 23% at 0.1 and 1 microgram/ml, respectively; for ametantrone they were 13%, 21%, and 26% at 0.1, 1, and 10 micrograms/ml, respectively. The overall in vitro activity for both new compounds was similar to that of their clinically used analogs, but TMQ was active in eight of 47 methotrexate-resistant specimens and ametantrone in nine of 62 mitoxantrone-resistant specimens. A comparison of these in vitro results with the results of phase II clinical trials with both drugs should allow an evaluation of the utility of the human tumor cloning system for predicting clinical antitumor activity of analogs of currently available antineoplastic agents.
Insights
New anticancer drugs trimetrexate (TMQ) and ametantrone show similar in vitro activity to existing analogs. Notably, TMQ and ametantrone demonstrated efficacy against drug-resistant tumors, suggesting potential for overcoming resistance.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Established anticancer agents like methotrexate and mitoxantrone are crucial in chemotherapy.
- Newer drug candidates are continuously being developed to improve treatment efficacy and overcome resistance.
Purpose of the Study:
- To evaluate the in vitro antitumor activity of trimetrexate (TMQ) and ametantrone.
- To compare the efficacy of these new agents against their clinical analogs, methotrexate and mitoxantrone.
- To assess the potential of TMQ and ametantrone in overcoming drug resistance.
Main Methods:
- Utilized a human tumor cloning system for drug-sensitivity assays.
- Tested trimetrexate (TMQ) and ametantrone across various concentrations.
- Evaluated drug response based on tumor colony-forming unit survival rates.
Main Results:
- Overall in vitro response rates for TMQ were 20% and 23% at 0.1 and 1 microgram/ml.
- In vitro response rates for ametantrone were 13%, 21%, and 26% at 0.1, 1, and 10 micrograms/ml.
- TMQ showed activity in 8/47 methotrexate-resistant and ametantrone in 9/62 mitoxantrone-resistant specimens.
Conclusions:
- Trimetrexate (TMQ) and ametantrone exhibit comparable in vitro antitumor activity to their analogs.
- Both new agents demonstrated activity against resistant tumor types, indicating potential to overcome drug resistance.
- The human tumor cloning system shows promise for predicting clinical efficacy of novel antineoplastic agents.
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