Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone marrow cells from children with leukemia in remission and lymphoblasts and myeloblasts from children with early and late-stage leukemia all accumulated methotrexate during short-term culture and converted it to poly-gamma-glutamyl derivatives. This metabolism was time and dose-dependent. Leukemia cells from two patients with chronic myelocytic leukemia also synthesized methotrexate polyglutamates. Patients varied one from another in the quantity of total non-exchangeable methotrexate and methotrexate polyglutamates present in cells, but highest levels of each of these were seen in late acute lymphoblastic leukemia and in acute myeloblastic leukemia. Co-incubation of leukemic cells with both methotrexate and a ten-fold excess of folinic acid decreased accumulation and polyglutamylation of methotrexate to the same extent as achieved by reducing methotrexate concentration ten-fold. Co-incubation with methotrexate and a ten-fold excess of vincristine did not increase total cell methotrexate and methotrexate polyglutamates in leukemic cells in culture. Such an increase had been anticipated from earlier studies with other cells. Indeed, levels of methotrexate and its derivatives were modestly reduced.
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PMID:Methotrexate metabolism by bone marrow cells from patients with leukemia. 619 91

The availability of an i.v. form of busulfan (Bu) has prompted investigation of administration schedules other than the 4-times-daily dosage commonly used with oral Bu. We have studied an allogeneic stem cell transplantation (SCT) preparative regimen comprising fludarabine (FLU) 50 mg/m2 on days -6 to -2 plus i.v. Bu 3.2 mg/kg daily in a 3-hour infusion on days -5 to -2. The regimen was given to 70 patients aged 15 to 64 years (median, 41 years) with hematologic malignancy. Thirty-six patients (51%) had high-risk malignancy, 28 (40%) had unrelated or genotypically mismatched related donors (alternate donors [AD]) and 29 (41%) received bone marrow rather than blood as stem cell source. Acute GVHD prevention comprised antithymocyte globulin 4.5 mg/kg over 3 days pretransplantation, cyclosporin A, and short-course methotrexate with folinic acid. Hepatic toxicity was transient and there was no clinically diagnosed veno-occlusive disease. Grade II stomatitis occurred in 49 patients (70%) and hemorrhagic cystitis in 9 patients (13%). One patient with subtherapeutic phenytoin levels had a convulsion 8 hours after the third i.v. Bu dose, but no other neurotoxicity was apparent. Incidence of acute GVHD grades II to IV was 8% and incidence of grade III-IV was 3%, with no deaths from this cause. Actuarial incidence of chronic GVHD at 2 years is 38%. There were 2 cases of graft failure in unrelated donor BMT recipients, 1 of which was reversed by asecond transplantation. With a median follow-up of 16 months (range, 6-27 months), transplantation-related mortality at 100 days and 2 years was 2% and 5% for matched related donor (MRD) SCT and 8% and 19% for AD SCT, respectively (P = not significant). Relapse rates were 21% for 34 patients with acute myeloid leukemia (AML) in complete remission or chronic myeloid leukemia in chronic phase (low-risk), 66% for 19 patients with high-risk AML, and 18% for 17 patients with other active malignancy. Projected disease-free and overall survival rates at 2 years were 74% and 88% for low-risk disease, 26% and 37% for advanced AML, and 65% and 71% for other high-risk disease, respectively. Pharmacokinetic studies were done using 11 samples with the first and fourth doses of Bu. Kinetics were linear, and for the first and fourth doses, the half-lives were 2.60 +/- 0.44 and 2.57 +/- 0.36 hours, respectively. Clearances were 106.77 +/- 16.68 and 106.86 +/- 21.57 mL/min per m2, peak concentrations (Cmax) were 3.92 +/- 0.31 and 3.96 +/- 0.28 mcg/mL, and Bu areas under the plasma concentration versus time curve (AUC) were 4866.51 +/- 771.42 and 4980 +/- 882.80 microM x min, respectively. Bu was completely cleared within 24 hours and the day 4 pharmacokinetic values were very similar to those on day 1 for every patient. The cumulative AUC was comparable to the target range established for p.o. Bu. This regimen incorporating once-daily i.v. Bu is convenient to give, is relatively well tolerated, gives predictable blood levels, and deserves further study in circumstances in which cytoreduction as well as immune suppression is needed.
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PMID:Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. 1237 50

Fluorouracil plus oxaliplatin (L-OHP) (FOLFOX) plus bevacizumab (BV) therapy is commonly administered to patients with metastatic colorectal cancer. However, few reports have described L-OHP therapy in hemodialysis patients, and the efficacy and safety remain uncertain in this population. Here, we report three cases of hemodialysis patients with colorectal cancer who received a modified FOLFOX-6 (mFOLFOX-6, or FOLFOX plus folinic acid) plus BV regimen every 3 weeks. One patient, a 65-year-old man with chronic renal failure consequent to diabetic nephropathy, underwent hemodialysis 3 times/week. He exhibited a partial response after 7 cycles of mFOLFOX-6 plus BV, with the major adverse events of Grade 1 peripheral neuropathy and Grade 2 thrombocytopenia. He died of perforation-related septic shock. A 71-year-old man previously treated with bosutinib for chronic myelocytic leukemia received 9 cycles of mFOLFOX-6 plus BV and achieved stable disease. Chemotherapy was administered every 4 weeks, and the 5-fluorouracil dose was reduced after he developed Grade 4 neutropenia. A 71-year-old woman with chronic renal failure consequent to diabetic nephropathy underwent hemodialysis 3 times a week. She received 3 cycles of mFOLFOX-6 plus BV, but exhibited disease progression and developed Grade 4 neutropenia, which necessitated a reduced 5-fluorouracil dose. After completing FOLFOX therapy, she began second-line irinotecan/5-fluorouracil/leucovorin (FOLFIRI) plus BV therapy. In two cases, bone marrow suppression increased the difficulty of L-OHP dose escalation. We conclude that mFOLFOX-6 plus BV, with appropriate dose reduction, is acceptable for patients with chronic renal failure. Further data are needed to determine the adequate chemotherapy dose.
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PMID:Modified FOLFOX-6 Plus Bevacizumab Chemotherapy for Metastatic Colorectal Cancer in Patients Receiving Hemodialysis: A Report of Three Cases and Review of the Literature. 3157 55