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Antitumour activity and retinotoxicity of ethyldeshydroxy-sparsomycin in mice
H P Hofs1, D J Wagener, D De Vos
1University of Amsterdam, Laboratory of Radiobiology, The Netherlands.
Abstract:
The colony formation in agar of human tumour xenografts was used as a test system to study the cytostatic activity of ethyldeshydroxy-sparsomycin (EdSm) at the cellular level. EdSm was additionally studied in vivo in human tumour xenografts and murine tumour models. EdSm showed a clear dose-response effect in vitro. At continuous exposure with 0.01 micrograms/ml, 2 out of 11 of the tumours responded (a gastric and a small cell lung carcinoma). At 0.1 mu/ml EdSm, the tumour response was 5/11 tumours and at 1 microgram/ml the compound was active in all tumours. The maximal tolerable doses of EdSm in vivo have been determined in non-tumour bearing CDF1 mice. In the intraperitoneally (i.p.) given multiple dose schedules the respective LD10 doses indicated that the tolerable cumulative dose increases when lower doses are given more frequently. This also enhances the antitumour activity in L1210 leukaemia to 172% T/C. On the other hand, continuous infusion strongly diminished the tolerable dose as well as the antitumour activity. EdSm was also active against i.p. inoculated P388 leukaemia (150% T/C), B16 melanoma (156% T/C), and RC carcinoma (197% T/C), and the subcutaneously (s.c.) inoculated L1210 (139% T/C) and RC (138% T/C). Absence of tumour responses was found in the following s.c. implanted murine tumours: M5076 sarcoma, osteosarcomas C22LR and CP369, and the LL carcinoma, as well as in the human tumour xenografts: LXFG 529, a non-small cell lung carcinoma; GXF 251, a gastric carcinoma; and FMa, an ovary carcinoma. Possible long-range retinotoxic effects of EdSm were investigated in tumour-bearing mice, cured after surviving treatment with LD50 doses of EdSm, by assaying the protein biosynthetic capacity of the retinal by assaying the ocular rhodopsin and opsin levels as parameters. In none of these cases could a significant reduction in either opsin or rhodopsin levels be measured and no changes were seen histologically.
Insights
Ethyldeshydroxy-sparsomycin (EdSm) demonstrates dose-dependent cytostatic activity against human tumors in vitro and shows significant antitumor effects in various murine models. EdSm exhibits no observed retinotoxicity, suggesting a favorable safety profile for cancer treatment development.
Area of Science:
- Pharmacology and Toxicology
- Cancer Research
- Drug Development
Background:
- Ethyldeshydroxy-sparsomycin (EdSm) is a compound investigated for its potential anticancer properties.
- Understanding its efficacy and safety profile is crucial for its development as a therapeutic agent.
- Previous studies may not have fully elucidated its dose-response relationship or in vivo activity across diverse tumor types.
Purpose of the Study:
- To evaluate the cytostatic activity of ethyldeshydroxy-sparsomycin (EdSm) at the cellular level using human tumor xenografts.
- To assess the in vivo antitumor efficacy of EdSm in both human tumor xenografts and murine tumor models.
- To determine the maximal tolerable doses and investigate potential long-range retinotoxic effects of EdSm.
Main Methods:
- In vitro cytostatic activity was assessed using colony formation assays of human tumor xenografts in agar.
- In vivo studies involved administering EdSm to tumor-bearing mice (human xenografts and murine models) via intraperitoneal (i.p.) and subcutaneous (s.c.) routes, as well as continuous infusion.
- Maximal tolerable doses were determined in non-tumor bearing mice, and retinotoxicity was evaluated by measuring ocular rhodopsin and opsin levels in treated mice.
Main Results:
- EdSm exhibited a clear dose-response effect in vitro, with activity increasing at higher concentrations.
- In vivo, EdSm demonstrated significant antitumor activity against various murine tumors including L1210 leukemia, P388 leukemia, B16 melanoma, and RC carcinoma, with optimal activity observed with frequent lower i.p. doses.
- No significant retinotoxic effects were observed, even at high doses (LD50), with rhodopsin and opsin levels remaining unchanged.
Conclusions:
- Ethyldeshydroxy-sparsomycin (EdSm) possesses significant cytostatic and antitumor activity against a range of cancers.
- The dosing schedule significantly impacts both tolerability and efficacy, with frequent lower doses being more beneficial.
- EdSm appears to have a favorable safety profile regarding ocular toxicity, warranting further investigation for clinical application.