Anti-idiotypic monoclonal antibodies (mAb) have been evaluated for actively induced immunotherapy with encouraging results. However, rational combination of cancer vaccines with chemotherapy may improve the therapeutic efficacy of these two approaches used separately. The main objective of this study was to evaluate the antitumor effect of the co-administration of 1E10 (Racotumomab), a monoclonal anti-idiotype tumor vaccine against an IgM mAb, named P3 that reacts specifically with NeuGc-containing gangliosides and low-dose Cyclophosphamide in a mammary carcinoma model. F3II tumor-bearing mice were immunized subcutaneously with 100 microg of 1E10 mAb in Alum or with 150 mg/m(2) of Cyclophosphamide intravenously 7 days after the tumor inoculation. While a limited antitumor effect was induced by a single 1E10 mAb immunization; its co-administration with low-dose Cyclophosphamide reduced significantly the F3II mammary carcinoma growth. That response was comparable with the co-administration of the standard high-dose chemotherapy for breast cancer based on 60 mg/m(2) of Doxorubicin and 600 mg/m(2) of Cyclophosphamide, without toxicity signs. Combinatorial chemo-immunotherapy promoted the CD8(+) lymphocytes tumor infiltration and enhanced tumor apoptosis. Furthermore, 1E10 mAb immunization potentiated the antiangiogenic effect of low-dose Cyclophosphamide. Additionally, splenic myeloid cells Gr1(+)/CD11b(+) associated with a suppressor phenotype were significantly reduced in F3II tumor-bearing mice immunized with 1E10 mAb alone or in combination with low-dose Cyclophosphamide. This data may provide a rational for chemo-immunotherapy combinations with potential medical implications in breast cancer.

TO THE EDITOR: The report by Jiralerspong et al 1 revealed a three-fold greater complete pathologic response in diabetic patients with breast tumors ingesting metformin undergoing neoadjuvant chemotherapy compared with diabetic patients not ingesting metformin. Chemotherapy included fluorouracil, doxorubicin, and cyclophosphamide; doxorubicin and cyclophosphamide; or fluorouracil, epirubicin, and cyclophosphamide. Additional taxane chemotherapy (paclitaxel or docetaxel) was administered to 1,909 patients. Assuming the absence of a statistical quirk, their observational finding begs for a rational explanation.Jiralerspong et al 1 present several possible explanations including population studies suggesting that metformin decreases the incidence of cancer and cancer-related mortality in diabetic patients. 2 Recently a report by Li et al 3 revealed a 62% reduction in the risk of pancreatic cancer in diabetic patients ingesting metformin. In addition, metformin has been shown to inhibit the growth of cancer cells, including breast cancer, in vitro 4-7 and of tumors in vivo. [6][7][8][9] We would like to suggest an additional possible mechanism of metformin enhancement of the observed chemotherapy effect. Metformin administration is associated with both folate and vitamin B 12 deficiency. However, since 1998 the US federal government has been spiking the food supply with folate, and folate deficiency is now quite rare. Metformin was found to induce B 12 deficiency (serum total B 12 level Յ 150 pmol/L) in up to 30% of diabetic patients ingesting the drug. 10 Only 20% of routinely measured serum total B 12 is metabolically active as holotranscobalamin (so-called active B 12 ) while approximately 80% of measured B 12 is metabolically inert holohaptocorrin (holotranscobalamin I plus holotranscobalamin III). Thus many times (up to 33% of untreated patients with cancer) there may be metabolic B 12 insufficiency (holotranscobalamin insufficiency, absence of active B 12 ) in the presence of normal total serum B 12 levels. 11 Since low levels of holotranscobalamin occur before total B 12 levels are abnormally low it is entirely reasonable to assume that some patients in the metformin treated group may have had occult, active B 12 insufficiency. In addition, our most recent work revealed that 18 of 21 patients undergoing a variety of chemotherapy protocols experienced large decreases in the active component of B 12 , holotranscobalamin. 12 Work by others demonstrated that rapid inactivation of B 12 by nitrous oxide anesthesia induced tumor-cell kill in vitro and increased tissue toxicity in patients receiving adjuvant chemotherapy with methotrexate. This was assumed to be due to acute, N 2 Oinduced B 12 deficiency. 13 Rapid N 2 O-induced B 12 deficiency decreased leukemia cell proliferation in patients with leukemia 14 and suppressed bone marrow cell proliferation in tetanus patients. 15 Thus we propose that an additional possible explanation for enhanced pathologic complete responses of breast tumors in the study reported ...

IntroductionThis is the first report of possible direct stimulation of hormone-resistant prostate cancer or interference of docetaxel cytotoxicity of prostate cancer in a patient with biochemical relapse of prostatic-specific antigen. This observation is of clinical and metabolic importance, especially at a time when more than 80 countries have fortified food supplies with folic acid and some contemplate further fortification with vitamin B12.Case presentationOur patient is a 71-year-old Caucasian man who had been diagnosed in 1997 with prostate cancer, stage T1c, and Gleason score 3+4 = 7. His primary treatment included intermittent androgen deprivation therapy including leuprolide + bicalutamide + deutasteride, ketoconazole + hydrocortisone, nilandrone and flutamide to resistance defined as biochemical relapse of PSA. While undergoing docetaxel therapy to treat a continually increasing prostate-specific antigen level, withdrawal of 10 daily doses of a supplement containing 500 μg of vitamin B12 as cyanocobalamin, as well as 400 μg of folic acid as pteroylglutamic acid and 400 μg of L-5-methyltetrahydrofolate for a combined total of 800 μg of mixed folates, was associated with a return to a normal serum prostatic-specific antigen level.ConclusionThis case report illustrates the importance of the effects of supplements containing large amounts of folic acid, L-5-methyltetrahydrofolate, and cyanocobalamin on the metabolism of prostate cancer cells directly and/or B vitamin interference with docetaxel efficacy. Physicians caring for patients with prostate cancer undergoing watchful waiting, hormone therapy, and/or chemotherapy should consider the possible acceleration of tumor growth and/or metastasis and the development of drug resistance associated with supplement ingestion. We describe several pathways of metabolic and epigenetic interactions that could affect the observed changes in serum levels of prostate-specific antigen.