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Occurrence of drug resistance in human tumor implanted in nude mice
Abstract:
A line of human breast tumor xenograft in nude mouse, MX-1, acquired resistance to vincristine or mitomycin C during multiple treatments; both drugs were effective against the parent line of this tumor. If the treatment was started when the tumor was smaller than 500 mm3 in size, MX-1 was responsive to the initial treatment with vincristine (0.8 mg/kg) or mitomycin C (3.4 mg/kg), and some animals survived with complete regression of the tumor. However, some of the recurrent tumors were able to tolerate multiple treatments with either of these agents, and finally acquired apparent resistance to the agent. On the other hand, when tumors larger than 5,000 mm3 were treated with vincristine, the occurrence of resistance was observed with much higher frequency than when small tumors were treated. Resistant tumors thus obtained exhibited significant refractoriness to each agent when they were reimplanted in new mice and treated in the same manner. This suggests that the occurrence of resistance can be ascribed to changes not in metabolic functions of the host animal but in the tumor cell populations.
Insights
MX-1 breast tumor xenografts developed resistance to vincristine and mitomycin C with repeated treatments. Tumor size significantly influenced resistance development, with larger tumors showing higher resistance frequency.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- The MX-1 human breast tumor xenograft model in nude mice was utilized.
- Initial sensitivity of the parent tumor line to vincristine and mitomycin C was established.
Purpose of the Study:
- To investigate the development of acquired resistance to vincristine and mitomycin C in the MX-1 xenograft model.
- To determine the influence of tumor size on the frequency of acquired drug resistance.
Main Methods:
- Multiple treatments with vincristine (0.8 mg/kg) or mitomycin C (3.4 mg/kg) were administered to MX-1 xenografts.
- Tumor size was varied (smaller than 500 mm3 vs. larger than 5,000 mm3) at the initiation of treatment.
- Acquired resistance was assessed by re-challenging resistant tumors in new host mice.
Main Results:
- Recurrent MX-1 tumors acquired resistance to vincristine or mitomycin C after multiple treatments.
- Smaller tumors (<500 mm3) showed initial responsiveness and occasional complete regression.
- Larger tumors (>5,000 mm3) exhibited a significantly higher frequency of acquired resistance.
- Resistant tumors demonstrated refractoriness to the respective agents upon re-implantation and treatment.
Conclusions:
- Acquired resistance to vincristine and mitomycin C in the MX-1 xenograft model is linked to tumor cell population changes, not host metabolic alterations.
- Tumor size is a critical factor influencing the rate of drug resistance development.
