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[Therapeutic approach against drug-resistant tumors and their biochemical nature]
Abstract:
One of the major causes of failure of cancer chemotherapy is the proliferation of specific drug-resistant tumor cells during treatment. Drug-resistant tumor cells, however, usually bear biochemical changes which are related to the resistance mechanisms. New modalities against resistant cells could be possible if we were able to characterize these biochemical changes. Vincristine (VCR)- and adriamycin (ADM)-resistant tumor sublines show cross-resistance (pleiotropic drug resistance) to other unrelated drugs. VCR- and ADM-resistant sublines possess an enhanced outward transport of antitumor agents, which results in a low accumulation of antitumor agents in the cells. The cells express unique glycoproteins in the plasma membrane, and possess a higher calcium content in the cells. They also have double-minute chromosomes and homogeneously staining regions in chromosomes. By targeting for these biochemical changes, we have established new modalities against drug-resistant tumor cells. Calcium channel blockers inhibited the enhanced outward transport of VCR and ADM from resistant tumor cells, and thus overcame resistance to these agents. This approach showed potential usefulness in clinical trials. Another possible approach against drug-resistant tumor cells could be the utilization of monoclonal antibodies against unique glycoproteins in the plasma membrane of resistant tumor cells. We have developed monoclonal antibodies against adriamycin-resistant human myelogenous leukemia K562. Our recent progress with work on calcium channel blockers and monoclonal antibodies are discussed in this paper.
Insights
Targeting biochemical changes in drug-resistant cancer cells, like enhanced outward transport and unique glycoproteins, can overcome chemotherapy failure. Calcium channel blockers and monoclonal antibodies show promise in combating resistant tumors.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Context:
- Chemotherapy failure is often due to drug-resistant tumor cells.
- These resistant cells exhibit unique biochemical alterations.
- Understanding these changes is crucial for developing new treatment strategies.
Purpose:
- To characterize biochemical changes in drug-resistant tumor cells.
- To develop novel therapeutic modalities targeting these specific changes.
- To evaluate the efficacy of calcium channel blockers and monoclonal antibodies against resistant cells.
Summary:
- Vincristine (VCR)- and adriamycin (ADM)-resistant sublines exhibit cross-resistance due to enhanced outward drug transport and increased intracellular calcium.
- These resistant cells express unique plasma membrane glycoproteins and chromosomal abnormalities.
- Calcium channel blockers were found to inhibit outward drug transport, overcoming resistance.
- Monoclonal antibodies targeting unique glycoproteins on resistant cells were also developed.
Impact:
- New therapeutic strategies targeting specific biochemical markers can overcome drug resistance in cancer.
- Calcium channel blockers offer a potential approach to reverse multidrug resistance.
- Monoclonal antibodies represent another promising avenue for targeting resistant cancer cells.