levoleucovorin and Leukemia--Lymphoid

Topics: Administration, Oral; Animals; Biological Transport; Central Nervous System; Drug Resistance; Folic Acid; Folic Acid Antagonists; Gene Amplification; Head and Neck Neoplasms; Humans; Kinetics; Leucovorin; Leukemia, Lymphoid; Lung Neoplasms; Methotrexate; Neoplasms; Osteoma, Osteoid; Thymidylate Synthase; Tissue Distribution

Topics: Child; Drug Resistance; Folic Acid Antagonists; Humans; Leucovorin; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Methotrexate

Topics: Adult; Animals; Carboxypeptidases; Carcinoma 256, Walker; Carcinoma, Squamous Cell; Deoxyuridine; Diet; Drug Combinations; Drug Synergism; Folic Acid Antagonists; Humans; Leucovorin; Leukemia L1210; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Methotrexate; Mice; Rats; Tritium

Topics: Adult; Animals; Antibiotics, Antineoplastic; Antimetabolites; Antineoplastic Agents; Asparaginase; Child; Drug Combinations; Drug Interactions; Drug Synergism; Folic Acid Antagonists; Humans; Injections, Subcutaneous; Leucovorin; Leukemia L1210; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Methotrexate; Mice; Mice, Inbred Strains; Nitrogen Mustard Compounds; Prednisone; Time Factors

Thirty-eight adults with acute lymphocytic leukemia (ALL), 24 previously untreated and 14 previously treated, were entered into a study in which sequential, moderate-dose methotrexate and asparaginase were added to vincristine and dexamethasone (MOAD) for remission induction therapy. Eighteen of 24 previously untreated patients (75%) and 11 of 4 previously treated patients (79%) achieved a complete remission (CR). Once in CR, patients were given remission continuation therapy, which included intravenous high-dose methotrexate that was used without prophylactic cranial irradiation and without intrathecal methotrexate because of its potential activity alone as prophylaxis against central nervous system (CNS) leukemia. The median duration of CR was 11.1 mo (range 0.7-55.9+) and median survival 17.0 mo (range 0.4-55.9+) for the 24 previously untreated patients. The median duration of CR was 7.5 mo (range 1.9-55.3+) for the 14 previously treated patients. Only 2 of 24 previously untreated patients (8.3%) developed CNS leukemia at 3.3 and 42.7 mo from start of MOAD. None of the previously treated patients developed CNS leukemia as the initial site of relapse. MOAD is useful as induction therapy for previously untreated adults with ALL, as well as for previously treated patients, and is superior to other regimens that we have used for the treatment of adult ALL.

Topics: Adolescent; Adult; Antineoplastic Agents; Asparaginase; Central Nervous System Diseases; Clinical Trials as Topic; Dexamethasone; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leucovorin; Leukemia, Lymphoid; Male; Methotrexate; Middle Aged; Vincristine

Gonadal and other types of leukemic "sanctuaries" are probably the main causes of hematological relapse in the treatment of acute leukemia. The introduction of high-dose Methotrexate (HDM) in a consolidation phase is based on theoretical considerations and the use of HDM in malignant tumors. Three courses of Methotrexate, 500 mg/sq.m. at 3-weekly intervals, has been used as part of a consolidation therapy in Norway during the last two years to 59 children with ALL and one with AML. One child died following HDM. Postmortem examination showed that she was not in complete remission at the time. Among 154 courses of HDM in the 60 patients were eight severe reactions, including six cases of allergic-toxic skin reactions. Two patients developed a Stevens-Johnson's like syndrome. Stomatitis was common in those with toxic reactions. The risk of HDM in patients who are not in complete remission is stressed and the use of rescue therapy with two doses of Leukovorin instead of one is recommended. Forty of forty-two children in 1st complete remission have been in sustained primary remission for 4 to 28 months. Two of these 40 children died after about a year from infections. Only two patients so far have relapsed.

Topics: Asparaginase; Child; Clinical Trials as Topic; Dexamethasone; Drug Eruptions; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Infant; Leucovorin; Leukemia, Lymphoid; Mercaptopurine; Methotrexate; Stevens-Johnson Syndrome; Stomatitis; Vincristine

Six adults with refractory acute lymphocytic leukemia (ALL) were treated with high-dose methotrexate, citrovorum factor, and vincristine. All patients had previously received extensive treatment with standard therapeutic agents, including vincristine, and all but one had received prior methotrexate. Two patients achieved complete remission and one achieved partial remission. Responses were seen at 3--6 gm/m2 of methotrexate. The durations of remission were 7--10 weeks. High-dose methotrexate with citrovorum factor is effective in the treatment of advanced ALL and should be considered for inclusion in initial combination chemotherapeutic regimens for adult ALL.

Topics: Adult; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Leucovorin; Leukemia, Lymphoid; Methotrexate; Middle Aged; Remission, Spontaneous; Time Factors; Vincristine

Cytocidal activity of a drug is dependent on both drug dosage and duration of exposure. In contrast to the 'conventional" 6-h infusion and in an attempto to improve its efficacy, the high-dose methotrexate therapeutic regimen was given over a 24-h period with 10% of the dose administered in the first hour. Citrovorum factor was initiated at hour 24 and continued for 72 h. Treatment was administered every 2-3 weeks. 57 infusions were performed in twelve patients aged 7-20 years (six with osteogenic sarcoma and six with acute lymphoblastic leukemia). Determinations of serum methotrexate levels revealed that the levels were dependent on the dose. Levels assayed at 24 h revealed the following results: 4.4 +/- 1.4 x 10(-5) molar with 4.5 g/m(2), 2.04 +/- 0.34 x 10(-4) molar with 7.5 g/m(2) and 4.59 +/- 0.80 x 10(-4) molar with 12.5 g/m(2). Major toxicity was myelosuppression in 12 of 57 patients. There were no responses. The study demonstrates that 24-h infusions of high-dose methotrexate can be tolerated every 2-3 weeks in patients without bone marrow involvement and levels of at least 10(-4) molar can be maintained during the infusion.

Topics: Adolescent; Adult; Child; Clinical Trials as Topic; Humans; Infusions, Parenteral; Kinetics; Leucovorin; Leukemia, Lymphoid; Methotrexate; Osteosarcoma; Time Factors

The relationship between changes in the bone marrow labeling index and the patient's subsequent response to cycle-specific agents was studied by the South-eastern Cancer Study Group in adults with acute leukemia. Ninety-eight patients were randomized to one of two treatment regimens. Schedule 1 consisted of a single intravenous (i.v.) push of cytosine arabinoside followed in 48 hours by a large dose of oral methotrexate distributed over 24 hours and i.v. vincristine. Leucovorin rescue was employed to control the toxic effects of the high dose methotrexate and the cycle was repeated every 7 days. Schedule 2 differed only in that there were three daily injections of cytosine arabinoside preceding vincristine and methotrexate injections and each cycle was given every 10 days. Cell kinetic studies were performed in 30 patients and revealed that the majority of patients who had a response to therapy had some increase in the marrow labeling index 48 hours after cytosine arabinoside injection. In general, those patients who had no response to therapy had little change. There was no significant difference between schedules in the ability to induce an increase in labeling index 48 hours after cytosine arabinoside or in the increment achieved by the responders. However, there was a significant difference in the response rate seen with these schedules. Schedule 1 achieved only a 24% remission rate in acute nonlymphocytic leukemia (ANLL) while schedule 2 was associated with a 52% remission rate. In acute lymphoblastic leukemia (ALL) both schedules induced a 60% remission rate while none of the four patients with blast crisis of chronic granulocytic leukemia (CGL) responded. Analysis of the characteristics associated with remission revealed that more females achieved a remission than males and that the presence of pretreatment infection was the greatest contributing cause of early death and thus severely limited the ability to achieve a remission. As opposed to the current regimens used in ANLL, schedule 2 did not require significant bone marrow hypoplasia (as judged by the degree of hematological toxicity) to achieve a remission and there was no decrease in response seen with increasing age. The data suggest that increased efficiency of cycle-specific, antitumor agents may occur by increasing the proportion of human leukemic cells in DNA synthesis.

Topics: Adult; Age Factors; Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Cell Division; Cytarabine; Female; Humans; Leucovorin; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Male; Methotrexate; Middle Aged; Remission, Spontaneous; Sex Factors; Vincristine

Topics: Bone Marrow; Bone Marrow Cells; Cytarabine; Daunorubicin; DNA, Neoplasm; Drug Therapy, Combination; Humans; Kinetics; Leucovorin; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Methotrexate; Mitotic Index; Thioguanine

One hundred and ninety-one cases of acute lymphoblastic leukaemia were entered in a trial in which, for five months, all received cytotoxic therapy with prednisolone, vincristine, mercaptopurine, L-asparaginase, and methotrexate (the latter in high dosage followed by folinic acid). Patients were then randomized to receive immunotherapy (B.C.G.), twice-weekly methotrexate, or no further treatment.One hundred and seventy-seven patients (93%) achieved full remission and at the time of analysis, 26 months from the beginning of the trial, 143 were still alive, including 70 in their first remission. Median "post-intensive" remission lengths were 17 weeks (no treatment), 27 weeks (B.C.G.), and 52 weeks (methotrexate). The prolongation of remission by methotrexate was most evident in those patients with low initial white cell counts. B.C.G. seemed to cause lymphocytosis but was without other conspicuous effect. The incidence of toxic reactions is reported, including an unusually low rate of anaphylaxis with L-asparaginase.These preliminary results are discussed and compared with those of similar trials.

Topics: Acute Disease; Adolescent; Adult; Anaphylaxis; Asparaginase; BCG Vaccine; Child; Child, Preschool; Clinical Trials as Topic; Humans; Infant; Leucovorin; Leukemia, Lymphoid; Leukocyte Count; Lymphocytes; Lymphocytosis; Mercaptopurine; Methotrexate; Prednisolone; Remission, Spontaneous; Skin Tests; Tuberculin Test; Vincristine

Topics: Child; Dose-Response Relationship, Drug; Humans; Leucovorin; Leukemia, Lymphoid; Methotrexate; Recurrence

Increased response rates in studies of patients with colon cancer have indicated that the cytotoxic effects of fluorouracil (5-FU) are potentiated by leucovorin (LV) and by methotrexate (MTX). However, preliminary studies using a sequential combination of MTX, LV, and 5-FU showed no additional potentiation.. We hypothesized that the lack of additional cell kill with this combination could be due to competition of LV with MTX for cellular uptake and reduced folate polyglutamylation. We have tested this possibility by comparing the cytotoxicity of drug combinations containing MTX with that of drug combinations containing trimetrexate (TMTX), an antifolate that does not compete with LV for uptake or polyglutamylation.. Human lymphocytic leukemia CCRF-CEM cells were exposed to MTX or TMTX for 24 hours and to 5-FU during the last 4 hours of antifolate exposure. LV was administered 30 minutes before 5-FU.. After 20 hours of exposure to TMTX or MTX, intracellular levels of phosphoribosyl pyrophosphate were elevated to a similar degree, and these levels did not decrease after a 30-minute exposure to LV. No additional cell kill was observed when LV was added to the MTX/5-FU combination, but cytotoxicity was enhanced when LV was added to the TMTX/5-FU combination.. This study supports the hypothesis that the lack of additional cell kill when high-dose LV is added to the MTX/5-FU combination may be due to competition of MTX with LV for cellular uptake and/or competition of MTX or its polyglutamates with polyglutamylation of reduced folates. Inasmuch as TMTX does not compete with LV and reduced folates for uptake and polyglutamylation, the synergy obtained with the combination of TMTX plus 5-FU and high-dose LV further supports this hypothesis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Fluorouracil; Humans; Leucovorin; Leukemia, Lymphoid; Methotrexate; Phosphoribosyl Pyrophosphate; Trimetrexate; Tumor Cells, Cultured

Leucovorin, a mixture of the natural (6S) and unnatural (6R) diastereomers of 5-formyltetrahydrofolate, is administered clinically to enhance the antitumor activity of 5-fluorouracil. Because the 6R isomer persists at high concentrations in plasma for prolonged periods after iv leucovorin administration (J Clin Oncol 4:685-696, 1986), we have examined it to ascertain whether the 6R isomer could interfere with the cellular effects of the 6S isomer. The 6R compound had a poorer uptake into human CCRF-CEM lymphoblastic cells than the 6S compound, but the 6R compound could competitively inhibit the uptake of the natural isomer as determined in defined buffers. However, the 6R compound failed to interfere with cell growth support and enhancement of 5-fluorouracil cytotoxicity by the 6S isomer in CCRF-CEM cells in tissue culture experiments at concentrations up to 1 mM. Thus, the unnatural isomer of 5-formyltetrahydrofolate present in leucovorin preparations seems unlikely to have clinically relevant consequences.

Topics: Cell Division; Drug Synergism; Fluorouracil; Humans; Leucovorin; Leukemia, Lymphoid; Stereoisomerism; Tumor Cells, Cultured

The pharmacokinetics of 8 g/m2 methotrexate (MTX) was compared following short (6 h) and long (24 h) infusions of the drug to 11 children with osteogenic sarcoma (OS; 42 infusion) and 28 children with acute lymphoblastic leukemia (ALL: 118 infusions), respectively. No difference was observed in the first-phase half-life, in systemic clearance or in the volume of distribution of the drug (P greater than 0.05). The concentration of MTX at the end of the infusion was approximately 4-fold higher when the drug was given over only 6 h. However, patients receiving 24-h infusions had approximately 9-fold higher levels by 24 h after the beginning of the infusion. The area under the data curve from start of the MTX infusion until the beginning of folinic acid rescue administration was significantly higher in patients with osteogenic sarcoma (6-h infusions), while the area under the log-data curve was significantly longer in the ALL group (24-h infusions) for the same period. The latter parameter is considered to be characteristic for the concentration-time-effect relationship. The longer duration of MTX administration (with delayed rescue) is thought to be more beneficial from the pharmacokinetic aspect. Patients with osteogenic sarcoma had significantly lower concentrations of MTX at the end of their last treatment with MTX than at the end of the first infusion. Patients developing MTX toxicity had shorter half-lives of MTX in the beta phase. It is suggested that cisplatin induced tubular loss of MTX and folinic acid is responsible for these observations. A wider application of clinical pharmacologic findings in the practice of the administration of cytostatics is indicated.

Topics: Child; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Leucovorin; Leukemia, Lymphoid; Male; Methotrexate; Osteosarcoma

The inhibitory effects of leucovorin (LV) combined with 5-fluorouracil (FUra) or floxuridine (FdUrd) on growth of human T-lymphoblast leukemia cells (CCRF-CEM) were determined as a function of time, dose, and sequence of exposure. Exposure of CCRF-CEM cells in exponential growth to LV (1-100 microM) for 4 hours and to FUra (100 microM) or FdUrd (0.5 microM) during the last 2 hours resulted in synergistic inhibitory effects on cell growth. Synergism was dependent on LV dose (100 greater than 10 greater than 1 microM) and did not occur at 0.1 microM. No clear dependence of synergy on sequence was observed with FUra and LV combinations. With LV and FdUrd combinations, synergism was dependent on sequence of exposure (LV + FdUrd and LV----FdUrd were synergistic, but FdUrd----LV was not). Thymidine (0.1 microM), added after drug treatment, substantially rescued CCRF-CEM cells from LV----FUra cytotoxicity. Concomitant hypoxanthine (100 microM) only partially protected CCRF-CEM cells from the toxicity of this combination. These results are consistent with the hypothesis that the mechanism by which LV potentiates fluoropyrimidine cytotoxicity is the enhancement of complex formation between thymidylate synthase and 5-fluorodeoxyuridylate, presumably as a consequence of an increase of intracellular levels of 5,10-methylenetetrahydrofolate generated from LV. Also, enhanced stability of this complex in the presence of high levels of the folate coenzyme may contribute to the synergy observed. These data also provide a rationale for use of FUra and especially FdUrd and LV in the treatment of lymphoid malignancies in man.

Topics: Cell Division; Cell Line; Cell Survival; Drug Synergism; Floxuridine; Fluorouracil; Humans; Leucovorin; Leukemia, Lymphoid; T-Lymphocytes; Thymidine

Children with Down syndrome and acute lymphocytic leukemia (ALL) have poor tolerance to antineoplastic drugs, including methotrexate (MTX). We evaluated MTX pharmacokinetics and toxicity in five patients with Down syndrome and ALL who had received multiple high doses of MTX (1 g/m2). Three control patients without Down syndrome were matched to each case according to sex, race, age, and initial leukocyte count. Median MTX plasma concentrations, measured 42 hours after infusion, were significantly higher in patients with Down syndrome versus control patients (average 0.47 vs 0.24 mumol/L, respectively, P = 0.03). When a 42-hour MTX concentration of 0.5 mumol/L was used to identify patients at risk for toxicity, more courses were considered at high risk for toxicity among patients with Down syndrome (31 of 62, 50%) than in control patients (13 of 214, 6.1%, P less than 0.0001). The average MTX clearance was 64.1 mL/min/m2 in Down syndrome vs an average control value of 80.6 mL/min/m2 (P = 0.13). Toxicity after each high-dose MTX course was graded according to standardized criteria. Grades 2 through 4 gastrointestinal toxicity and grades 3 and 4 hematologic toxicity occurred more frequently in the patients with Down syndrome (36% and 13.4% of courses, respectively) vs the control patients (3.6% and 0.9% respectively, P less than 0.0001 for both). This higher frequency of toxicity occurred despite higher doses and prolonged duration of leucovorin given to all patients with Down syndrome. We conclude that altered MTX pharmacokinetics may contribute to the higher incidence of MTX-induced toxicity seen in patients with Down syndrome.

Topics: Adolescent; Child; Child, Preschool; Down Syndrome; Humans; Leucovorin; Leukemia, Lymphoid; Methotrexate

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infant; Leucovorin; Leukemia, Lymphoid; Male; Methotrexate; Nervous System Neoplasms; Prednisolone; Prognosis; Time Factors; Vincristine

Malignant lymphomas, Burkitt's type, and B-ALL are rarely encountered in adult patients. Rapid initial responses are usually followed by early relapse and death. In a pilot study four adult patients, two presenting with B-ALL, were successfully treated with an aggressive protocol developed by the BFM study group for childhood lymphomas of B-type. Rapid clearance of tumor masses was achieved in all patients; no relapse occurred during an observation period ranging from 19-33 months of complete remission.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Burkitt Lymphoma; Cyclophosphamide; Cytarabine; Doxorubicin; Female; Humans; Infusions, Parenteral; Injections, Spinal; Leucovorin; Leukemia, Lymphoid; Male; Methotrexate; Middle Aged; Prednisolone; Teniposide

Nine children in remission from hematologic malignancies received infusion of methotrexate (2,000-6,000 mg/m2) for 24 hours followed by citrovorum factor rescue (beginning 36 hours after the start of MTX infusion). Marrow cell kinetics of these patients were studied by flow cytometry with computer analysis. An accumulation of cells in the early-mid S phase and a decrease of cells in the G2/M phase were observed at 24-48 hours after exposure to MTX except for one infant case. By the 6th day after MTX infusion, the DNA histograms returned to pretreatment values. No kinetic perturbation was observed in the marrow cells of a 1-year, 5-month-old infant who showed high plasma MTX concentrations over the median values of the other eight children. These results show that profound but reversible changes are observed in marrow cell kinetics in most patients treated with our current high-dose MTX therapy with CF rescue and that a repeated course would be possible without cumulative marrow toxicity. More studies in young infants are needed to clarify the relationship between age and marrow toxicity of MTX so that treatment schedules with a higher therapeutic index can be designed.

Topics: Bone Marrow; Cell Cycle; Child; Child, Preschool; DNA, Neoplasm; Drug Administration Schedule; Drug Therapy, Combination; Female; Flow Cytometry; Humans; Infant; Infusions, Parenteral; Injections, Intravenous; Leucovorin; Leukemia, Lymphoid; Lymphoma; Male; Methotrexate

A 20-year-old Caucasian male with acute leukemia developed acute organic brain failure after treatment with intensive cytostatic chemotherapy. His delirious state was successfully controlled by neuroleptic therapy with intravenous haloperidol and lorazepam. We propose that this regimen may be useful in treating organic brain failure following intensive chemotherapy for malignant disease.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Antipsychotic Agents; Asparaginase; Cytarabine; Humans; Leucovorin; Leukemia, Lymphoid; Male; Methotrexate; Substance-Related Disorders

Twenty-nine children with acute lymphocytic leukemia were given 24-hr infusions of intermediate-dose methotrexate (MTX, 1000 mg/m2) with and without intrathecal (IT) MTX (12 mg/m2), followed by leucovorin rescue. There was substantial interpatient variability in MTX systemic clearance (98.3 +/- 51 ml/min/m2), inducing total steady-state serum MTX concentrations ranging from 5.4 to 33.7 microM. The cerebrospinal fluid (CSF) concentration at the end of the infusion was 0.27 (+/- 0.1) microM when no IT-MTX was given and correlated with total steady-state (24-hr) serum concentration of MTX. By stepwise regression, the CSF MTX concentration correlated better with the nonprotein bound (free) steady-state serum MTX concentration (r = 0.66, P less than 0.01) than with total steady-state serum MTX concentration. Mean CSF: serum MTX concentration ratio was 0.023 (+/- 0.04) when no IT MTX was given. When an IT MTX dose (12 mg/m2) was given at the start of the MTX infusion, the steady-state CSF MTX concentration was 1.1 (+/- 0.4) microM, leading to a mean CSF: serum ratio of 0.073 (+/- 0.05). Despite 7-hydroxy-MTX serum concentrations exceeding MTX concentrations immediately after infusion, 7-hydroxy-MTX was not detectable in CSF of most patients (21 of 29), and was less than 50% of the concurrent MTX concentration when detectable. These data establish the substantial interpatient variability in CSF distribution of MTX after intermediate-dose MTX infusions and establish a significant correlation between steady-state free concentration of MTX in serum and CSF MTX concentration.

Topics: Child; Child, Preschool; Humans; Infusions, Parenteral; Kinetics; Leucovorin; Leukemia, Lymphoid; Methotrexate

Methotrexate (MTX) shows consistent cytotoxicity for melanoma cells in vitro but it is ineffective in clinical use at equivalent concentrations in vivo. This apparent paradox has been investigated by cell culture techniques and results quantified by cell number. In an in vitro model of high dose MTX therapy followed by leucovorin rescue (HD-MTX-LCR) there was survival of both melanoma and choriocarcinoma cell lines but not of an acute lymphocytic leukaemia cell line. The 70H metabolite of MTX was identified by HPLC in plasma samples of melanoma patients treated by HD-MTX-LCR, in which MTX concentrations approximately 10(-5) M were maintained for 24 h. However, metabolism per se is unlikely to account for the lack of response to MTX clinically. In vitro 70H MTX (10(-7) - 10(-6) M) was two orders of magnitude less cytotoxic for melanoma than MTX (10(-9) - 10(-8) M). The cellular accumulation of [3H]-MTX, using a rapid gradient centrifuge technique for separation of melanoma cells from medium, was reduced in the presence of 70H-MTX. The results suggest that reduced cellular uptake of MTX combined with biochemical rescue of tumour cells may partially explain the paradoxical lack of clinical response of melanoma to the drug.

Topics: Animals; Cell Count; Cell Line; Cell Survival; Choriocarcinoma; Humans; Leucovorin; Leukemia, Lymphoid; Male; Melanoma; Methotrexate; Mice

Current therapy for childhood ALL is effective and certainly much better than what was available 10 years ago. According to our protocol 721, 745, and 765 studies, between 40% and 60% of children with ALL are now on long-term survival, even after discontinuation of the therapy for several years. However, results are not nearly as good in patients who have identifiable poor risk features. A review of 162 patients with ALL was undertaken to determine the important factors, other than therapy, influencing survival. Childhood ALL can be divided into two groups according to major prognostic factors such as age and initial leukocyte counts; Group I -standard risk group and Group II -high risk group. To minimize side effects while trying to improve further efficacy of therapy and to prevent late relapse, our new protocol 811 has been initiated for standard risk patients of ALL. The more aggressive use of current agents such as methotrexate and adriamycin to prevent early relapse has been applied for high risk patients of ALL. The preliminary results of protocol 811 showed that early intensification with high-dose methotrexate and adriamycin seemed to prolong the remission duration of high risk ALL, but further long follow-up study is needed. With considerable progress being made toward the cure of childhood leukemias, the issue of late effects assumes increasing importance. The next generation of treatment studies, in addition to further attempts at improving the proportion of survivors, will need to develop strategies aimed at clearly defining and minimizing these late sequelae.

Topics: Adolescent; Age Factors; Child; Child, Preschool; Doxorubicin; Drug Administration Schedule; Female; Humans; Leucovorin; Leukemia, Lymphoid; Male; Methotrexate; Prognosis; Time Factors

The clinical course of a two-year-old girl with acute lymphocytic leukemia (ALL) who inadvertently received intrathecal vincristine is presented. Despite aggressive treatment with parenteral folinic acid and extensive central nervous system washout, the outcome was fatal. The pharmacologic aspects of vincristine and folinic acid that may explain why treatment was unsuccessful, are reviewed.

Topics: Central Nervous System; Female; Humans; Infant; Injections, Spinal; Leucovorin; Leukemia, Lymphoid; Medication Errors; Vincristine

Topics: Child; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Humans; Leucovorin; Leukemia, Lymphoid; Methotrexate

A human acute lymphoblastic T-cell line, MOLT-3, was fed with Roswell Park Memorial Institute Medium 1640-10% fetal bovine serum-antibiotics, containing increasing concentrations of methotrexate (MTX). After 10 months of feeding, the cells became resistant to 10(-7) M MTX; resistance was not reversed when the cells were placed in the original MTX-free medium. At 10(-7) M MTX, the concentration which produced complete inhibition of the parent MOLT-3 cell growth, the resistant cells were not inhibited at all. On a 50% inhibitory concentration basis, the resistant cells were approximately 30-fold more resistant to MTX. The parent MOLT-3 and the resistant line had the same doubling time of approximately 36 hr. There were no differences in light microscopic morphology. MOLT-3 produced loose colonies on 0.5% agar enriched with fetal bovine serum, whereas the colonies of the resistant line were tightly packed. The development of resistance was accompanied by a 4- to 5-fold decrease in [3H]MTX transport (MOLT-3/MTXt). Kinetic analysis of MTX uptake showed that the resistant subline did not have an altered Km for MTX (6.6 microM) but had a decreased Vmax of about 20% of the parent cell line. These data suggest that either the number of folate transport sites or the turnover rate of these sites has been reduced in the MTX-resistant cell line. Dihydrofolate reductase was only minimally elevated in the resistant cell line. The MTX-resistant cell line was cross-resistant to dichloromethotrexate. The sensitivity of the resistant line to the substituted 2,4-diaminoquinazoline and pyrimidine compounds, 2,4-diamino-5-methyl-6-[(3',4',5'-trimethoxyanilino) methyl] quinazoline (JB-11) and 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine, increased more than 3-fold. While leucovorin equally reversed the MTX effects on the parent and resistant cells, leucovorin reversal of 2,4-diamino-5-methyl-6-[(3',4',5'-trimethoxyanilino) methyl] quinazoline and 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine effects was limited only to the parent cell line. 2,4-diamino-5-methyl-6-[(3',4',5'-trimethoxyanilino) methyl] quinazoline or 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine plus leucovorin might prove to be unique in treating patients with acute lymphoblastic leukemia when the leukemic cells develop transport resistance to MTX.

Topics: Animals; Biological Transport; Cells, Cultured; Drug Interactions; Drug Resistance; Folic Acid Antagonists; Humans; Kinetics; Leucovorin; Leukemia, Experimental; Leukemia, Lymphoid; Methotrexate; Quinazolines; Tetrahydrofolate Dehydrogenase

Subcutaneous cerebrospinal fluid reservoirs (Ommaya) were placed in 27 children and adolescents with acute lymphoblastic leukemia. Eleven of the reservoirs were used for administration of preventive central nervous system therapy and the remaining 16 reservoirs were used in the management of overt meningeal leukemia. Seven of the 11 patients treated prophylactically had recurrence of leukemia. The first site of recurrence was the central nervous system in three (42%) cases. Four of the 16 patients with reservoirs placed for the treatment of overt meningeal leukemia have not had recurrent disease. Of the 12 patients who relapsed, the site of first recurrence was the central nervous system in five cases. The incidence of major complications was 26%.

Topics: Adolescent; Antineoplastic Agents; Asparaginase; Cerebral Ventricles; Cerebrospinal Fluid; Child; Cytarabine; Dexamethasone; Drainage; Drug Therapy, Combination; Humans; Infant; Leucovorin; Leukemia, Lymphoid; Meningeal Neoplasms; Methotrexate; Skull

Trimethoprim-Sulfamethoxazole (TMP-SMZ) is a fixed combination of antibiotics which is widely used for prophylaxis and treatment of infections in patients undergoing cancer chemotherapy. TMP has been reported to inhibit growth of haemopoietic stem cells in vitro. If TMP-SMZ inhibits leukaemic cell growth, it could interfere with antileukaemic treatment, especially with S phase specific agents. TMP-SMZ at a concentration of 10 micrograms/ml (TMP) produced 50% inhibition of incorporation of 3H-deoxyuridine in DNA of L1210 and human lymphoblastic leukaemia cell. TMP-SMZ (1 g/ml TMP) produced 30% prolongation of doubling time of L1210 in vitro. Pure TMP (10 micrograms/ml) but not SMZ (50 micrograms/ml) produced the same effect as TMP-SMZ. Cell inhibitory effects could be completely reversed by folinic acid. These findings suggest that TMP produces some degree of inhibition of dihydrofolic acid reductase in mammalian cells and can potentially influence the effects of chemotherapy on tumour and/or host cells.

Topics: Animals; Cell Survival; Cells, Cultured; Child; Deoxyuridine; Dose-Response Relationship, Drug; Humans; Leucovorin; Leukemia L1210; Leukemia, Lymphoid; Mice; Sulfamethoxazole; Trimethoprim

Topics: Antineoplastic Agents; Brain Neoplasms; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Infant; Injections, Spinal; Leucovorin; Leukemia, Lymphoid; Male; Methotrexate; Neoplasm Recurrence, Local; Norway; Pilot Projects

Topics: Adrenal Cortex Hormones; Brain Diseases; Child; Child, Preschool; Humans; Leucovorin; Leukemia, Lymphoid; Male; Methotrexate

Topics: Cell Line; Cell Survival; Cells, Cultured; Colony-Forming Units Assay; Daunorubicin; Hematopoietic Stem Cells; Humans; Hydrocortisone; Leucovorin; Leukemia, Lymphoid; Methotrexate; Vincristine

The liquid-chromatographic measurement of 5-methyltetrahydrofolate in biological fluids is described. The sensitivity of the spectrophotofluorometric detector used allows direct evaluation of basal concentrations of the compound in plasma. Because it is resolved from the other common folates and from methotrexate, the procedure is suitable for monitoring it in plasma of patients receiving high-dose therapy with methotrexate.

Topics: Adult; Animals; Chromatography, High Pressure Liquid; Dogs; Folic Acid; Humans; Leucovorin; Leukemia, Lymphoid; Lymphoma; Male; Middle Aged; Spectrophotometry, Ultraviolet; Tetrahydrofolates; Time Factors

Serious complications can follow treatment with intermediate dose methotrexate of acute lymphoblastic leukemia in childhood. Toxicity has been shown to be correlated to plasma methotrexate concentrations. During intravenous infusions of methotrexate (500 mg/m2) the mean concentrations achieved 1 to 41/2 hours after the start of infusion were 1.3 X 10(-7) mol/l in cerebrospinal fluid and 1.7 X 10(-5) mol/l in plasma. At 72 hours after start of methotrexate infusion, plasma methotrexate concentrations were significantly higher in cases with symptoms of toxicity. In all the children who developed toxic symptoms 72-hour plasma methotrexate concentration was above 1 X 10(-7) mol/l. Assuming that leucovorin is given 48 hours after the start of methotrexate infusion, 72-hour plasma methotrexate is suitable for detection of patients at risk for toxicity. In children treated with intermediate dose methotrexate we therefore recommend estimating plasma methotrexate concentration 72 hours after the start of infusion, and instituting supplementary leucovorin when plasma methotrexate concentration exceeds 1 X 10(-7) mol/l.

Topics: Brain Neoplasms; Child; Humans; Leucovorin; Leukemia, Lymphoid; Methotrexate

The rationale for and the clinical use of regimens that utilize methotrexate (MTX) in high dose (greater than 500 mg/m2) are reviewed. Advantages of high pulse doses are (a) increased cell kill; (b) prevention or delay of resistance; (c) penetration into the cerebrospinal fluid (CSF); and (d) relative lack of toxicity, if used with appropriate monitoring and patient surveillance. Disadvantages are its cost and the cost of patient followup required. Some examples of its use in combination illustrate the point that antagonistic as well as synergistic antitumor or antinormal cell effects can result, depending upon the sequence of administration of MTX and another drug.

Topics: Animals; Asparaginase; Brain Diseases; Child, Preschool; Cisplatin; Cytarabine; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Fluorouracil; Humans; Infant; Injections, Spinal; Leucovorin; Leukemia L1210; Leukemia, Lymphoid; Methotrexate; Mice

High dose methotrexate followed by citrovorum factor reversal has been utilized in twenty-six patients with advanced cancer. Four of 10 patients with head and neck cancer had an objective response. One of 7 patients with metastatic osteosarcoma to the lungs had stabilization with twenty treatments over 23 months. One patient with acute lymphocytic leukemia developed marrow aplasia but did not attain remission. The regimen was well tolerated when meticulous attention was paid to hydration, urine alkalinization, renal function and third space fluid accumulation. Life-threatening or lethal toxicity was encountered when these phenomena were not scrupulously observed.

Topics: Adolescent; Adult; Aged; Female; Head and Neck Neoplasms; Humans; Leucovorin; Leukemia, Lymphoid; Male; Methotrexate; Middle Aged; Neoplasms; Osteosarcoma

Topics: Adolescent; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Kinetics; Leucovorin; Leukemia, Lymphoid; Lymphoma; Male; Methotrexate

Topics: Animals; Antimetabolites; Biological Transport, Active; Cell Line; Cell Membrane; Folic Acid; Humans; Kinetics; Leucovorin; Leukemia, Experimental; Leukemia, Lymphoid; Lymphocytes; Methotrexate; Temperature

A rapid propidium iodide staining method was used for analysis of single-cell suspensions of bone marrow and tumor biopsies by flow microfluorometry. With this technique, information on the proliferative status of target tissues can be obtained within 10 min of sample removal. DNA histograms and labeling index of sequential bone marrow biopsies from a patient with Stage IV diffuse lymphocytic leukemia and treated with 1-beta-D-arabinofuranosylcytosine infusion showed pronounced reduction in the percentage of cycling cells. In contrast, sequential tumor biopsies from a melanoma patient on methotrexate-citrovorum factor rescue therapy showed no changes. In sequential bone marrow biopsies of 3 patients on high-dose methotrexate-citrovorum factor rescue, initial accumulation of cells in G1-S (Day 1) was followed by a significant proliferative response (Days 4 to 7) and return to pretherapy values. In contrast, no recovery similar to that of the bone marrow was seen in tumor cells.

Topics: Antineoplastic Agents; Bone Marrow Cells; Cell Division; Cytarabine; Ethidium; Fluorometry; Humans; Leucovorin; Leukemia, Lymphoid; Melanoma; Methotrexate; Neoplasms; Staining and Labeling

Topics: Adult; Bone Marrow; Bone Marrow Cells; Child; Cytarabine; Deoxyuridine; DNA; Drug Administration Schedule; Female; Humans; In Vitro Techniques; Leucovorin; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Mitosis; Thymidine; Thymine

Topics: Cell Division; Cell Line; Deoxycytidine; Deoxyuridine; DNA, Neoplasm; Floxuridine; Folic Acid Antagonists; Humans; Hypoxanthines; Leucovorin; Leukemia, Lymphoid; Methotrexate; Purines; Thymidine

Topics: Animals; Biological Transport; Carbon Radioisotopes; Cell Line; Chlorobenzenes; Diamines; Kinetics; Leucovorin; Leukemia, Lymphoid; Methotrexate; Mice; Pyrimethamine; Pyrimidines

Topics: Biological Transport; Cell Line; Cell Survival; Drug Resistance; Leucovorin; Leukemia, Lymphoid; Lymphocytes; Methotrexate; Pyrimethamine

Topics: Animals; Antineoplastic Agents; Biological Transport; Cell Line; Chlorobenzenes; Drug Resistance; Kinetics; Leucovorin; Leukemia, Lymphoid; Lymphocytes; Methotrexate; Mice; Pyrimidines; Temperature

Topics: Brain Diseases; Central Nervous System; Child; Folic Acid; Humans; Leucovorin; Leukemia, Lymphoid; Methotrexate

Topics: Adolescent; Adult; Bone Marrow; Bone Marrow Cells; Cell Biology; Cell Survival; Child; DNA, Neoplasm; Humans; In Vitro Techniques; Leucovorin; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Leukocytes; Methotrexate; Purines; Remission, Spontaneous; Thymidine; Tritium

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Cyclophosphamide; Cytarabine; Evaluation Studies as Topic; Female; Humans; Leucovorin; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Remission, Spontaneous; Time Factors

Topics: Adolescent; Adult; Age Factors; Aged; Amantadine; Asparaginase; BCG Vaccine; Child; Child, Preschool; Cytarabine; Humans; Hydrocortisone; Immunity, Active; Immunization, Passive; Immunotherapy; Infant; Leucovorin; Leukemia, Lymphoid; Mercaptopurine; Methotrexate; Middle Aged; Prednisone; Radiotherapy, High-Energy; Remission, Spontaneous; Vincristine

Topics: Antidotes; Female; Hodgkin Disease; Humans; Leucovorin; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Neoplasms

Topics: Breast Neoplasms; Choriocarcinoma; Female; Head; Head and Neck Neoplasms; Humans; Leucovorin; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Methotrexate; Neoplasm Metastasis; Neoplasms; Ovarian Neoplasms; Pregnancy; Remission, Spontaneous; Uterine Cervical Neoplasms

Topics: Cell Line; Cells, Cultured; Child; Deoxyuridine; Humans; In Vitro Techniques; Leucovorin; Leukemia, Lymphoid; Methotrexate; Methyltransferases; Thymidine; Uracil Nucleotides

Topics: Ampicillin; Bone Marrow Diseases; Child; Cloxacillin; Female; Humans; Inhalation; Injections, Intramuscular; Leucovorin; Leukemia, Lymphoid; Lung; Methotrexate; Pneumonia; Prednisone; Remission, Spontaneous; Vincristine

Topics: Adolescent; Adult; Aged; Carcinoma, Squamous Cell; Child, Preschool; Choriocarcinoma; Chorionic Gonadotropin; Female; Humans; Infusions, Parenteral; Injections, Intravenous; Leucovorin; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lung Neoplasms; Male; Methotrexate; Middle Aged; Pregnancy; Teratoma; Testicular Neoplasms

Topics: Agranulocytosis; Antineoplastic Agents; Breast Neoplasms; Female; Hemangiosarcoma; Hodgkin Disease; Humans; Kidney Neoplasms; Leucovorin; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Lung Neoplasms; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Melanoma; Methotrexate; Osteosarcoma; Pancreatic Neoplasms; Radiography; Rectal Neoplasms; Rhabdomyosarcoma; Testicular Neoplasms; Thrombocytopenia

Topics: Child, Preschool; Female; Humans; Injections, Spinal; Leucovorin; Leukemia, Lymphoid; Methotrexate; Nervous System

Topics: Anilides; Child; Child, Preschool; Cyclophosphamide; Female; Humans; Leucovorin; Leukemia, Lymphoid; Leukemia, Myeloid; Male; Mercaptopurine; Methotrexate; Prednisone; Urethane; Vincristine

Topics: Adolescent; Child; Hematoma; Hematoma, Epidural, Cranial; Hematoma, Subdural; Humans; Hydrocephalus; Leucovorin; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Meninges; Mercaptopurine; Methotrexate; Pathology; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Radiography; Subarachnoid Hemorrhage; Vinblastine

Topics: Aminopterin; Humans; Leucovorin; Leukemia; Leukemia, Lymphoid; Meninges; Methotrexate

Topics: Ethinyl Estradiol; Humans; Leucovorin; Leukemia; Leukemia, Lymphoid; Lymphocytes; Male; Prednisone; Prostatic Neoplasms; Steroids

Topics: Aminopterin; Antimetabolites; Folic Acid; Leucovorin; Leukemia; Leukemia, Lymphoid; Lymphatic Vessels