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Schedule-dependent enhancement of antitumor activity of ethyldeshydroxy-sparsomycin in combination with classical
H P Hofs1, D J Wagener, V de Valk-Bakker
1Department of Internal Medicine, Nijmegen University Hospital, The Netherlands.
Abstract:
The efficacy of the protein synthesis inhibitor ethyldeshydroxy-sparsomycin (EDSM) as a biochemical response modifier of several antitumor agents against L1210 leukemia and B16 melanoma is described. Seven drugs with different intracellular targets were selected for this combination study. Tumor implantation and drug treatment were both i.p., and the time interval between the administration of EDSM and the cytostatic agent was varied. Our results show that in the B16 tumor model EDSM is not able to potentiate any of these drugs, whereas antagonism is seen in combination with doxo-rubicin (DX). In the L1210 tumor model, however, no loss of activity is seen for this specific combination. The effect of the combination of cytosar (Ara-C), 5-fluorouracil (5-FU) or vincristine (VCR) with EDSM in the L1210 model is strongly time interval dependent. Loss of 5-FU antitumor activity is seen when EDSM is given 3 or 24 h after 5-FU; however, no effect is observed when EDSM is given 6 h after 5-FU. Enhancement of the 5-FU activity is not noticed. The VCR activity is potentiated when EDSM is given at least 6 h after VCR administration, which increases the antitumor response from 32 to > 60 days and the percentage survivors from 33 to 83% (p = 0.04). In combination with Ara-C, potentiation of antitumor activity is seen only when EDSM is given 24 h after Ara-C, which increases the antitumor response from 32 to > 55 days and the percentage survivors from 11 to 50% (p = 0.008). No modulatory effects are found when EDSM is combined with carmustine or DX.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Ethyldeshydroxy-sparsomycin (EDSM) showed varied effects as a combination therapy for cancer. It potentiated vincristine and cytosar in L1210 leukemia models but was antagonistic with doxorubicin in B16 melanoma.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Protein synthesis inhibitors can modulate antitumor drug efficacy.
- Ethyldeshydroxy-sparsomycin (EDSM) is a protein synthesis inhibitor.
- Combination therapies are crucial for overcoming cancer drug resistance.
Purpose of the Study:
- To evaluate ethyldeshydroxy-sparsomycin (EDSM) as a biochemical response modifier for antitumor agents.
- To investigate the efficacy of EDSM in combination with various chemotherapeutic drugs against L1210 leukemia and B16 melanoma models.
- To determine the impact of administration timing on combination therapy outcomes.
Main Methods:
- Seven antitumor agents with distinct intracellular targets were selected.
- Tumor implantation and drug treatments were administered intraperitoneally.
- The time interval between EDSM and cytostatic agent administration was systematically varied.
Main Results:
- EDSM did not potentiate any drugs against B16 melanoma and showed antagonism with doxorubicin.
- In L1210 leukemia, EDSM combination efficacy was highly dependent on the time interval.
- Significant potentiation of vincristine and cytosar (Ara-C) activity was observed when EDSM was administered at specific intervals post-cytostatic agent.
Conclusions:
- EDSM's role as a response modifier is tumor- and drug-specific.
- Optimal timing of EDSM administration is critical for achieving synergistic effects in combination chemotherapy.
- EDSM shows potential for enhancing specific antitumor agents in certain leukemia models.