Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flavone acetic acid (FAA) is a new antitumor agent with broad activity against transplantable solid tumors of mice but with only scant or no activity against leukemias and lymphomas. The technique of alkaline elution was used to study DNA lesions in s.c. implanted Glasgow osteogenic sarcoma in C57BL/6 x DBA/2 F1 mice treated i.v. with FAA. At efficacious dosages (235 and 200 mg/kg), FAA produced extensive single strand breakage. Formation of single strand breaks was dependent on time of assay after exposure to FAA with only minimal damage occurring prior to 5 h posttreatment. Apparently Glasgow osteogenic sarcoma had no capacity to repair single strand breaks for at least 45 h after drug administration. Thus, FAA differs in its mechanism from other scission agents (e.g., VP-16). Neither interstrand cross-links nor DNA-protein cross-links were detected. DNA single strand breaks did not occur in the bone marrow cells or in the unresponsive P388 leukemia cells at dosages causing extensive DNA damage in solid tumor cells.
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PMID:Flavone acetic acid (NSC 347512)-induced DNA damage in Glasgow osteogenic sarcoma in vivo. 342 92

Flavone acetic acid (FAA) is a new antitumor agent that has recently entered Phase I clinical trials. In preclinical studies, we have found that FAA was broadly active against a variety of transplantable solid tumors of mice (colon #51, #07, #10, #26; pancreatic ductal adenocarcinomas #02 and #03; mammary adenocarcinoma #16/C/Adr; M5076 reticulum cell sarcoma and Glasgow's osteosarcoma). FAA was curative for colon adenocarcinoma #10 and pancreatic ductal adenocarcinoma #03. Thus, for the first time an agent has been identified with very broad, perhaps nearly universal solid tumor activity. FAA was also found to be orally active and stable in solution at 37 degrees C for 48 h. FAA was selectively cytotoxic in vitro for solid tumors over leukemias L1210 and P388 (in a soft-agar colony formation assay), thus correlating cellular selectivity in vitro with in vivo antitumor activity. The finding that FAA was active in vitro, established that the agent did not need metabolism (activation) outside the tumor cell. The main drawback of FAA was an unusual 'threshold' behavior in which only a narrow range of doses were active and splitting the dose markedly decreased activity.
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PMID:Activity of flavone acetic acid (NSC-347512) against solid tumors of mice. 354 83

Cl-920 is a structurally novel phosphate ester antibiotic that contains an unsaturated lactone and a conjugated triene system. It has potent antileukemic activity in mice. At doses of 25 mg/kg given i.p. once daily for 5 days to mice bearing approximately 10(7) L1210 leukemia cells, Cl-920 is curative in about 10% of the mice. Life span increases in noncured mice are typically in excess of 150%. The unsaturated lactone and phosphate ester moieties are required for activity against L1210 leukemia. Ring hydroxylation or removal of the terminal hydroxyl group have only modest effects on activity. Schedule studies suggest that prolonged exposure to low levels of Cl-920 is considerably more toxic than is daily or intermittent administration. Daily administration produces optimal activity against L1210 leukemia. Administration i.p. and i.v. of Cl-920 produce roughly equal toxicity and equal activity against an i.p. implant of L1210 leukemia. Cl-920 is inactive when given p.o. or s.c. Cl-920 failed to show confirmed activity against the following tumors in mice: M5076 sarcoma, B16 melanoma, and Ridgway osteogenic sarcoma. The lack of solid tumor activity in mice may be caused by a transport deficiency similar to that found with methotrexate.
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PMID:Anticancer activity of the structurally novel antibiotic Cl-920 and its analogues. 654 97

Six human osteosarcomas were transplanted subcutaneously in the back of nude mice and three of the six were found to be serially transplantable. Two of three transplantable solid tumors were called DOS tumor and KOS tumor. The 4th generation of DOS tumor and the 1st generation of KOS tumor grew to invade the peritoneum and tumor cells were spilt spontaneously into the abdominal cavity. These two cases were transformed to ascites tumor, called DOS-NM ascites tumor and KOS-NM ascites tumor. They were found to be serially transplantable by an intraperitoneal injection of free tumor cells (10-20 x 10(5) cells). DOS-NM and KOS-NM ascites tumor cells were analysed to have human karyotype and alkaline phosphatase activity. Ascites tumor cells were studied under light and electron microscopes. A large number of elongated and ballooned mitochondria were characteristically seen in the cytoplasm of two ascites tumor cells by electron microscope. Development of rough surfaced endoplasmic reticulum and Golgi's apparatus was poor, and no production of collagen fiber was seen in these materials. There is no report referring to ascites tumor of human osteosarcoma, therefore ascites tumor of osteosarcoma was made deliberately and the following results were obtained. 1) Several blocks of DOS tumor were implanted intraperitoneally into 5 nude mice, and only solid tumors grew in the abdominal cavity without ascites. 2) Minced DOS tumor was implanted subcutaneously close to the peritoneum and 2 out of 6 nude mice developed ascites tumor. 3) Cell suspension of DOS tumor was injected intraperitoneally and 3 out of 4 nude mice developed ascites tumors. As mentioned above, human osteosarcoma was successfully induced to ascites tumor (DOS-NM), which was established earlier compared with solid tumor (DOS). Characteristics of human osteosarcoma are easily examined with ascites tumor and in vivo screening test of anticancer drugs can be quantitatively done. Therefore ascites tumor is considered to be a valuable experimental model.
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PMID:[Experimental studies on ascites tumor of human osteosarcoma in nude mice (author's transl)]. 694 13

It is generally accepted that oxygen has a limited ability to diffuse into solid tumor masses. However, the question of the ability of chemotherapy agents to penetrate solid tumor masses has not been evaluated. This clearly would have an impact on the ability of chemotherapy to control microscopic disease during the "avascular" phase of growth. An attempt was made to evaluate the ability of methotrexate to penetrate solid tumor masses when grown in three dimensions (spheroids). Since methotrexate is used in the clinical management of human osteosarcoma, we chose this drug-tumor combination for our studies. This was done by growing human osteosarcoma cells into spheroids and exposing spheroids of various sizes to tritiated methotrexate. Audioradiographs were obtained from sections through the center of spheroids of various sizes. Our findings suggest that methotrexate has a limited ability to penetrate into avascular tumor masses when grown in three dimensions. This is most evident when the tumor masses are approximately 250 micron and larger in diameter. In addition, we compared the degree of penetration of methotrexate to the growth fraction of the tumor, as measured by tritiated thymidine, and found that the growth fraction was much greater than the fraction of cells reached by methotrexate. We conclude that the limited ability of methotrexate to penetrate solid tumor masses offers an alternative explanation for the limited effectiveness of methotrexate when used as an adjuvant for osteosarcoma. We question whether the established biochemical mechanisms for methotrexate resistance are comprehensive explanations for its limited clinical effectiveness.
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PMID:Limited penetration of methotrexate into human osteosarcoma spheroids as a proposed model for solid tumor resistance to adjuvant chemotherapy. 743 49

Intratumoral heterogeneity has been identified as a potential problem in the efficacy of predictive assays. Canine osteosarcoma is an extremely heterogeneous solid tumor that has been shown to be an excellent model for the human disease. Intratumoral heterogeneity of kinetic parameters and the effect of heterogeneity on predicting outcome of treatment (time until metastasis) were studied in dogs with naturally occurring osteosarcoma. Dogs were treated with amputation or tumor excision and limb-sparing followed by chemotherapy with cisplatin. Kinetic parameters evaluated included v, duration of DNA synthesis (Ts), and potential doubling time (Tpot), determined using in vivo labeling with bromodeoxyuridine and flow cytometry. In 30 tumors, multiple samples were obtained and evaluated. There was significantly more variation between tumors from different dogs than intratumoral variation of v, Ts, and Tpo. Variations in v, Ts, and Tpot within a tumor were associated with both sample location and tumor subpopulation. Time to metastasis was determined in 51 dogs with tumors sampled for kinetics. Multiple samples were available from 25 of these tumors. Cox proportional hazard analysis was performed using either the fastest or slowest Tpot from each sample. The fastest available Tpots were highly significant (P < 0.001) for prediction of outcome. The slowest available Tpots were also significant predictors, although the statistical strength was compromised (P = 0.024). Obtaining at least two samples in large tumors known to be heterogeneous is recommended to improve the predictive ability of Tpot. v is a more limited predictor but can useful when Tpot is not available. In canine osteosarcoma, an extremely heterogeneous tumor, kinetic parameters were shown to be predictors of outcome.
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PMID:Impact of heterogeneity in the predictive value of kinetic parameters in canine osteosarcoma. 803 16

Intoplicine (RP 60475, NSC 645008) is a new 7H-benzo[e]pyrido [4,3-b] indole derivative which interacts with DNA and inhibits both topoisomerases I and II. In vitro it was found cytotoxic against various cell types with greater cytotoxicity towards solid tumor cells. We report here the anticancer activity of RP 60475 against a variety of transplantable tumors of mice, and also its cross-resistance profile in leukemias. The end points used were % T/C (median tumor weight of the Treated over the Control x 100) and logCK (log10 cell kill total). RP 60475 administered i.v. was found schedule-independent with a peak plasma level problem. It had a good therapeutic index and host recovery usually occurred 7.5 days post last treatment. RP 60475 was found to be highly active against early stage colon 38 (T/C = 0%, 2.9 logCK) and could induce 5/5 complete regressions of advanced stage tumor. It was found active against colon adenocarcinoma 51 (T/C = 3.6%, 1.9 logCK) and colon carcinoma 26 (T/C = 11.7%, 1.2 logCK). Most of the mammary adenocarcinomas were found very responsive, MA16/C (T/C = 0%, 2.8 logCK), MA14/A (T/C = 0%, 1.4 logCK), MA13/C (T/C = 0%, 3.1 log CK) and MA44 (T/C = 34%). Excellent activity was also observed against early stage pancreatic ductal adenocarcinoma 03 (T/C = 0%) and RP 60475 could achieve 5/5 complete regressions of upstaged tumor. Activity was also obtained on Glasgow osteogenic sarcoma (T/C = 0%, 3.3 logCK), on B16 melanoma (T/C = 14%, 1.3 logCK) and to a lesser extent on Lewis lung carcinoma (T/C = 33.2%). Evaluation of RP 60475 against leukemia sublines with acquired resistance, revealed that L1210/cisplatin and L1210/BCNU were not cross-resistant to RP 60475 whereas P388/vincristine was partially cross-resistant to RP 60475 and P388/doxorubicin was cross-resistant to RP 60475. Based on RP 60475 broad activity against transplantable tumors of mice, its effectiveness against some resistant sublines, its original mechanism of action and its acceptable toxicological profile, this compound was selected for clinical trials.
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PMID:Antitumor activity of intoplicine (RP 60475, NSC 645008), a new benzo-pyrido-indole: evaluation against solid tumors and leukemias in mice. 815 69

We report four cases of extraskeletal osteosarcoma of the thigh to illustrate MRI findings of this rare neoplasm. Calcifications or osteoid material were not discernible in these tumors on MRI or conventional radiography. Three tumors were well demarcated on MRI and corresponded to pseudoencapsulation on radiologic-pathologic correlation. These three tumors were heterogeneous in appearance and were hyperintense to muscle on T1-weighted imaging and demonstrated high signal intensity on T2-weighted imaging. In the fourth tumor, which occupied almost the entire thigh, MRI before and after intravenous gadopentetate dimeglumine administration revealed cystic, hemorrhagic, and solid components. Pathological examination revealed a cystic hemorrhagic cavity containing necrotic and viable tumor and a large solid tumor component. The MRI findings in extraskeletal osteosarcoma are non-specific. However, in the appropriate age group the differential diagnosis of a soft-tissue mass in the thigh should include extraskeletal osteosarcoma, even in the absence of radiographically discernible calcifications or osteoid material within the soft-tissue mass.
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PMID:MRI of extraskeletal osteosarcoma. 849 3

Irinotecan (CPT-11) is a semi-synthetic derivative of camptothecin currently in clinical trials. In vitro, CPT-11 presented preferential cytotoxicity toward some solid tumor cells (mouse colon 38 and pancreas 03; human pancreas MIA PaCa-2) as compared to leukemia cells (L1210), whereas SN-38, a metabolite of CPT-11, was not solid tumor selective. In vivo, schedule of administration studies in P388 leukemia and mammary adenocarcinoma 16/C (MA16/C) showed that CPT-11 was not markedly schedule dependent. In order to determine its spectrum of anticancer activity, CPT-11 was evaluated against a variety of mouse and human tumors. The end points used were total log cell kill (Lck) for solid tumors and increase in life span (% ILS) for leukemia. Intravenous CPT-11 was found highly active against both early and advanced stage pancreatic ductal adenocarcinoma 03 (P03), with 60% long-term survivors and 100% complete regressions, respectively. Other responsive tumors included: colon adenocarcinomas 38 and 51 (both 1.0 Lck); MA16/C (3.4 Lck); MA13/C (1.0 Lck); human Calc18 breast adenocarcinoma (2.8 Lck); Glasgow osteogenic sarcoma (1.8 Lck); Lewis lung carcinoma (1.4 Lck); B16 melanoma (1.4 Lck); P388 leukemia (170% ILS) and L1210 leukemia (64% ILS). Of interest, CPT-11 was active against tumors with acquired resistance to vincristine (P388/Vcr), to doxorubicin (P388/Dox) and to docetaxel (Calc18/TXT). CPT-11 was also found highly active after oral administration in mice bearing P03 and MA16/C tumors. Pharmacokinetic evaluations performed i.v. at the highest non-toxic dosage in mice bearing P03 tumors revealed CPT-11 peak plasma concentrations (Cmax) of 8.9 micrograms/ml and a terminal half-life of 0.6 h. The metabolite SN-38 plasma concentrations presented a Cmax of 1.6 micrograms/ml and a terminal half-life of 7.4 h. Although the CPT-11 tumor levels were similar to the plasma concentrations for early time points, drug levels decreased more slowly in the tumor compared to plasma (half-life, 5.0 h). SN-38 tumor levels reached concentrations in the range of 0.32-0.34 micrograms/g and decayed with a half-life of 6.9 h. No significant difference in plasma or tumor pharmacokinetics of either CPT-11 or SN-38 were noted after one or five daily i.v. injections. Overall, these data show that CPT-11 has good activity in experimental models, when administered both by the i.v. and the oral routes. Compared to humans, a similar schedule of administration independence was observed and similar CPT-11 levels could be reached at efficacious dosages although metabolite SN-38 levels were found higher in mice.
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PMID:Experimental antitumor activity and pharmacokinetics of the camptothecin analog irinotecan (CPT-11) in mice. 882 13

Treatment of episodes of fever and neutropenia in pediatric hematology-oncology patients includes hospitalization and administration of intravenous antibiotics until the patient is afebrile and no longer neutropenic. The present analysis characterizes retrospectively febrile episodes in neutropenic pediatric hematology-oncology patients with regard to frequency of documented infections, organisms associated with these infections, efficacy of a standardized antibiotic regimen, and safety of early antibiotic discontinuation under defined conditions. A total of 149 pediatric febrile neutropenic episodes were identified during a 4-year period between 1990 and 1994. These occurred in 47 male and 19 female patients, of a mean age of 7.6 years (range 0.5-15). The most frequent diagnoses were leukemia (41% of patients), lymphoma (21%), rhabdomyosarcoma (7%), soft tissue sarcoma (5%), Ewing's sarcoma (5%), and osteosarcoma (4%). Infection was certain in 36% of febrile episodes, probable in 14%, and not determined in 50%. Patients with severe neutropenia (absolute neutrophil count < 100) had a slightly, although not significantly higher incidence of documented and probable infection (57%). Patients with solid tumor had documented infection in 40% of their febrile episodes, and the detection rate in the children with leukemia was 31% (P < .20) Blood cultures were positive in 21 (14%) of 149 episodes. Staphylococci (both coagulase-negative and coagulase-positive strains) and Pseudomonas were the organisms most frequently isolated (six episodes each). Mouth and throat (11), lungs (10), and skin (10) were the next most frequent sites of localized infection. Initial treatment consisted of piperacillin and amikacin or of vancomycin and amikacin when the source of fever was thought to be an infected central line catheter, with addition of amphotericin B by the seventh day of treatment when fever with neutropenia persisted or upon clinical suspicion of underlying fungal infection. There was a single fatality, of a patient with Burkitt's lymphoma. Antibiotics were discontinued when initial blood cultures had no growth after at least 48 hours and no source of infection was found, the blood count was improving, and if the patient became afebrile and clinically well. No patient needed readmission during the fortnight that followed discontinuation of antimicrobial therapy. Patients with negative blood cultures under defined conditions, as described above, could safely be discharged early, thus shortening the duration of intravenous antibiotic therapy and hospital stay.
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PMID:Fever and neutropenia in children with malignant disease. 894 Jul 33


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