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)

The chemotherapeutic activity of thymidine (dThd) was tested against four human tumor xenografts growing in nude mice, including a melanoma, an oat cell carcinoma of the lung, a colon carcinoma, and a breast carcinoma. Tumor-bearing mice were given an infusion of dThd (1 g/kg/day) s.c. for 72 hr each week for three weeks. Tumor growth in the treated mice was compared to that in randomized concurrent control mice infused with media alone. A significant effect was found only for the melanoma, and it was cytostatic rather than cytotoxic. Even when melanomas of very small initial volume were treated, there were no complete regressions, and tumor growth resumed when dThd treatment was stopped. In culture, sustained dThd concentrations of greater than 3.2 mM were required to cause death of the melanoma cells; in the mice the dThd level during infusion ranged from 1 to 5 mM. This exposure to dThd, although failing to produce a tumor response, did produce significant toxicity in the nude mice in the form of myelosuppression and leukopenia. Flow cytometric analysis of marrow cells during the dThd infusion showed an accumulation of cells in S phase, but proliferation was not completely halted since cells with G2-M content of DNA were present in the marrow even after 72 hr of dThd exposure. This study failed to demonstrate a therapeutically useful effect of dThd on these tumors.
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PMID:Activity of thymidine as a chemotherapeutic agent against human tumor xenografts in nude mice. 47 23

Based on the in vitro and in vivo data suggesting synergistic cytolysis by the combination of 5-fluorouracil and interferon-gamma against a variety of malignant cell lines including a human colon carcinoma cell line (HT-29), we initiated studies in patients with advanced colon or rectal carcinoma. Forty-six patients received 5-fluorouracil as an intravenous injection on days 1-5 and recombinant human interferon-gamma as an intramuscular injection on days 1-14, followed by a rest period of 14 days; courses were repeated every 28 days. In the phase I study, cohorts of two patients received a stepwise dose level increase to achieve the maximum tolerated dose (MTD), at which a total of six patients were studied. The dose levels constituting the MTD were as follows: 5-fluorouracil (500 g/m2/day) and recombinant gamma-interferon (0.5 mg/m2/day). Four patients achieved a partial response in the phase I study. In the phase II study, 30 patients received therapy at the MTD. Among 29 evaluable patients in the phase II study, two patients achieved a partial response. Common toxicities included malaise, fever, anorexia, nausea and vomiting, and diarrhea. Transient severe myelosuppression was common but did not result in significant morbidity. Our data suggest that the combination of 5-fluorouracil and recombinant gamma-interferon did not have the same antitumor effect in patients as it had in the preclinical experiments.
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PMID:Phase I and II studies of the combination of recombinant human interferon-gamma and 5-fluorouracil in patients with advanced colorectal carcinoma. 249 63

Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, and human leukocyte interferon (IFN-alpha) have synergistic anti-tumor activities in vivo in B 16 melanoma and in vitro against several human cancer cell lines. We have, therefore, carried out a phase I combination study with DFMO plus alpha interferon in the following manner: DFMO was maintained at a steady dose for the first four levels, 1.5 g/m2 every 6 hr. IFN-alpha was given in 100% increments ranging from 0.4 X 10(6)U/m2 to 3.2 X 10(6)U/m2 i.m. daily. At the fifth dose level both IFN-alpha and DFMO were raised by 100 and 50% respectively. From levels one through four the combination was well tolerated with no dose interruptions required because of G.I. toxicity or myelosuppression. However, at dose level 5, one-third of the patients required dose cessation and decrease due to nausea, vomiting and diarrhea. We conclude that for phase II studies the maximal tolerated dose is 3.2 million units of IFN-alpha/m2 and 1.5 g/m2 of DFMO every 6 hr. Of 12 patients with metastatic melanoma, 2 had partial remissions lasting 58+ and 36+ weeks. Two additional patients had minor responses lasting 29 and 32+ weeks. Minor responses were observed in a patient with colon carcinoma and a patient with renal carcinoma. The clinical activity of the combination is currently being pursued in a phase II study among patients with metastatic malignant melanoma.
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PMID:Difluoromethylornithine and leukocyte interferon: a phase I study in cancer patients. 309 71

A phase I study of single i.v. doses of a new sugar containing nitrosourea 6-deoxy-3,5 di-O-methyl 6-(3 methyl-3-nitrosoureido)-alpha-D-glucofuranoside (CGP 6809, EDMN) has been carried out in 47 patients with advanced solid tumors. Nine dose levels between 200 and 4500 mg/m2 were examined. Nausea and vomiting were seen in most patients but were controlled with antiemetics. Myelosuppression was minimal. The dose-limiting toxicity was hepatotoxicity, occurring early (peak at days 2-4) and resolving rapidly. No cumulative toxicity was seen with an every 6 weeks schedule. Other toxicities were abdominal pain, diarrhea, arm pain, restlessness, and headache. Pharmacokinetic studies in 20 patients using an HPLC assay and in 5 patients using [14C]EDMN showed a short half-life, rapid plasma clearance, rapid metabolism, and minimal excretion of unchanged drug. There was one partial response in a patient with colon carcinoma. The recommended dose for phase II studies in 3750 mg/m2 every 6 weeks.
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PMID:Phase I clinical trial of ethyl 6-deoxy-3,5-di-O-methyl 6-(3 methyl-3-nitrosoureido)-alpha-D-glucofuranoside (CGP 6809). 330 87

The antitumor effect of flavone acetic acid, LM975, and its diethylaminoethyl ester derivative, LM985, was studied in four human malignant cell lines [WiDr, a colon carcinoma; LICR (LON) HN-3, a tongue carcinoma; MCF7, a breast carcinoma; K-562, a leukemia] using a colorimetric assay based on the reduction of dimethylthiazol-2-yl-diphenyltetrazolium. The cell lines were exposed continuously for 4-6 days to drug concentrations ranging between 0.1 and 500 micrograms/ml. For LM975, the concentrations inhibiting the growth of the various cell lines by 50% were 200 +/- 10, 97 +/- 7, 171 +/- 16 and greater than 500 micrograms/ml for LICR (LON) HN-3, WiDr, MCF-7, and K-562, respectively. The corresponding concentrations for LM985 were 151 +/- 3, 36 +/- 4, 86 +/- 3 and 140 +/- 18 micrograms/ml, respectively. The difference between LM985 and LM975 was statistically significant for the WiDr and LICR (LON) HN-3 lines. We also evaluated the cytotoxic activity of the two agents on normal human marrow myeloid progenitor cells in a colony-forming assay. Continuous exposure to the drugs gave a dose-dependent inhibition. The concentrations inhibiting the growth by 50% were 76 +/- 31 micrograms/ml for LM975 and 134 +/- 41 micrograms/ml for LM985. One hour incubation with either compound had no toxic effect on the myeloid progenitor cells. In conclusion, LM975 and LM985 do not appear to have a specific cytotoxicity for tumor cells. Our results indicate that, in vitro, toxicity on bone marrow myeloid progenitor cells is concentration dependent. Considering the low plasma concentration found in man after i.v. administration of LM985, our observations correlate well with the absence of drug-induced myelosuppression in patients.
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PMID:In vitro chemosensitivity testing of flavone acetic acid (LM975; NSC 347512) and its diethylaminoethyl ester derivative (LM985; NSC 293015). 365 9

Fourty-four evaluable patients were treated with 6-methylmercaptopurine riboside (MMPR) at a dose of 20 mg/m2/day X 5 by continuous IV infusion (days 1-5 and 5-fluorouracil (5-FU) on an escalating dose schedule of 300-1519 mg/m2/day X 5 by continuous IV infusion (days 2-6). Dose-limiting oral mucositis occurred at a 5-FU dose of 1,381 mg/m2/day; other toxicities included nausea, vomiting, diarrhea, skin rash, and occasional myelosuppression. A partial and a complete response were observed in two previously untreated patients with metastatic colon carcinoma given the highest 5-FU doses (1,381 and 1,519 mg/m2/day). Bone marrow phosphoribosyl pyrophosphate (PRPP) levels monitored after 24 h of MMPR treatment indicated increases of 7.8- and 9.2-fold those found prior to therapy.
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PMID:Phase-I trial of combination therapy with continuous-infusion MMPR and continuous-infusion 5-FU. 620 81

Indicine-N-oxide, a pyrrolizidine derivative, was selected for development because of activity in the murine P388 leukemia model. Route and schedule dependency have been demonstrated. It is believed that the antitumor activity of the drug is mediated via antimitotic effects and chromosomal damage. However, the active metabolic species responsible for these antitumor properties is not yet known. The major toxic effect was myelosuppression. Phase I clinical trials have arrived at recommended doses for further study. Colon carcinoma has been found to be possibly responsive, and several tumor types were reported stable during phase I testing. In a single phase II study in refractory leukemia, there were three responses, including one complete response, among seven patients. Phase II studies in all panel tumors are indicated, especially colon carcinoma and leukemias.
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PMID:Indicine-N-oxide: a new antitumor agent. 693 84

Starch microspheres 40 micrometers in diameter, which are rapidly degraded by serum amylase, have been administered through hepatic arterial catheters to five patients with primary and metastatic liver cancer to determine whether (1) arterial blood flow through the liver could be temporarily blocked, and (2) such occlusion at the level of the arteriolar capillary bed would enhance regional uptake and catabolism and decrease systemic exposure to simultaneously administered hepatic arterial bischlorethylnitrosourea (BCNU). It was possible with 10 ml of microspheres (9 X 10(6) microspheres/ml) injected into the hepatic artery to transiently (for 15-30 minutes) reduce hepatic flow by 80-100% in the five patients. When BCNU (50 mg/m2 in one minute) was given with microspheres there was a 30-90% reduction in systemic nitrosourea exposure and in peak levels. No myelosuppression was noted and hepatic toxicity consisted of acute pain due to BCNU and 1.5-2.0 fold transient enzyme elevations. One patient with cholangiocarcinoma showed a partial response lasting three months; three patients had stable disease and one patient with colon carcinoma had progressive disease. Thus, this pilot study suggests that concurrent intra-arterial microspheres and BCNU may have the potential to improve selective regional drug effect with marked diminution in systemic toxicity.
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PMID:Improved regional selectivity of hepatic arterial BCNU with degradable microspheres. 704 7

Methyl-GAG was given to 71 patients with advanced malignancies as a weekly brief infusion (30-120 minutes) or as a biweekly 24- or 120-hour infusion. Mucositis (stomatitis, pharyngitis, esophagitis, and, rarely, inflammation of other mucous membranes) was dose-limiting in all three schedules. Generalized fatigue, malaise, myalgia, dysesthesias, nausea, and vomiting were more frequent in the brief-infusion schedule. Myelosuppression was mild and not dose-related. Fever, ventricular arrhythmias, skin rash, tender swelling of the palms, neuropathy, and paralytic ileus were rare. Toxicity was increased in patients with renal insufficiency or "third-space" fluid but was not increased by hepatic dysfunction. Cumulative and overlapping toxicity was evident only in the weekly schedule. Higher doses of methyl-GAG were tolerated when the duration of infusion was increased. The recommended doses for phase II trials are 700 mg/m2 weekly as a 1-2 hour infusion, 850 mg/m2/24 hours biweekly, and 1500 mg/m2/120 hours biweekly. Therapeutic effects were seen in all schedules and included objective responses in colon carcinoma (one of 13 patients), renal cell carcinoma (one of nine), and Hodgkin's lymphoma (one of two) and objective improvements in esophageal carcinoma (one of three), endometrial carcinoma (two of two), and leiomyosarcoma (one of three).
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PMID:Methyl-GAG in patients with malignant neoplasms: a phase I re-evaluation. 705 68

Antitumor and radiosensitizing effects of (E)-2'-deoxy-2'-(fluromethylene) cytidine (FMdC), a novel inhibitor of ribonucleotide reductase, were evaluated on nude mice bearing s.c. xenografts and liver metastases of a human colon carcinoma. FMdC given once daily or twice weekly has a dose-dependent antitumor effect. The maximum tolerated dose in the mice was reached with 10 mg/kg applied daily over 12 days. Twice weekly administration of FMdC reduced its toxicity but lowered the antitumor effect. Treatment of preestablished liver micrometastases obtained via intrasplenic injection of tumor cells, with 5 or 10 mg/kg FMdC, significantly prolonged the survival of the mice as compared to controls (P < 0.025 and P < 0.001, respectively). Ten mg/kg resulted in longer survival than 5 mg/kg FMdC (P < 0.05). Radiotherapy alone of s.c. xenografts (10 fractions over 12 days) yielded the radiation dose required to produce local tumor control in 50% of the treated mice (TCD50) of 43.0 Gy. When combined with FMdC, TCD50 was reduced to 22.5 and 19.0 Gy at doses of 5 and 10 mg/kg given i.p. 1 h before each irradiation, respectively. The corresponding enhancement ratios were 1.91 and 2.43, respectively. FMdC produced moderate and reversible myelosuppression. When 5 mg/kg FMdC was combined with irradiation, there was no increased skin or hematological toxicity as compared to radiotherapy or FMdC alone. At the 10 mg/kg level, however, lower leukocyte counts were observed. These results show that FMdC appears to be a potent anticancer drug and radiosensitizer.
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PMID:Antitumor and radiosensitizing effects of (E)-2'-deoxy-2'-(fluoromethylene) cytidine, a novel inhibitor of ribonucleoside diphosphate reductase, on human colon carcinoma xenografts in nude mice. 930 88


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