Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. A rationale for high-dose methotrexate.

Methotrexate (MTX) is one of the most widely used drugs for the treatment of childhood acute lymphoblastic leukemia (ALL) and is commonly given in high doses. However, the rationale for high-dose MTX (HDMTX) has been challenged recently. To determine whether higher MTX polyglutamate (MTXPG) concentrations in ALL blasts translate into greater antileukemic effects, 150 children with newly diagnosed ALL were randomized to initial treatment with either HDMTX (1,000 mg/m2 intravenously over 24 h) or lower-dose MTX (30 mg/m2 by mouth every 6 h x 6). ALL blasts accumulated higher concentrations of MTXPG and long-chain MTXPG (MTXPGLC) after HDMTX (P < 0.00001). Of 101 patients evaluable for peripheral blast cytoreduction, MTXPG concentrations were higher in patients whose blast count decreased within 24 h (P = 0.005) and in those who had no detectable circulating blasts within 4 days (P = 0.004). The extent of inhibition of de novo purine synthesis in ALL blasts was significantly related to the blast concentration of MTXPGLC (IC95% = 483 pmol/10(9) blasts). The percentage of patients with 44-h MTXPGLC exceeding the IC95% was greater after HDMTX (81%) than LDMTX (46%, P < 0.0001). These data indicate that higher blast concentrations of MTXPG are associated with greater antileukemic effects, establishing a strong rationale for HD-MTX in the treatment of childhood ALL.

Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia.

High-dose methotrexate (HDMTX) is a component of most treatment protocols for childhood acute lymphoblastic leukemia (ALL), yet recent studies of receptor-mediated transport and saturable polyglutamylation have questioned its rationale. To investigate this in vivo, methotrexate and its active polyglutamated metabolites (MTX-PG) were measured in bone marrow blasts obtained from 101 children randomized to single-agent therapy with either HDMTX (1 g/m2 per 24 h i.v., n = 47) or low-dose MTX (LDMTX, 30 mg/m2 by mouth every 6 h x 6, n = 54), before remission induction therapy. Blast concentrations of total MTX-PGs (median 460 vs 1380 pmol/10(9) cells) and of long-chain MTX-glu4-6 were both significantly higher after HDMTX (P < 0.001). With either treatment, MTX-PGs were significantly higher in B-lineage blasts than in T-lineage blasts (LDMTX P = 0.001, HDMTX P = 0.03). In a multiple regression analysis of B-lineage ALL, blast MTX-PG was significantly related to MTX dose (or plasma MTX concentration), lymphoblast ploidy (hyperdiploid > nonhyperdiploid), and percentage S-phase. This is the first evidence that HDMTX achieves higher MTX-PG concentrations in ALL blasts in vivo, establishing a rationale for HDMTX in the treatment of childhood ALL, especially T-lineage or nonhyperdiploid B-lineage ALL, disease characteristics associated with a poor prognosis on conventional therapy.

Dextromethorphan and caffeine as probes for simultaneous determination of debrisoquin-oxidation and N-acetylation phenotypes in children.

The feasibility and reliability of simultaneously determining debrisoquin oxidation and N-acetylation phenotypes was assessed in children with use of two innocuous substrate probes given by mouth, 30 mg dextromethorphan (Pertussin ES) and 25 to 46 mg caffeine (Coca-Cola beverage). Twenty-six children and adolescents (aged 3 to 21 years) were studied three times, once with each substrate given alone and once with the two substrates given together. Urine was collected for 4 hours, and the molar urinary metabolic ratios for dextromethorphan:dextrorphan and for two caffeine metabolites (AFMU:1X) were determined by HPLC ultraviolet assays. The urinary metabolic ratios for both substrates were not significantly different when the substrates were given alone compared with when they were given together. There also was no difference in either the oxidation or acetylation phenotype assignments when the two substrates were given alone and when they were given together. No adverse effects were observed. We conclude that dextromethorphan and caffeine can be given together to simultaneously determine oxidation and acetylation phenotypes and can thereby provide an innocuous, noninvasive method for the assessment of polymorphic drug metabolism in various pediatric populations.

A review of one hundred forty-seven popliteal aneurysms with long-term follow-up.

A 20-year experience with a collected series of 147 popliteal aneurysm in 87 patients is reviewed; there were 84 male patients. Ages ranged from 42 to 90 years with a median age of 60.2. Bilateral aneurysms were found in 60 patients (68%). Ninety-eight extremities presented with symptoms, whereas 94 aneurysms had one or more preoperative complications. Sixty-six (45%) were thrombosed, 34 (23%) had embolized, and four (3%) had ruptured. Associated aneurysms were found in 55% of the total group and in 68% of those with bilateral popliteal aneurysms. Forty percent of all patients had abdominal aortic aneurysms, whereas 34% had femoral aneurysms and 25% had iliac aneurysms. Therapy included bypass grafting (99), observations (26), primary amputation (12), sympathectomy (3), and exploration only (7). In 32 limbs, grafts became occluded during the follow-up period. All except one of the occluded grafts were in patients with preoperative symptoms related to the aneurysm, and all but one primary form of therapy and 22 as a secondary procedure. All were associated with preoperative vascular ischemia or a complicated aneurysm. Complete, detailed, long-term follow-up of 1 to 14 years is reported for 65 patients. The overall follow-up averaged 44 months. Death rates were shown by life-table analysis to be significantly greater than rates among the general population. Complications of aneurysms were very common (64%) and when the occurred, 36% ended in amputation. Therefore, elective replacement of the aneurysm at the time of diagnosis is recommended.

Successful simultaneous renal transplantation and abdominal aortic aneurysmectomy.

At the time of related donor renal transplantation, a 49-year-old man with chronic glomerulinephritis was found to have a large fusiform aneurysm involving the internal and external iliac arteries, the abdominal aorta, and both common iliac arteries. Transplantation and abdominal aneurysmectomy using a standard Dacron bifurcation graft were successfully carried out. This patient has had no associated complications and is currently five years after transplantation and aneurysmectomy, with excellent renal function. It is believed that transplantation may now be offered to an older age group of patients with end-stage renal disease in whom atherosclerosis wll have developed as a natural process of aging.

Kinking of a Warren shunt as a cause of recurrent variceal hemorrhage.

Upper gastrointestinal hemorrhage after portal decompression requires appropriate endoscopic and radiologic evaluation for unrelated causes. Splenoportography may be more definitive than selective visceral angiography and in the present case showed a patent but kinked venovenous anastomosis with a high splenic pulp pressure. A mesocaval interposition shunt controlled the hemorrhage. Various technical factors responsible for anastomotic narrowing and kinking of the Warren shunt are briefly mentioned.

Deoxythioguanosine triphosphate impairs HIV replication: a new mechanism for an old drug.

Inhibition of HIV-1 reverse transcriptase (RT) and HIV protease are effective mechanisms for anti-retroviral agents, and the combined use of mechanistically different medications has markedly improved the treatment of HIV infected patients. The active metabolite of mercaptopurine and thioguanine (TG), deoxythioguanosine triphosphate, was shown to be incorporated into DNA by the polymerase function of HIV-1 RT and then to abrogate RNA cleavage by HIV-1 RNaseH. Treatment of human lymphocyte cultures with thioguanine produced substantial inhibition of HIV replication (IC(50)=0.035 microM, IC(95)=15.4 microM), with minimal toxicity to host lymphocytes (<10% at 15.4 microM TG, P<0.000005). Furthermore, low concentrations of TG and zidovudine were synergistic in inhibiting HIV replication in human lymphocytes (synergy volume=19 microM(2)%), without additive cytotoxicity to host lymphocytes. Thus, thiopurines are novel anti-retroviral agents that alter the DNA-RNA substrates for HIV RNaseH, thereby abrogating early stages of HIV replication.