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Chemoresistance and multiple myeloma: from biological to clinical aspects
1Service d'Hématologie-Oncologie, CHU Lapeyronie, Montpellier, France.
Abstract:
Resistance to chemotherapy represents a major cause for cancer treatment failure. Several biological mechanisms implicated in chemoresistance have been described, including multidrug resistance (MDR1/P-glycoprotein [P-gp] or p170), resistance-related proteins (p95 and p110), multidrug resistance-associated protein (p190), proteins implicated in cell detoxification such as glutathione S-transferase and genes affecting DNA structure (topoisomerases). MDR1 has been the most studied in hematological malignancies, particularly in lymphoma and multiple myeloma (MM), diseases generally considered as overexpressing such mechanisms in relapse. Overexpression of chemoresistance is generally an induced phenomenon caused or amplified by the drugs, as demonstrated by the development of drug-resistant cell lines in vitro. It may be defined as a profile of chemoresistance depending on the drug used for induction. This may have a potential implication for monitoring chemoresistance to modulate or to prevent its amplification. Several questions are always open to discussion, including the method of detection, the true prognostic impact of chemoresistance, the dynamic expression of such mechanisms, depending on the cell status, the host response and the mechanism of induction. In MM, the over-expression of MDR1/P-gp is usually less than 10% at diagnosis, leading to 59-80% at relapse, depending on the clinical status. The percentage of positivity depends on the cumulative dose of vincristine and/or doxorubicin. GST pi is (over)expressed in 10-70% of patients at diagnosis, and in 30% at relapse, but in small series, as well as for topoisomerases I and II which are concerned in 53% and 6%, respectively, at diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Chemoresistance mechanisms like MDR1/P-glycoprotein are crucial in cancer treatment failure, especially in lymphoma and multiple myeloma. Monitoring these resistance profiles may help tailor therapies and prevent amplification.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemotherapy resistance is a primary driver of treatment failure in various cancers.
- Mechanisms include multidrug resistance (MDR1/P-glycoprotein), resistance-related proteins, and altered DNA topoisomerases.
- Overexpression of chemoresistance is often induced or amplified by therapeutic agents.
Purpose of the Study:
- To review the biological mechanisms of chemoresistance.
- To discuss the implications of chemoresistance in hematological malignancies, particularly lymphoma and multiple myeloma (MM).
- To explore the potential for monitoring chemoresistance to guide treatment strategies.
Main Methods:
- Literature review of studies on chemoresistance mechanisms.
- Analysis of data on the expression of MDR1/P-glycoprotein, glutathione S-transferase (GST), and topoisomerases in cancer.
- Discussion of diagnostic and prognostic implications.
Main Results:
- MDR1/P-glycoprotein overexpression increases significantly from diagnosis to relapse in MM (10% to 59-80%).
- Expression levels correlate with cumulative drug dosage (vincristine, doxorubicin).
- GST pi and topoisomerases also show variable expression patterns at diagnosis and relapse.
Conclusions:
- Chemoresistance, particularly MDR1/P-gp, is a dynamic and often induced phenomenon in hematological malignancies.
- Understanding these mechanisms is vital for managing relapsed diseases.
- Further research is needed on detection methods, prognostic impact, and dynamic expression of resistance markers.