Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lactic acidosis has been described in patients with leukemia and lymphoma, but its occurrence in other malignant diseases is not documented. We treated two patients with oat cell carcinoma of the lung and extensive liver metastases in whom lactic acidosis developed. Tumor-induced hepatic dysfunction appeared to be a major factor in the pathogenesis of the lactic acidosis observed in these patients.
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PMID:Lactic acidosis in oat cell carcinoma with extensive hepatic metastases. 21 48

In recent literature numerous papers have been published concerning the accuracy of scintigraphic detection of liver metastases. Unfortunately however, the problem of false positive results is not particularly discussed in these papers. Because of the lack of information it was our aim to compare our own scintigraphic results with postmortem histopathological findings. Our investigations were carried out in 139 patients with various types of malignancy. Included in the investigations were 20 patients with primary liver tumor. The interval between scintigraphic examination and the histological verification ranged from 3 days to 1 year. In 62 of the patients with liver metastases, histopathology revealed liver metastases, while 77 patients showed no liver involvement. We arrived at the correct diagnosis "liver metastasis" in 50 out of 62 patients (80.6%). False negative scintigrams (19.4%) were found in most of the respective cases when diffuse malignant involvement such as leukemia and Hodgkin's disease was present, and also when the size of the metastases was less than 2 cm in diameter. Fifty six out of 77 patients (72.7%) without histopathological evidence of liver metastases revealed negative scintigrams. Twenty one (27.3%) false positive scintigrams were mostly due to (diffuse) nonmalignant disease e.g. fibrosis and cirrhosis. The overall accuracy of liver scintigraphy in our study was 76.2%. In 18 of 20 (90%) patients with focal liver disease correct diagnosis was established. 7 patients with benign liver tumors and 11 of 13 patients with hepatocellular carcinoma showed focal defects. Considering the fact that liver scintigraphy is a non-invasive procedure, it can be recommended as screening method. In connection with sonography and computer tomography liver scintigraphy can undoubtedly improve the diagnostic accuracy in detecting liver metastases and primary liver tumors.
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PMID:[Accuracy of liver scintigraphy in focal liver disease; a comparison with postmortem studies in 159 cases (author's transl)]. 53 Aug 44

The 14-O-palmitoyl ester of 3'-deamino-3'-hydroxydoxorubicin was synthesized to study the liposomal formulation and biological activity properties conferred by the attachment of a lipophilic group to position 14 of the anthracycline molecule. The entrapment efficiency of 14-O-palmitoyl-hydroxyrubicin in multilamellar vesicles composed of dimyristoylphosphatidyl choline and dimyristoylphosphatidyl glycerol was greater than 99%. In addition, the stability of liposomes containing 14-O-palmitoyl-hydroxyrubicin was greater than 99% at 14 days as assessed by the amount of drug leaking out of the liposomes and the absence of crystals of free drug in the liposome pellet. Esterification at position 14 did not significantly decrease the potency of the parent compound 3'-hydroxydoxorubicin. Liposome-entrapped 14-O-palmitoyl-hydroxyrubicin was significantly more active than doxorubicin against two murine tumor models. Against ip L-1210 leukemia, liposome-entrapped 14-O-palmitoyl-hydroxyrubicin injected i.p. into mice at doses of 60 and 80 mg/kg resulted in a %T/C value (median survival of treated/control animals x 100) of greater than 600, with 3-4 of 6 animals being cured, whereas in the same experiments, doxorubicin injected at the optimal dose (10 mg/kg) resulted in a %T/C value of 340, with 1 of 6 animals being cured. In animals bearing liver metastases of M-5076 reticulosarcoma, liposome-entrapped 14-O-palmitoyl-hydroxyrubicin showed significant antitumor activity when given on a three-i.v.-injection schedule of 20 mg/kg on days 4, 8, and 12 (%T/C, 175), whereas doxorubicin injected at optimal doses of 6-8 mg/kg on the same days was devoid of antitumor activity (%T/C, 129-133). These results indicate that esterification at position 14 enhances the affinity of this type of compounds for lipid bilayers without negatively affecting their biological activity.
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PMID:Liposomal formulation and antitumor activity of 14-O-palmitoyl-hydroxyrubicin. 164 93

The 1-beta-D-arabinofuranosylcytosine (ara-C) conjugates 1-O-alkyl (ether) and 1-S-alkyl (thioether) phospholipids, being analogues of ara-CDP-sn-1,2-O-dipalmitoylglycerol (1), showed significant antitumor activity against L1210 and P388 leukemia in vivo. The more active conjugates include the 1-O-alkyl analogues, ara-CDP-rac-1-O-hexadecyl-2-O-palmitoylglycerol (2) and ara-CDP-rac-1-O-octa-decyl-2-O-palmitoylglycerol (3), and the corresponding 1-S-alkyl analogues, ara-CDP-rac-1-S-hexadecyl-2-O-palmitoyl-1-thioglycerol (4) and ara-CDP-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (5, Cytoros). The conjugates were formulated by sonication, in which the conjugates existed as discs (size 0.01-0.04 microns). Among the conjugates of the three different phospholipids, the 1-S-alkyl analogues 4 and 5 displayed the strongest antitumor activity against L1210 leukemia in mice, followed by the 1-O-alkyl (2 and 3) and the 1-O-acyl (1) analogues. The 1-S-alkyl analogue 5 was considerably more effective than the 1-O-acyl analogue 1 against myelomonocytic WEHI-3B leukemia in mice. Conjugate 5 (Cytoros) showed a significant therapeutic activity in mice with colon 26 carcinoma, M5076 sarcoma, and C-1300 neuroblastoma. Furthermore, this agent inhibited liver metastases of M5076 sarcoma. Conjugates 3 and 5 also inhibited the metastasis of 3-Lewis lung carcinoma to the lungs of mice. Cytoros (5) and its analogues, with other ether and thioether phospholipids, appear to offer increased therapeutic benefit to mice with tumors.
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PMID:1-beta-D-arabinofuranosylcytosine conjugates of ether and thioether phospholipids. A new class of ara-C prodrug with improved antitumor activity. 181 47

cis-Bis(neodecanoato)(trans-(R,R)-1,2-diaminocyclohexane)platinum( II) [L-NDDP] is a liposome incorporated lipophilic cisplatin analogue that has shown promising antitumor activity against tumors resistant to cisplatin and liver metastases in mice. L-NDDP is currently under clinical evaluation. However, NDDP is an isomeric mixture of different species having various isomeric neodecanoic moities as liganded leaving groups. A series of new highly lipid-soluble cis-bis(neodecanoato)(trans-(R,R)- and -(S,S)-1,2-diaminocyclohexane)platinum(II) [Pt] complexes, using single isomers of neodecanoic acid, were synthesized and characterized by analytical and spectroscopic techniques (infrared and 195Pt NMR). Multilamellar vesicles (MLVs) composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) at a molar ratio of 7:3 were used as carriers of the Pt complexes. The efficiency of incorporation of the liposomal-platinum (L-Pt) preparations was greater than 95% and stability in normal saline at 4 degrees C was greater than 95% at day 14 in each case. The iv LD50 values of all L-Pt preparations tested were in the range of 62.3 to 104 mg/kg. The % T/C obtained after a single ip injection of the optimal dose of L-Pt preparations against L1210 leukemia was in the range of 150 to 253 (160 for cisplatin). When a multiple ip injection schedule was used (on days 1, 5, and 9) the L-Pt preparations of R,R complexes (1, 7, and 9) were more active than cisplatin at the optimal dose (% T/C = 257 for each vs 220 for cisplatin). The L-Pt preparations of R,R complexes were also markedly active against L1210 leukemia resistant to cisplatin (% T/C 355, 231, and 185 respectively vs 112 for cisplatin). These studies show that the single isomers of NDDP are comparable to the original isomeric mixture in terms of toxicity and biological activity.
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PMID:Chemical and biological studies on a series of lipid-soluble (trans-(R,R)- and -(S,S)-1,2-diaminocyclohexane)platinum(II) complexes incorporated in liposomes. 199 34

We evaluated the entrapment of 21 different water-insoluble aglycones or anthracycline antibiotics in multilamellar liposomes composed of dimyristoyl phosphatidyl choline and dimyristoyl phosphatidyl glycerol at a 7:3 molar ratio. The drug:lipid weight ratio was 1:15 to 1:50. The different analogues tested were modified at position 4 in the aglycone portion (4-demethoxy) and/or positions 2' (halo), 3' (hydroxy, acetoxy), or 4' (epi, acetoxy) in the sugar portion. The entrapment efficiency was assessed by measuring the amount of free drug remaining in the supernatant after centrifugation of the liposomes and by direct examination of the pellets by fluorescent microscopy. Optimal entrapment (greater than 98%) was observed with only four compounds: 4-demethoxyadriamycinone; 2'-iododaunorubicin; 4-demethoxydaunorubicin; and 2'-iodo-3'-hydroxy-4'-epi-4-demethoxydoxorubicin (Compound 22). All other compounds showed significant drug precipitation outside the multilamellar vesicles when observed by fluorescent microscopy. Compound 22, entrapped in liposomes, was evaluated in vivo against i.p. L-1210 leukemia by the i.p. route, and liver metastases of M5076 reticulosarcoma by the i.v. route. In both models, liposome-entrapped Compound 22 was more active than doxorubicin at the optimal dose [median survival (given in percentage) of treated to control animals was for L-1210, greater than 600 versus 212; for M5076, 200 versus 133]. 4-Demethoxy and 2'-iodo are structural modifications that markedly enhance the affinity of anthracycline antibiotics for lipid bilayers without compromising biological activity. These findings will serve as a guideline to obtain liposome-anthracycline preparations, with optimal formulation characteristics, enhanced tumor-targeting properties, and non-cross-resistance with doxorubicin.
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PMID:Anthracycline antibiotics with high liposome entrapment: structural features and biological activity. 219 51

1-beta-D-Arabinofuranosylcytosine 5'-diphosphate-rac-1-S-octadecyl-2-O- palmitoyl-1-thioglycerol (ara-CDP-DL-PTBA) is an effective stable 1-beta-D-arabinofuranosylcytosine (ara-C) conjugate of thioether phospholipid against a variety of transplantable tumors in mice. The conjugate was formulated in a micellar solution by sonication, in which the conjugate exists as micellar discs (size, 0.01 to 0.04 micron). Analyses on thin-layer and high-pressure liquid chromatography showed that the conjugate was chemically stable upon storage at 3-4 degrees C for more than a 6-mo period. However, stored at room temperature for 3 mo it began to degrade (3 to 11%) to 1-beta-D-arabinofuranosylcytosine 5'-monophosphate and phosphatidic acid. At 3-4 degrees C, the micellar structure remained generally unchanged for 6 mo (size, less than 0.1 micron). Samples stored for 4 mo at room temperature formed some larger vesicles (size, 0.1 to 0.4 micron). Antitumor activity against i.p. implanted L1210 leukemia in mice remained relatively constant with samples stored for 6 mo at 3-4 degrees C or 3 mo at room temperature. 1-beta-D-Arabinofuranosylcytosine 5'-triphosphate (ara-CTP) levels were elevated (greater than 500 pmol/10(7) cells) in L1210 leukemia cells within 1 h following i.p. administration of 400 mg/kg of ara-CDP-DL-PTBA to mice. More importantly, retention of cellular ara-CTP was prolonged (greater than 24 h) in these tumor cells as compared with ara-C treatments. Administration of ara-CDP-DL-PTBA to mice with colon 26 carcinoma (s.c.) resulted in both significant antitumor activity with an increased life span greater than 100% and decreased tumor size. The conjugate also demonstrated a dose-dependent therapeutic effect in mice with M5076 sarcoma (s.c.) as demonstrated by decreases in tumor size and liver metastases. Overall, ara-CDP-DL-PTBA, a stable lipid conjugate of ara-C in a micellar solution, appears to offer substantial therapeutic benefit to mice with leukemia and solid tumors warranting its further development and clinical investigation.
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PMID:Formulation, stability, and antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugate of thioether phospholipid. 236 92

A new series of highly lipid-soluble cis-bis-carboxylato(trans-R,R-1,2-diaminocyclohexane)platinum(II) complexes were synthesized and characterized by their elemental analysis and by various spectroscopic techniques [infrared (IR), 195pt nuclear magnetic resonance (NMR)]. cis-bis-Neopentanoato(trans-R,R-1,2-diaminocyclohexane)platinum(II ) (NPDP), cis-bis-neodecanoato(trans-R,R-1,2-diaminocyclohexane)-platinum(II ) (NDDP), and cis-bis-n-decanoato(trans-R,R-1,2-diaminocyclohexane)-platinum(II) (DEDP) complexes were entrapped in multilamellar vesicles composed of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) at a 7:3 molar ratio and tested for toxicity and antitumor activity. The entrapment efficiency of the liposomal platinum (L-Pt) complexes (L-NPDP, L-NDDP, L-DEDP) was greater than 95%, and the stability in 0.9% NaCl solution at 4 degrees C was greater than 95% at day 14 in each case. The LD50 values of L-NPDP, L-NDDP, and L-DEDP when injected i.v. were 30, 54, and 150 mg/kg, respectively. L-NPDP, L-NDDP, and L-DEDP had no significant nephrotoxicity [as evidenced by a lack of elevated blood urea nitrogen (BUN) levels]. The percentages of T/C obtained after a single i.p. injection of the optimal dose of L-NPDP, L-NDDP, and L-DEDP tested against L1210 leukemia were 175%, 187%, and 212%, respectively [160% for cisplatin (CDDP)]. When a multiple i.p. injection schedule was used (on days 1, 5, and 9), L-NPDP, L-NDDP, and L-DEDP were more active than CDDP (percentage of T/C: 312%, 312%, 277%, and 220%, respectively). When injected i.v., only L-NDDP showed significant activity against L1210 leukemia i.v. (percentage of T/C: 186%). L-NDDP and L-DEDP were markedly active against L1210 leukemia resistant to CDDP (percentage of T/C: 200% and 145% vs 112% for CDDP). L-NPDP, L-NDDP, and L-DEDP also had good activity against i.p. B16 melanoma when they were injected i.p. on days 1, 5, and 9 (percentage of T/C: 206%, 225%, and 306%, respectively). L-NDDP and L-DEDP were more effective than CDDP in inhibiting the growth of liver metastases of murine M5076 reticulosarcoma, whereas L-NPDP was not active. The results obtained to date suggest that L-NDDP is the best L-Pt-complex candidate for further developmental studies.
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PMID:Toxicity and antitumor activity of cis-bis-carboxylato(trans-R,R-1,2-diaminocyclohexane) platinum(II) complexes entrapped in liposomes. 264 11

Recurrent or persistent small-cell carcinoma of the lung (SCCL) after chemotherapy (CT) alone has shown a poor response to conventional salvage radiotherapy (RT). Accelerated RT is judged more effective than conventional RT for rapidly growing tumors such as SCCL. The objectives of this study were: to determine the tolerability of accelerated RT; and to test the ability of accelerated RT plus CT to achieve local tumor control (LTC) of SCCL recurrent after CT. Patients whose localized tumor was not controlled were selected from Arm III of the Cancer and Leukemia Group B (CALGB) protocol 8083 (Proc. ASCO 2:230, 1984) as eligible for this study. The program of accelerated RT consisted of the delivery of 50.1 Gray (Gy) in 30 fractions over a period of 21 days to the chest. New chemotherapy different from the first began 2 weeks after the completion of RT and was repeated every 3 weeks for 18 months (M). Of 29 potentially eligible patients with locally recurrent SCCL after the first line CT alone from Arm III of the CALBG protocol 8083, 12 were enrolled initially in this study. The analysis of LTC included 11 patients excluding one patient who died 4 weeks after the start of RT from liver metastases. The LTC achieved was as follow: complete remission in 8/11 (72%) and partial remission in 3/11 patients. None of the patients was converted to CR by subsequent chemotherapy. Survival ranged from 2 to 20 M, with a median survival time of 6 M. Tolerance to the subsequent CT, normal tissue reaction to accelerated RT, and the theoretical advantage of accelerated RT over conventional RT for SCCL were evaluated.
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PMID:Accelerated radiotherapy followed by chemotherapy for locally recurrent small-cell carcinoma of the lung. A phase II study of Cancer and Leukemia Group B. 302 96

cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ +-(II) (NDDP) was encapsulated in multilamellar vesicles composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol at a 7:3 molar ratio. Compared with cisplatin, i.v. administration of an equimolar dose of liposome-encapsulated NDDP (L-NDDP) resulted in 15-fold higher peak platinum levels in the spleen (204.7 versus 13.3 micrograms/g dry tissue), 5-fold higher in the lungs (116.4 versus 21.0 micrograms/g dry tissue), 3-fold higher in the liver (71.6 versus 23.9 micrograms/g dry tissue), and 4-fold higher in the blood (14.8 versus 3.9 micrograms/ml). At the optimal dose and schedule, L-NDDP administered i.p. in mice bearing peritoneal L1210 leukemia resulted in the percentage of median survival time of treated mice divided by median survival time of control mice (%T/C) of 312 versus 225 for cisplatin and free NDDP. When administered i.v., L-NDDP was also more active than cisplatin against L1210 leukemia inoculated i.v. (%T/C 186 versus 142). L-NDDP was markedly active against L1210 leukemia resistant to cisplatin (%T/C, 200 versus 112 for cisplatin). In mice bearing liver metastases of M5076 reticulosarcoma, L-NDDP was significatnly more effective than cisplatin at equimolar doses (mean survival time, 57 +/- 9 (SD) days for L-NDDP versus 42 +/- 3 days for cisplatin, P less than 0.05). L-NDDP was also effective in preventing liver metastases of M5076 when administered up to 24 h prior to tumor inoculation (mean survival, 28 +/- 2 days for L-NDDP versus 22 +/- 2 days for cisplatin, P less than 0.05). L-NDDP is significantly non-cross-resistant with cisplatin and more effective against phagocytic and nonphagocytic murine tumors.
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PMID:Treatment and prophylaxis of experimental liver metastases of M5076 reticulosarcoma with cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) encapsulated in multilamellar vesicles. 331 88


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