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The uptake of the radiosensitizing compound Ro 03-8799 (Pimonidazole) in human tumors
S Dische1, M H Bennett, R Orchard
1Marie Curie Research Wing, Mount Vernon Hospital, Northwood, Middlesex, England.
Abstract:
The nitroimidazole, Ro 03-8799, has proved unique among the drugs tested as chemical hypoxic cell radiosensitizers because of the preferential concentration which has been observed in tumors. Our accumulation of experience has allowed new analyses to be performed upon 127 samples from 39 patients; 47 samples of normal tissue were also obtained from 26 of these patients. Tissue sampling was performed usually between 20 and 30 minutes after initiation of infusion of Ro 03-8799. By expressing results as tumor: plasma ratios, difficulties in comparison because of differing doses and body sizes, together with a variation in the actual time of sampling, have been avoided. A small portion of each specimen which was analyzed for drug concentration was also examined histologically to give an impression of the percentage of the specimen occupied by tumor cells. Analyses have shown that the average tumor concentration is approximately twice that of normal tissues which have been sampled and four times that in plasma. In 38 breast tumor samples, the concentration of drug varied directly as the proportion occupied by tumor cells. The highest tumor: plasma ratios were seen in samples taken from some samples of malignant melanoma. These findings confirm that a greater potency can be expected for this drug as a radiosensitizer because of its ability to enter tumor cells in high concentration. In drug development programs for chemical sensitizing and cytotoxic agents, drugs which show this phenomenon should be explored.
Insights
The nitroimidazole Ro 03-8799 preferentially concentrates in tumors, showing higher levels than in normal tissues or plasma. This preferential tumor uptake suggests enhanced efficacy as a hypoxic cell radiosensitizer.
Area of Science:
- Pharmacology
- Oncology
- Radiotherapy
Background:
- Hypoxic tumor cells are resistant to radiation therapy.
- Chemical hypoxic cell radiosensitizers aim to improve radiation efficacy in hypoxic tumors.
- Nitroimidazoles are a class of compounds investigated for radiosensitizing properties.
Purpose of the Study:
- To evaluate the tumor-specific concentration of the nitroimidazole Ro 03-8799.
- To determine the relationship between drug concentration and tumor cell content.
- To assess the potential of Ro 03-8799 as a hypoxic cell radiosensitizer.
Main Methods:
- Analysis of Ro 03-8799 concentration in 127 tumor samples and 47 normal tissue samples from 39 patients.
- Tissue sampling performed 20-30 minutes post-infusion.
- Calculation of tumor:plasma ratios to standardize drug concentration comparisons.
- Histological examination to determine the percentage of tumor cells in specimens.
Main Results:
- Average tumor concentration of Ro 03-8799 was approximately twice that of normal tissues and four times that of plasma.
- In breast tumor samples, drug concentration correlated directly with tumor cell proportion.
- Highest tumor:plasma ratios were observed in malignant melanoma samples.
- Ro 03-8799 demonstrated preferential accumulation in tumor tissues.
Conclusions:
- Ro 03-8799 exhibits preferential tumor uptake, supporting its role as a potent hypoxic cell radiosensitizer.
- The drug's ability to concentrate in tumor cells suggests increased radiosensitizing efficacy.
- Further exploration of Ro 03-8799 and similar agents in drug development is warranted.