Dear Dr Shahrasbi There are two papers 1. Reappraisal of the use of procarbazine in the treatment of lymphomas and brain tumors by Jean-Pierre Armand Early studies reported overall response rates of 53% to 69% with single agent procarbazine in patients with advanced Hodgkin’s lymphoma. However, these responses were generally very short-lived and there were few complete responses. In the early 1970s, procarbazine was used successfully in combination with three other drugs in the regimen known as MOPP (mechlorethamine [nitrogen mustard], Oncovin [vincristine], procarbazine, and prednisone) in the treatment of advanced Hodgkin’s lymphoma. A complete remission rate of 84% was attained, with relapse-free and overall survival rates of 66% and 48%, respectively, after more than 20 years. Unfortunately, although the acute toxic effects of MOPP are manageable, it is associated with significant long-term toxicity. For example, more than 90% of men, and 80%–100% of women over 25 years old, become irreversibly infertile. There is also a risk of secondary acute leukemia, which is frequently resistant to treatment and has an extremely poor prognosis. A number of MOPP-like regimens were developed in an attempt to reduce this toxicity. It would appear that procarbazine plays an important role in MOPP, as lower complete remission rates of shorter duration were reported with MOPP-like regimens that did not contain procarbazine . ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) subsequently became the regimen of choice for advanced disease after showing superior efficacy and less long-term toxicity than MOPP and MOPP hybrid regimens. The combination of MOPP plus epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine (MOPPEBVCAD) has recently been suggested to be as effective as ABVD and more effective than the Stanford V schedule (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone). However, despite lower toxicity than normally expected with MOPP analogues, the incidence of second cancers remains somewhat higher than with ABVD. It is, nevertheless, a good option for patients who are not suitable for high-dose chemotherapy. the second paper PharmGKB summary: very important pharmacogene information for G6PD Ellen M. McDonagh G6PD deficiency and cancer therapeutics Several agents involved in the treatment of cancer patients have the potential to result in severe adverse side effects in G6PD-deficient individuals, due to induction of oxidative stress in RBCs. Carmustine [3-bis(chloroethyl)-1-nitrosourea (BCNU)] treatment results in a deficiency in glutathione reductase in erythrocytes, platelets, and leukocytes. This lowers the levels of reduced glutathione and leads to insufficient removal of hydrogen peroxide and susceptibility to oxidative hemolysis, particularly in RBCs that are G6PD deficient. Doxorubicin (adriamycin) stimulates the PPP, but to a lower extent in G6PD-deficient RBCs, and results in oxidative stress through the accumulation of hydrogen peroxide due to an inability to increase G6PD activity [see the PharmGKB Doxorubicin Pathway (Cancer Cell), Pharmacodynamics. This response can also be mirrored in ‘normal’ RBCs when cells are pretreated with carmustine before doxorubicin treatment, resulting in diminished glutathione stability and enhanced susceptibility to oxidative stress. A number of cases of methemoglobinemia and acute hemolysis after treatment with rasburicase in G6PD-deficient individuals have been described. The FDA labeling has contraindicated rasburicase for G6PD-deficient individuals. The anti-leukemia drug daunorubicin is metabolized into the less potent form daunorubinol, a process dependent on NADPH via G6PD. This biotransformation was considerably reduced in RBCs from A- or Mediterranean G6PD-deficient individuals, and thus may have implications in the clinic, raising the issue of whether or not the drug is more effective in these individuals due to prolonged exposure to the more active form and possible toxicity concerns. NADPH inhibitors, including primaquine aldehyde, were also shown to reduce daunorubicin metabolism and daunorubinol appearance.