At a meeting of the East of Scotland and Newcastle Lymphoma Group papers were presented from the major U.K. groups and from North America. The themes focused on the clinical management of poor prognosis non-Hodgkin's lymphoma, and the identification and treatment of bad risk Hodgkin's disease.
DRUG RESISTANCE
A. L. Harris (Newcastle) drew a parallel between the intrinsic chemosensitivity of the lymphomas, leukaemias and testicular tumours contrasted against that of solid tumours, and pointed out that in normal tissues differential sensitivity to chemotherapy and radiotherapy is also quite striking. Whereas bone marrow CFU-Cs are sensitive to drug effects, stem cells (as evidenced by almost invariable marrow recovery) are far more chemoresistant. He has begun to elucidate the normal repair mechanisms and to determine the differences between sensitive tissues and normal tissues. Using the Chinese hamster ovary (CHO) cell lines he has isolated seven sub-lines of which five show enhanced sensitivity to mitomycin C and two to bleomycin. These were chosen as being typical of two mechanisms of DNA damage, one causing crosslinking and one causing damage to DNA double strand breaks. Transfection of some of the cell lines with human DNA has conferred the restoration of wild-type resistance. Cross sensitivity patterns of the mutant CHO lines show that single gene defects can regulate sensitivity to a wide range of drugs such as bleomycin, VP-16, X-irradiation, doxorubicin, BCNU, mitomycin C and UV irradiation. Mechanisms of primary or secondary resistance may differ after response and relapse. In the latter case it is frequently observed that chemosensitivity is retained using different drugs. Thus primary resistance may be broad spectrum whereas secondary resistance may result from more specific mechanisms.
Broad spectrum (multidrug) resistance is associated with a surface glycoprotein (P glycoprotein). This mechanism is an example of the ability of the cell to extrude exogenous toxic agents of completely different classes even though the cell has been exposed to drugs of only one class. The typical spectrum of resistance after single drug exposure is seen following exposure to doxorubicin, mitoxantrone, mAMSA, VP16, the vinca alkaloids, actinomycin-D and, to a lesser extent, mitomycin-C and melphalan. P glycoprotein acts in effect as a membrane pump, clearing drugs by an energy-dependent process. Evidence exists for this mechanism in vivo in acute leukaemia, ovarian cancer and some soft tissue sarcomas. ADP ribosyl transferase is a chromatinassociated enzyme activated by DNA strand breaks to convert NAD into polyADP ribose. The enzyme is activated by irradiation and bleomycin-induced strand breaks and by methylating agents.