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Preclinical activity of hepsulfam and busulfan in solid human tumor xenografts and human bone marrow
D P Berger1, B R Winterhalter, W A Dengler
1Department of Internal Medicine, University of Freiburg, Germany.
Abstract:
Hepsulfam (1,7-heptanediol disulfamate, NSC 329680) is a new antineoplastic alkanesulfonate agent which has demonstrated a broader preclinical activity than busulfan. The compound is currently undergoing clinical trials. We have studied the activity of hepsulfam and busulfan simultaneously in human tumor xenografts in vitro in a clonogenic assay and in vivo in tumor-bearing animals in order to assess the activity of both compounds in model systems of slowly growing malignancies. In a total of 37 different tumors of various histologies, both agents demonstrated broad spectrum in vitro activity. The median IC50 of hepsulfam and busulfan was determined as 0.93 and 3.31 micrograms/ml, respectively. At a concentration of 1.0 micrograms/ml, hepsulfam was active in eight of 37 tumors (22%) in the clonogenic assay, whereas busulfan effected inhibition of colony formation in one of 37 lines (3%). At the same concentration, however, hepsulfam demonstrated a clear in vitro toxicity to human bone marrow cells (CFU-GM) from healthy donors, whereas busulfan did not reveal a myelosuppressive effect. Evaluation of equitoxic concentrations in vitro revealed a higher activity of hepsulfam, especially in non-small cell lung cancer. In tumor-bearing nude mice, the approximate LD10 dose was determined as 150 mg/kg single bolus injection given i.p. on day 1 for both compounds. Hepsulfam demonstrated superior in vivo activity in a large cell lung cancer xenograft and a gastric carcinoma model. The preclinical activity of hepsulfam suggests a possible role of this compound in the treatment of solid human malignancies. However, the increased bone marrow toxicity of hepsulfam as compared with busulfan might be critical for further clinical application.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Hepsulfam shows promising preclinical anticancer activity against various tumors, outperforming busulfan in vitro and in vivo. However, hepsulfam also exhibits greater bone marrow toxicity, a critical factor for clinical use.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Hepsulfam (1,7-heptanediol disulfamate) is a novel alkanesulfonate antineoplastic agent.
- Preclinical studies indicate hepsulfam possesses broader activity than busulfan.
- Hepsulfam is currently undergoing clinical trials.
Purpose of the Study:
- To compare the in vitro and in vivo activity of hepsulfam and busulfan.
- To assess their efficacy in preclinical models of slowly growing malignancies.
- To evaluate their toxicity profiles, particularly bone marrow effects.
Main Methods:
- In vitro clonogenic assay using human tumor xenografts.
- In vivo studies in tumor-bearing nude mice.
- Determination of median IC50 values and equitoxic concentrations.
- Assessment of myelosuppressive effects on human bone marrow cells (CFU-GM).
Main Results:
- Both agents showed broad-spectrum in vitro activity against 37 human tumors.
- Hepsulfam had a lower median IC50 (0.93 µg/ml) than busulfan (3.31 µg/ml).
- Hepsulfam demonstrated superior in vitro activity (22% vs 3%) and in vivo efficacy in lung and gastric cancer models.
- Hepsulfam exhibited significant in vitro bone marrow toxicity, unlike busulfan.
Conclusions:
- Hepsulfam displays significant preclinical anticancer activity, suggesting potential for treating solid human malignancies.
- Its superior efficacy in preclinical models warrants further investigation.
- Increased bone marrow toxicity compared to busulfan is a critical consideration for clinical application.