Upregulation of ADAM12 contributes to accelerated cell proliferation and cell adhesion-mediated drug resistance (CAM-DR) in Non-Hodgkin’s Lymphoma

PURPOSE To investigate the prognostic value of cell proliferation rate in non-Hodgkin's lymphoma, study its association with histologic classification, and investigate whether its predictive value is influenced by the type of treatment given. PATIENTS AND METHODS The S-phase fraction (SPF) size was determined by DNA flow cytometry from paraffin-embedded tissue obtained at diagnosis from 490 patients with non-Hodgkin's lymphoma, diagnosed in a defined geographic area from 1970 to 1991. Clinical data were collected from hospital records and the files of the Finnish Cancer Registry. RESULTS SPF size correlated well with histologic grading performed either according to the Working Formulation or Kiel classification (P < .0001 for both). The mean SPFs of low-, intermediate-, and high-grade malignant lymphomas were 4.9% (95% confidence interval [CI], 4.2% to 5.5%), 10.3% (95% CI, 9.3% to 11.4%), and 15.5% (95% CI, 14.0% to 16.9%), respectively. Lymphomas with an SPF lower than the median (7.9%) had a 58% 5-year and 44% 15-year survival rate, whereas those with an SPF larger than the median had a 44% 5-year and 40% 15-year survival rate (P < .0001). SPF size was not significantly associated with prognosis in some subgroups, such as among patients treated primarily with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (n = 114) or cyclophosphamide, vincristine, and prednisone (COP) (n = 124) with or without radiotherapy (P > .05), whereas a stronger association was found among patients with stage I or II lymphoma treated with radiotherapy only (n = 100; P = .003) and among patients with stage III or IV lymphoma who did not receive chemotherapy (n = 44; P < .0001). In multivariate analyses that included the factors used to construct the International Prognostic Index, SPF had independent prognostic value both in low-grade and intermediate- or high-grade lymphomas, but not in the subset of patients treated with combination chemotherapy with or without radiotherapy. CONCLUSION Cell proliferation rate measured as SPF is closely associated with histologic grading in non-Hodgkin's lymphoma, and it has independent prognostic value. The treatment given influences considerably the prognostic value of SPF.

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Drug-resistance in multiple myeloma and non-Hodgkin's lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.1989.7.4.415 ◽

1989 ◽

Vol 7 (4) ◽

pp. 415-424 ◽

Cited By ~ 364

Author(s):

W S Dalton ◽

T M Grogan ◽

P S Meltzer ◽

R J Scheper ◽

B G Durie ◽

...

Keyword(s):

Multiple Myeloma ◽

Drug Resistance ◽

Tumor Cells ◽

Hodgkin’S Lymphoma ◽

Progressive Disease ◽

Hodgkin's Lymphoma ◽

Drug Resistant ◽

P Glycoprotein ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma

The B-cell neoplasms, multiple myeloma and non-Hodgkin's lymphoma, frequently become drug resistant, despite initial responses to chemotherapeutic drugs. Tumor cells from eight patients with clinically drug-refractory disease were evaluated by immuno-histochemical staining for monoclonal immunoglobulin (Ig) expression, nuclear proliferation antigen, P-glycoprotein (P-gly) expression, and other cellular antigens. P-gly was detected on tumor cells from six of eight patients with drug-resistant disease. Of the six patients with P-gly-positive tumors, five patients had advanced multiple myeloma and one had a drug-refractory non-Hodgkin's lymphoma. Cellular RNA analysis confirmed the over-expression of P-gly. In an effort to overcome drug resistance, a pilot study evaluated possible verapamil enhancement of chemotherapy in these eight patients. All patients had developed progressive disease while receiving a regimen containing vincristine and doxorubicin, and seven of eight patients had previously received continuous infusion vincristine and doxorubicin plus oral dexamethasone (VAD). At the time of progressive disease, continuous infusion verapamil was added to the VAD regimen. Three of the eight patients who were refractory to vincristine and doxorubicin alone responded when verapamil was added to VAD. The three patients who responded had P-gly-positive tumors. Verapamil increased the intracellular accumulation of doxorubicin and vincristine in vitro for both a P-gly-positive myeloma cell line and tumor cells from two patients with end-stage myeloma which over-expressed P-gly. The dose-limiting side effect associated with the addition of verapamil to chemotherapy was temporary impairment of cardiac function, manifest as hypotension and cardiac arrhythmia. We conclude that P-gly expression occurs in drug-refractory B-cell neoplasms and may contribute to the development of clinical drug resistance. However, other factors, such as the proliferative activity of the tumor, may also play a role in determining response to chemotherapy. The administration of verapamil along with VAD chemotherapy may partially circumvent drug resistance in patients whose tumors over-express P-gly.

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