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Reactivity of P-glycoprotein monoclonal antibodies in childhood cancers
A O'Meara1, A Imamura, P Johnson
1Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin, Ireland.
Abstract:
P-Glycoprotein (P-gp), the product of the mdr-1 gene, is implicated in the development of chemoresistance in a variety of, mostly adult, cancers. Its role in paediatric tumours, most of which are non-epithelial in origin, has yet to be fully elucidated. A study was undertaken to investigate reactivity of two P-gp monoclonal antibodies (MAbs), JBS-1 and MRK16, recognising cytoplasmic and surface epitopes, respectively, of the P-gp molecule, in a variety of newly diagnosed and relapsed childhood cancers. P-gp was not expressed in any of 36 tumours examined (neuroblastoma 13, nephroblastoma 12, rhabdomyosarcoma 6, lymphoma 3, teratoma 1, Ewings 1), 14 of whom had chemoresistant disease. Reactivity to both MAbs was also investigated in patients with acute leukaemia. Out of 10 diagnostic acute lymphoblastic leukaemia (ALL) samples, a positive reaction with JSB-1 was observed in 1 patient who failed to remit on standard induction therapy and in 3 of 6 patients in ALL relapse, only 1 of whom showed low grade positivity with MRK16. Both MAbs reacted positively in 1 patient with acute non-lymphocytic leukaemia (ANLL) at diagnosis who achieved remission with teniposide and cytosine arabinoside, but relapsed 7 months later and was again positive with both Mabs. JSB-1 also showed varying degrees of positivity in 4 out of 4 other patients in ANLL relapse. It would therefore appear that P-gp is unlikely to mediate chemoresistance in most solid tumours of childhood, but may well play a major role in the development of chemoresistance in acute leukaemia.
Insights
P-glycoprotein (P-gp) is not expressed in most childhood solid tumors, suggesting it does not cause chemoresistance. However, P-gp expression may contribute to chemoresistance in childhood acute leukemias.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- P-glycoprotein (P-gp), encoded by the mdr-1 gene, is linked to multidrug resistance in adult cancers.
- The role of P-gp in pediatric cancers, particularly non-epithelial tumors, remains unclear.
- Understanding P-gp's role is crucial for developing effective pediatric cancer therapies.
Purpose of the Study:
- To investigate P-gp expression in various newly diagnosed and relapsed childhood cancers.
- To determine if P-gp expression correlates with chemoresistance in pediatric solid tumors and acute leukemias.
- To evaluate the utility of P-gp monoclonal antibodies (MAbs) JSB-1 and MRK16 in detecting P-gp.
Main Methods:
- Analysis of P-gp expression using two monoclonal antibodies (MAbs), JSB-1 (cytoplasmic) and MRK16 (surface).
- Testing included 36 pediatric solid tumors (neuroblastoma, nephroblastoma, rhabdomyosarcoma, lymphoma, teratoma, Ewing's sarcoma) and acute leukemia samples.
- Samples were from newly diagnosed and relapsed cases, some with known chemoresistant disease.
Main Results:
- P-gp was not detected in any of the 36 pediatric solid tumors examined, irrespective of chemoresistance status.
- In acute lymphoblastic leukemia (ALL), JSB-1 positivity was observed in 1/10 diagnostic samples and 3/6 relapsed samples.
- P-gp expression (JSB-1 and MRK16) was noted in acute non-lymphocytic leukemia (ANLL) at diagnosis and relapse, correlating with treatment response and relapse.
Conclusions:
- P-glycoprotein is unlikely to be a significant factor in chemoresistance for most pediatric solid tumors.
- P-gp may play a crucial role in the development of chemoresistance in pediatric acute leukemias.
- Further research into P-gp targeted therapies for pediatric acute leukemias is warranted.