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

The effect of dipyrone along with doxorubicin and mitoxantrone was studied alone and in combination on the 3H-thymidine (3H-TdR) incorporation in P388 leukaemia sensitive (P388/S) and resistant (P388/ADR) to doxorubicin. Dipyrone 10(-4) M demonstrated minimal inhibitory effect on DNA biosynthesis in both the sensitive and resistant cells. Doxorubicin and mitoxantrone at equimolar concentrations, indicated time and dose-dependent inhibition in 3H-TdR incorporation in the sensitive cells. The inhibition was more at the higher drug concentrations at 4 h drug exposure. Mitoxantrone showed cross-resistance in P388/ADR compared to P388/S. Both the drugs along with 10(-4) M dipyrone in the incubating medium revealed synergistic inhibitory activity in P388/S and P388/ADR. Observations indicate circumvention of doxorubicin and mitoxantrone resistance in P388/ADR by dipyrone.
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PMID:Restoration of doxorubicin responsiveness in doxorubicin-resistant P388 murine leukaemia cells by dipyrone. 356 29

Study of a series of aniline-substituted 9-anilinoacridines related to the antileukemic drug amsacrine showed that a 1'-carbamate group provided increased activity against the multidrug-resistant P388/ADR leukemia subline in vivo. Since activity against such resistant tumors is of great clinical significance, a series of acridine-substituted carbamate derivatives were evaluated against both wild-type and ADR/resistant P388 leukemia and the Lewis lung solid tumor in vivo. Structure-activity relationships for all three tumor lines were similar, with 3-halo-5-methyl and 3-halo-5-methoxy compounds proving the most active. This substitution pattern also provided the highest DNA binding. Such compounds (particularly the 3-chloro-5-methyl and 3-chloro-5-methoxy) have in vivo activity against wild-type P388 and Lewis lung comparable to that of the best amsacrine analogues previously developed (greater than 50% cures), as well as P388/ADR activity. This work essentially completes the development of the amsacrine series of antitumor agents.
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PMID:Potential antitumor agents. 52. Carbamate analogues of amsacrine with in vivo activity against multidrug-resistant P388 leukemia. 362 6

Doxorubicin was covalently linked to divinyl ether-maleic anhydride copolymer (pyran copolymer) in its polycarboxylate form via the methylketone side chain through a nucleophilic substitution reaction of the 14-bromo derivative of the drug. The drug conjugated to the synthetic polyanionic polymer was tested for antitumor activity in a range of experimental murine tumor systems. When administered ip to mice bearing ip implanted tumors (P388 leukemia or macrophage tumor J774), the polymer-linked drug was superior to free doxorubicin and daunorubicin in increasing the life span of treated animals. Treatment with the conjugate also resulted in an improvement in survival time of mice bearing ascitic M50 tumor, although the effects of a single dose of free drug, in the range of maximum tolerated doses, were marginal. When given iv, the conjugate was more effective than free drug against systemic Gross leukemia. The therapeutic advantage of the polymer-linked doxorubicin over free drug was more marked when a multiple treatment schedule was used. Studies in vitro showed that the drug following covalent fixation to the polymer had only marginally decreased cytotoxicity against HeLa and P388 cells when compared with that of free anthracycline. This effect paralleled the lack of reduction in in vivo potency. Moreover, the covalent linkage of the drug to synthetic polymer reduced drug toxicity. This effect was more marked with the ip route of administration than with the iv route.
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PMID:Increased therapeutic efficacy and reduced toxicity of doxorubicin linked to pyran copolymer via the side chain of the drug. 382 13

Adriamycin (Doxorubicin) is an important chemotherapeutic agent, but is limited in its clinical usefulness by dose-related cardiomyopathy. Attempts are being made to reduce this toxicity while retaining anti-tumor activity. These include development of chemically modified anthracycline derivatives and coupling of adriamycin to or into macromolecular carriers. We and several other laboratories have shown that entrapment of adriamycin in liposomes (phospholipid vesicles) can reduce toxicity while retaining or, in some cases, enhancing anti-tumor activity. Here we report further results of experiments in mice on toxicity reduction and anti-tumor activity. Approximate maximum tolerated doses (MTD) of adriamycin were determined from normal mouse survival at 240 days after initial treatment. I.V. bolus injection of liposomal-adriamycin was superior to i.v. bolus or i.v. infusion of free drug after a single injection, 5 daily injections or 5 biweekly (every 2 weeks) injections. Using L1210 tumor as a model for systemic leukemia, liposomal adriamycin was as effective as free adriamycin at equal doses, however liposomal-adriamycin was more effective at MTD. M5076 tumor was used as a limited model for comparisons of the effects of liposomal-adriamycin on "primary" and "metastatic" disease. The results showed that whereas free and liposomal adriamycin were without significant effect on "primary", subcutaneous tumor, that liposomal adriamycin, but not free adriamycin had very strong effects on liver "metastases". The results suggest that liposomally administered drugs, including adriamycin, may have utility for treatment of certain types of cancer and for metastases in organs where liposomes accumulate. Where improved anti-tumor activity is coupled with toxicity reduction and simplicity of administration, liposomal administration could be a useful method of drug delivery.
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PMID:The use of liposomes as carriers of therapeutic agents. 388 26

Combination chemotherapy using the water-soluble nitrosourea MCNU with various anti-cancer agents was studied using L1210 leukemia and P388 leukemia. In titration experiments MCNU showed remarkable antitumor effects at doses from 5 mg/kg to 80 mg/kg, producing numbers of 60-day survivors with L1210 leukemia. In L1210 leukemia, respective combinations of MCNU with the antimetabolites, MTX, 6-MP, 6-TG, MCNU, 5-FU and Cyclo-C showed enhanced antitumor effects. MCNU combined with each of ADR, MMC and CPM also showed marked anti-tumor effects with 60-day survivors. In P388 leukemia MCNU combined with each of ADR, MMC, VDS and CPM produced strong anti-tumor effects with numbers of 60-day survivors. In the results of these combinations, especially the combinations of MCNU + 5-FU in L1210 leukemia and MCNU + CPM in both L1210 and P388 leukemia, a significant increase in mean survival time was achieved. These combinations also produced many 60-day survivors which were considered to be due to the synergistic antitumor effects of the combined drugs.
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PMID:[Effects of combination chemotherapy of MCNU with various anti-cancer agents]. 391 6

The antitumor activity of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes was evaluated in P388 ascitic leukemia, disseminated Gross leukemia, and advanced mammary carcinoma. In P388 leukemia, free drug and drug entrapped in liposomes demonstrated equivalent antitumor activity at doses of 2.2 and 4.4 mg/kg, demonstrating 52% and 69% ILS (increase in life-span), respectively. Free doxorubicin at a dose of 10 mg/kg was superior, producing a 185% ILS against 82% with liposomal doxorubicin. With an increase in administered dose the antitumor response with liposomal doxorubicin was much more pronounced; at doses of 20 and 25 mg/kg the ILS was in excess of 376%, with five of ten mice surviving tumor-free. In Gross leukemia, the optimum dose of free doxorubicin, 10 mg/kg, brought about 186% T/C (median survival in treated mice over that in controls, X 100), whereas with liposomal doxorubicin the optimum dose was 16.9 mg/kg, which yielded 214% T/C. In advanced mammary carcinoma, the maximum tumor regression with free doxorubicin was at a dose of 7.5 mg/kg, with two of six mice dying of toxicity. Liposomal doxorubicin caused maximum tumor regression at 10.8 mg/kg dose with no toxic deaths. Doxorubicin entrapped in cardiolipin liposomes was much less toxic than free drug at high doses in normal mice.
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PMID:Antitumor and toxicity evaluation of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes. 394 Feb 17

Doxorubicin-induced DNA damage was studied in the P388 leukemia cell line and in a doxorubicin-resistant subline by alkaline elution techniques. DNA single-strand breaks and DNA-protein cross-links were determined. Whereas, in the sensitive line, 1 hr exposure to drug induced DNA damage in a concentration-dependent manner, in the resistant line only a marginal effect was observed at high drug concentrations. In contrast, elution kinetics of DNAs from cells irradiated with X-rays were similar in both lines. Although a reduced intracellular drug accumulation was found in resistant cells, this difference could not account for the marked reduction in doxorubicin-induced DNA damage. The degree of resistance of the P388 subline was reduced about 7-fold by verapamil, whereas the extent of DNA damage was unaffected. These results suggest the presence of alternative modes of resistance, independent of membrane changes, in highly resistant cells.
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PMID:Comparison of doxorubicin-induced DNA damage in doxorubicin-sensitive and -resistant P388 murine leukemia cells. 394 21

Doxorubicin possesses high affinity for binding to cardiolipin. We have utilized these properties in preparing stable liposomes of doxorubicin and cardiolipin with a net positive charge. Doxorubicin liposomes were formed by using 11.2 mumol of drug, 5.6 mumol of cardiolipin, 28.5 mumol of phosphatidylcholine, 19.5 mumol of cholesterol, and 11.1 mumol of stearylamine. These liposomes were sonicated for 90 min at 37 degrees followed by extensive dialysis against buffer. The pharmacological, toxicological, and therapeutic effects of doxorubicin entrapped in cardiolipin liposomes were compared with those of free doxorubicin in mice. At a dose of 4 mg/kg i.v., the peak cardiac concentration was achieved in 30 min following free doxorubicin administration, the value being 8.1 micrograms/g. The peak cardiac concentration with doxorubicin in cardiolipin liposomes was obtained at 5 min with a value of 2.8 micrograms/g of tissue. The cardiac concentration X time values for free doxorubicin for the 24-hr period of observation were 55.1 micrograms X hr/g, whereas it was only 7.8 micrograms X hr/g with the drug entrapped in cardiolipin liposomes. Compared to free drug, the liposomal entrapped doxorubicin significantly reduced the histopathological lesions in cardiac tissue of mice at a dose of 15 mg/kg as determined by electron microscopy. The nadir of peripheral white blood cell counts in mice with free drug, 6 mg/kg, was observed on Day 3 which was 50% of control, whereas with liposomal encapsulated drug it was reduced only 23% on Day 7. Doxorubicin in cardiolipin liposomes demonstrated enhanced chemotherapeutic potential against murine ascitic P388 leukemia with a 144% increased life span compared to 55% increased life span with free drug at a dose of 7.5 mg/kg on Days 1, 3, and 7. We conclude that doxorubicin liposomes developed in these studies possess improved therapeutic action as demonstrated by their ability to reduce the toxicity of the drug substantially.
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PMID:Pharmacological, toxicological, and therapeutic evaluation in mice of doxorubicin entrapped in cardiolipin liposomes. 396 47

A series of quinone- and sugar-modified analogs of adriamycin have been tested for growth inhibition of adriamycin-sensitive (P388/S) and -resistant (P388/ADR) sublines of P388 murine leukemia cells in vitro. P388/ADR is less resistant to analogs of adriamycin containing either a 3'-deamino-3'-(4"-morpholinyl) group, MRA; or a -(3"-cyano-4"-morpholinyl) group, MRA-CN, than to adriamycin. However, MRA-CN was the most potent growth inhibitor of either subline. This potency is reduced by either modification of the quinone unit with a 5-imino substituent or restriction of the cyano-morpholinyl ring by an oxygen bridge to the daunosamine sugar. The calcium antagonist verapamil substantially increases the cytotoxicity of adriamycin to P388/ADR but has no appreciable effect on the cytotoxicity of either MRA or MRA-CN. The results suggest that increased uptake and retention by both MRA and MRA-CN may contribute to their increased cytotoxicity, but that the intense potency of the cyano-morpholinyl analogs must be due to other unique properties of these compounds.
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PMID:Comparative cytotoxicities of various morpholinyl anthracyclines. 397 81

Studies were performed with the anthracycline-responsive P388 murine leukemia cell line, and with P388/ADR, a subline selected for doxorubicin resistance. In the P388/ADR cell line, the observed 100-fold daunorubicin resistance is associated with an outward drug transport system which can be inhibited by several calcium antagonists, eg, verapamil and nifedipine. An examination of compounds related to tiapamil, a verapamil analog, has identified a structure which is tenfold more effective than verapamil at potentiating anthracycline accumulation and responsiveness in P388/ADR cells. At no nontoxic level of any calcium antagonist examined was it possible to wholly reverse the degree of daunorubicin resistance found in the P388/ADR cell line.
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PMID:Promotion of daunorubicin uptake and toxicity by the calcium antagonist tiapamil and its analogs. 401 70


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