Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Following surgery for Stages T3-4N0-2M0 primary and recurrent resectable rectal cancer limited to the pelvis, 25 patients have been entered on a Phase I trial of pelvic radiation therapy (RT) [5040 cGy] and 12 cycles of postoperative 5-FU and high dose Leucovorin (LV) chemotherapy. 5-FU was escalated 50 mg/m2 while the LV remained constant at 200 mg/m2. The initial doses of 5-FU were: combined-RT/chemotherapy = 200 mg/m2 and post-RT chemotherapy = 325 mg/m2. The median F/U was 25 months (range: 13-36). Two maximum tolerated doses (MTD's) have been determined, one for combined-RT/chemotherapy and one for post-RT chemotherapy. The MTD for combined-RT/chemotherapy was 250 mg/m2; therefore, the recommended dose of 5-FU is 200 mg/m2. The MTD for post-RT chemotherapy was 375 mg/m2; therefore, the recommended dose of 5-FU is 325 mg/m2. The dose limiting toxicities were diarrhea, tenesmus, frequent bowel movements, dysuria, and myelosuppression. For the nine patients who received 5-FU at the recommended dose level the median low counts were WBC 3.5 (2.2-4.0), HGB 10.3 (9.0-12.3), and PLT (x 1000) 167 (133-280), and the incidence of any grade greater than or equal to 3 toxicity was 22% diarrhea, 17% tenesmus, and 22% frequent bowel movements. The recommended dose of combined-RT/chemotherapy as used in this protocol was relatively well tolerated. However, optimal doses of 5-FU cannot be delivered until the fourth postoperative month. Therefore, despite the encouraging results reported with high dose LV in patients with advanced disease, we do not recommend that high dose LV be used with combined RT and 5-FU in the treatment regimen as presently designed.
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PMID:Phase I trial of postoperative 5-FU, radiation therapy, and high dose leucovorin for resectable rectal cancer. 172 11

One hundred and nine patients suffering from various malignancies underwent 285 apheresis procedures for PBPC collection. A median of two leukaphereses (range: 2-5) resulted in median numbers of 4.6 x 10(8) MNC/kg, 14.1 x 10(4) CFU-GM/kg, and 6.0 x 10(6) CD34+ cells/kg. Preleukapheresis peripheral blood CD34+ cells correlated significantly with collected CD34+ cells/kg (r = 0.94; p < 0.0001) and with CFU-GM/kg (r = 0.52; p < 0.0001). A value > 4 x 10(4) CD34+ cells/ml was highly predictive for a collection yield > 2.5 x 10(6) CD34+ cells/kg harvested by a single leukapheresis. Sixty patients were evaluated for hematologic reconstitution and engrafted in a median time of 10 days for WBC > 1.0 x 10(9)/l (range: 7-21 days), 10 days for ANC > 0.5 x 10(9)/l (7-20) and 11 days for PLT > 20 x 10(9)/l (7-62). Reinfused CD34+ cells/kg correlated significantly with hematologic engraftment (r = 0.44-0.52 and p < 0.006-0.001) as well as CFU-GM/kg (r = 0.36-0.44 and p < 0.007-0.001). A progenitor cell dose > 2.5 x 10(6) CD34+ cells/kg or > 8.0 x 10(4) CFU-GM/kg led to a significantly faster recovery for WBC, ANC, and PLT when compared with patients receiving < 2.5 x 10(6) CD34+ cells/kg or < 8.0 x 10(4) CFU-GM/kg. We conclude that rapid hematopoietic engraftment after high-dose therapy and PBPC reinfusion correlates well with a progenitor cell dose > 2.5 x 10(6) CD34+ cells/kg or > 8.0 x 10(4) CFU-GM/kg, and that above a preleukapheresis threshold of 4 x 10(4) CD34+ cells/ml a PBPC autograft containing > 2.5 x 10(6) CD34+ cells/kg can be collected by a single leukapheresis. We suggest that patients recovering from myelosuppression should be monitored for CD34+ cells in serial blood samples to determine the course of circulating hematopoietic progenitor cells. This issue will help to define the optimal time point to start apheresis and to predict a PBPC autograft harvested by a single leukapheresis, which will lead to rapid and stable hematopoietic reconstitution following transplantation.
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PMID:Autografting with blood progenitor cells: predictive value of preapheresis blood cell counts on progenitor cell harvest and correlation of the reinfused cell dose with hematopoietic reconstitution. 749 25

Myelopoietins (MPOs) constitute a family of engineered, chimeric molecules that bind and activate the IL-3 and G-CSF receptors on hematopoietic cells. This study investigated the in vivo hematopoietic response of rhesus monkeys administered MPO after radiation-induced myelosuppression. Animals were total body irradiated (TBI) in 2 series, with biologically equivalent doses consisting of either a 700 cGy dose of Cobalt-60 ((60)Co) gamma-radiation or 600 cGy, 250 kVp x-irradiation. First series: On day 1 after 700 cGy irradiation, cohorts of animals were subcutaneously (SC) administered MPO at 200 microg/kg/d (n = 4), or 50 microg/kg/d (n = 2), twice daily, or human serum albumin (HSA) (n = 10). Second series: The 600 cGy x-irradiated cohorts of animals were administered either MPO at 200 microg/kg/d, in a daily schedule (n = 4) or 0.1% autologous serum (AS), daily, SC (n = 11) for 23 days. MPO regardless of administration schedule (twice a day or every day) significantly reduced the mean durations of neutropenia (absolute neutrophil count [ANC] < 500/microL) and thrombocytopenia (platelet < 20,000/microL) versus respective control-treated cohorts. Mean neutrophil and platelet nadirs were significantly improved and time to recovery for neutrophils (ANC to < 500/microL) and platelets (PLT < 20,000/microL) were significantly enhanced in the MPO-treated cohorts versus controls. Red cell recovery was further improved relative to control-treated cohorts that received whole blood transfusions. Significant increases in bone marrow-derived clonogenic activity was observed by day 14 after TBI in MPO-treated cohorts versus respective time-matched controls. Thus, MPO, administered daily was as effective as a twice daily schedule for multilineage recovery in nonhuman primates after high-dose, radiation-induced myelosuppression.
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PMID:Myelopoietin, an engineered chimeric IL-3 and G-CSF receptor agonist, stimulates multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression. 1064 94

This study evaluated the ability of daniplestim, a high affinity interleukin 3 receptor agonist, to enhance the hematopoietic response of Mpl ligand (Mpl-L) administration in nonhuman primates following severe, radiation-induced myelosuppression. Rhesus monkeys were total body x-irradiated (TBI) to 600 cGy, midline tissue dose. Beginning on day 1 post-TBI, animals were s.c. administered daniplestim (100 microg/kg bid; n = 4), Mpl-L (10 microg/kg qd; n = 3), daniplestim (100 microg/kg bid) plus Mpl-L (10 microg/kg qd) (n = 4) or 0.1% autologous serum (AS) (n = 11) for 18 days. CBCs were monitored for 60 d after TBI. The duration of thrombocytopenia (platelet count; PLT <20,000/microl) was significantly decreased by the administration of daniplestim (6.5 d, p = .01), Mpl-L (3.0 d, p = .003) and the coadministered daniplestim/Mpl-L (1.3 d, p = .001) compared to controls (10.4 d). As monotherapy Mpl-L but not daniplestim significantly improved the PLT nadir (21,000/microl, p = .023 and 5,000/microl, p = .266, respectively) compared to the control (3,000/microl). The combined administration of daniplestim and Mpl-L significantly improved the PLT nadir (28,000/microl, p = .007) compared to both the control cohort (3,000/microl) and the daniplestim only cohort (5,000/microl, p = .043). Recovery of PLT to preirradiation values occurred earlier in the daniplestim only (d 21) or the daniplestim/Mpl-L cohorts (d 18) than in the Mpl-L only or control cohorts (d 28, d 29, respectively). The administration of daniplestim or Mpl-L alone neither shortened the duration of neutropenia (ANC<500/microl) compared to the controls (15.8 d, 16.0 d versus 16.2 d, respectively), nor improved the recovery time of neutrophils to baseline values (d 22, d 25, and d 23, respectively). The ANC nadir was significantly improved by daniplestim alone but not Mpl-L administration (76/microl, p = .001 and 50/microl, p = .093, respectively) compared to the controls (8/microl). Coadministration of daniplestim and Mpl-L significantly improved the ANC nadir (196/microl, p = .001) compared to either the AS- or the monotherapy-treated cohorts. Also the duration of neutropenia observed in the AS-controls (16.2 d) was significantly reduced in the daniplestim/Mpl-L cohort (10.8 d, p = .002). The combined administration of daniplestim and Mpl-L significantly improved hematopoietic recovery and further enhanced the stimulatory effect of cytokine monotherapy, as well as reducing clinical support requirements after radiation-induced bone marrow myelosuppression.
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PMID:The combined administration of daniplestim and Mpl ligand augments the hematopoietic reconstitution observed with single cytokine administration in a nonhuman primate model of myelosuppression. 1101 86

Since mid-1997, we have treated 60 patients with advanced NSCLC with carboplatin (CBDCA) plus docetaxel (TXT). CBDCA (300-400 mg/m2) and TXT (60 mg/m2) were given on day 1 every 3 weeks. The mean treatment cycle was 2.3 +/- 1.4 (range 1-7). Fifty-four patients had measurable tumors, of whom 2 patients achieved a complete response and 19 patients achieved a partial response (37.0%, 95% CI: 24.3-51.3%) (Ad 12/29, Sq 7/23, Lar 1/2). Median survival time was 12.8 months and 1 year survival was 53.6%. AUC of CBDCA was not related to response (AUC of responders and non-responders was 3.29). Myelosuppression was moderate (WBC 2,284 mm3, range 800-4,700, PLT 16.4 x 10(4) mm3, range 6.6-41.5 x 10(4), Hb 10.9 g/dl, range 6.4-15.8). Leukocytopenia was related to AUC of CBDCA (R2 = 0.1093) but thrombocytopenia was not related to AUC of CBDCA (R2 = 0.0553). Gastrointestinal toxicity was mild (grade 0-1: 57%, grade 2: 35%, grade 3: 8%, grade 4: 0%). Treatment with CBDCA plus TXT combination is safe and effective in patients with NSCLC.
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PMID:[Combination chemotherapy of carboplatin and docetaxel for advanced non-small cell lung cancer (NSCLC)]. 1147 43

Preservation of hematopoietic stem and progenitor cell survival is required for recovery from radiation-induced myelosuppression. We recently showed that short-term injection of antiapoptotic cytokine combinations into mice soon after lethal gamma irradiation promoted survival. The present study investigated the hematopoietic response of cynomolgus monkeys to a single dose of stem cell factor, FLT-3 ligand, megakaryocyte growth and development factor, and interleukin-3 in combination (4F, each factor given intravenously at 50 microg/kg) administered 2 hours after 5-Gy gamma irradiation. Treated monkeys (n = 4) experienced no thrombocytopenia. Only 1 in 4 displayed a transient period of neutropenia (neutrophil [ANC] count < 0.5 x 10(9)/L), whereas all irradiated controls (n = 4) experienced neutropenia (5-12 days) and thrombocytopenia (platelet [PLT] count < 20 x 10(9)/L, 5-31 days). Treated animals exhibited an impressive 2-wave PLT response that peaked at days 8 and 22 after total body irradiation (TBI). Areas under the curve (AUC) of PLTs, ANCs, white blood cells (WBCs), and red blood cells (RBCs) between days 0 and 90 were significantly higher in treated animals than in controls. Humeral bone marrow-derived clonogenic activity was significantly spared at 24 hours and 4 days after TBI in treated monkeys. No apparent impairment of the hematopoietic status and stem cell pool, in terms of long-term culture-initiating cells (LTC-ICs) and side population (SP) cells, was observed after 15 months. These results strongly suggest that the 4F cytokine combination, as a single dose regimen, could act as an emergency treatment for nuclear accident or terrorism victims.
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PMID:Single administration of stem cell factor, FLT-3 ligand, megakaryocyte growth and development factor, and interleukin-3 in combination soon after irradiation prevents nonhuman primates from myelosuppression: long-term follow-up of hematopoiesis. 1452 91