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The combination of 5-fluorouracil with misonidazole in patients with advanced colorectal cancer
Abstract:
Misonidazole (MISO) has produced differential enhancement of tumor cell killing with a range of cytotoxic drugs including 5-fluorouracil (FU) in experimental mouse tumors and human xenografts. Since concomitant enhancement of normal tissue damage has been observed, a Phase I study of MISO and FU has been undertaken in patients with advanced colorectal cancer. Mild nausea and vomiting occurred more frequently after MISO and FU compared with FU alone; however, the incidence of leucopenia was similar with both treatment. No patients receiving the MISO/FU combination developed central nervous system toxicity or peripheral neuropathy. Twenty-four hour plasma nitroimidazole kinetics were analyzed and were not modified by the concomitant administration of the cytotoxic drug. Thus, in this preliminary study FU has been safely combined with MISO without significant modification of plasma nitroimidazole pharmacokinetics. Tumor regression was documented in 2/9 (22%) patients receiving more than 2 courses of MISO/FU. A Phase II study is proposed to investigate tumor response.
Insights
Misonidazole (MISO) combined with 5-fluorouracil (FU) showed safe administration in colorectal cancer patients, with manageable side effects. This combination therapy did not alter MISO pharmacokinetics, paving the way for further investigation.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Misonidazole (MISO) enhances tumor cell killing with cytotoxic drugs like 5-fluorouracil (FU).
- Previous studies indicated potential for increased normal tissue damage with MISO combination therapy.
Purpose of the Study:
- To assess the safety and tolerability of combining MISO with FU in patients with advanced colorectal cancer.
- To evaluate the impact of FU on MISO pharmacokinetics.
Main Methods:
- A Phase I clinical study involving patients with advanced colorectal cancer.
- Concomitant administration of MISO and FU, with analysis of plasma nitroimidazole kinetics.
- Monitoring for adverse events, including nausea, vomiting, leucopenia, and neurological toxicities.
Main Results:
- Mild nausea and vomiting were more frequent with MISO/FU compared to FU alone.
- Incidence of leucopenia was similar between treatment groups.
- No central nervous system or peripheral neuropathy toxicities were observed.
- Plasma nitroimidazole pharmacokinetics remained unchanged with combined MISO/FU treatment.
Conclusions:
- MISO can be safely combined with FU in patients with advanced colorectal cancer.
- The combination does not significantly alter MISO pharmacokinetics.
- Tumor regression was observed in 22% of patients, supporting further investigation.