Biomedical subjects

R Perez-Soler

Publications and source records attributed to R Perez-Soler.

At least 73 records · Page 4Linked to original sources

PubMed1993

Apoptosis induced by anthracycline antibiotics in P388 parent and multidrug-resistant cells.

The effect of the topoisomerase II inhibitor doxorubicin and its non-cross-resistant analogue annamycin on DNA degradation and programmed cell death was examined in murine leukemia P388 cells. P388 parental cells exposed to various concentrations of doxorubicin and annamycin for 24 h displayed dose-dependent DNA cleavage: at 1 microM, both doxorubicin and annamycin were effective in inducing DNA breakdown, but at 10 microM, the effect was markedly decreased or totally absent. In multidrug-resistant P388/Dox cells, doxorubicin did not cause DNA cleavage, while 10 microM annamycin had a significant effect. By agarose gel analysis, drug-induced DNA fragmentation showed the characteristic pattern of internucleosomal ladder. Morphologically, P388 cells treated with 1 microM doxorubicin or annamycin for 24 h showed a reduction in cell volume and condensation of nuclear structures. Similar changes were observed in P388/Dox cells exposed to 10 microM annamycin for 24 h but not in cells exposed to 10 microM doxorubicin. Time course studies demonstrated that DNA fragmentation was detected 12 h after incubation with 1 microM doxorubicin or annamycin, while loss of membrane integrity appeared at 24 h, thus indicating that DNA degradation was a preceding event. DNA fragmentation caused by doxorubicin and annamycin was inhibited by the RNA synthesis inhibitor actinomycin D, the protein synthesis inhibitor cycloheximide, and the endonuclease inhibitor aurintricarboxylic acid. Drug-induced cell death was partially prevented by cycloheximide and aurintricarboxylic acid, thus suggesting that the apoptotic process caused by these drugs requires gene expression, synthesis of new proteins, and activation of endogenous nucleases. In contrast, DNA cleavage was not affected by incubating cells with 1 mM ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid, thus indicating that intracellular calcium depletion does not affect anthracycline-induced apoptosis. The results obtained demonstrate that the cell killing effect of anthracyclines is mediated, at least in part, by the induction of apoptosis.

Animals↗

PubMed1993

In vitro cytotoxicity, cellular pharmacology, and DNA lesions induced by annamycin, an anthracycline derivative with high affinity for lipid membranes.

Annamycin (AN) is an anthracycline antibiotic with high affinity for lipid membranes which is being developed for clinical studies formulated in liposomes. We studied the in vitro cytotoxicity, cellular pharmacology, and DNA damage induced by AN in P388 cells sensitive and resistant to doxorubicin (DOX). AN was as cytotoxic as DOX against P388-sensitive cells and about 50 times more cytotoxic than DOX against P388-resistant cells (resistance index 5 for AN versus 250 for DOX). Cellular uptake of AN by sensitive cells was 2-3-fold higher than that of DOX. In resistant cells, cellular uptake of AN and DOX was approximately 65% and 30%, respectively, of the cellular uptake in sensitive cells. As a result, cellular uptake of AN by resistant cells was higher than uptake of DOX by sensitive cells. DOX was fully retained in sensitive cells while it was effluxed rapidly from resistant cells. In contrast, efflux of AN was similar in sensitive and resistant cells, thus suggesting that it is not mediated by P-glycoprotein. AN was more effective than DOX in inducing single DNA breaks, double DNA breaks, and DNA-protein cross-links, both in sensitive and resistant cells, although DNA damage was lower in resistant cells than in sensitive cells. DNA lesions induced by AN in resistant cells were similar to or greater than those induced by DOX in sensitive cells. These studies indicate that the lack of cross-resistance between DOX and AN appears to be related, at least in part, to the relatively higher cellular uptake of AN compared with DOX and is associated with the ability of AN to induce significant DNA damage in resistant cells.

Animals↗

PubMed1993

Quantitative analysis of the lipophilic doxorubicin analogue annamycin in plasma and tissue samples by reversed-phase chromatography.

A rapid and sensitive HPLC method was developed to detect and quantitate the lipophilic doxorubicin analogue annamycin (Ann) and its metabolites in biological samples. Reversed-phase chromatography coupled with fluorescence detection was used. The emission and excitation wavelengths of the fluorescent detector were set at 550 and 472 nm, respectively. The optimal mobile phase was acetonitrile:methanol:water at a 115:95:90 ratio (v/v/v). The lower limit of detection was 0.35 ng of Ann (7 ng/mL). The retention times of 4-demethoxyadriamycinone (Anone) and Ann were 2.6 and 4.3 min, respectively, and their resolution was 1.3. The precision of the determination of Ann and Anone were 0.5 +/- 0.3 and 0.8 +/- 0.7%, respectively. Ann dissolved in methanol was stable under the determination conditions. With chloroform, 60-90% of Ann was extracted from biological samples. Apart from Anone, two Ann metabolites (retention times 3.4 and 6.0 min) were detected in plasma and tissues from C57BL/6 mice bearing subcutaneous B16 tumors 6 h after intravenous administration of a 5-mg/kg suspension of Ann. No peaks were detected in blank tissues and plasma.

Animals↗

PubMed1993

Organ distribution and antitumor activity of free and liposomal doxorubicin injected into the hepatic artery.

The plasma levels, organ distribution, and in vivo antitumor activity of free and liposomal doxorubicin injected into the hepatic artery of rats bearing W256 liver tumors were studied. The administration of liposomal doxorubicin resulted in liver-tumor and liver-parenchyma doxorubicin areas under the curve (AUCs) that were 4.7- and 3.8-fold, respectively, those obtained after the administration of free doxorubicin. Spleen and plasma AUCs were also increased by 2.8 and 2.5 times, respectively, following administration of the liposomal form. In contrast, liposomal doxorubicin did not affect heart AUCs; peak doxorubicin levels in heart tissue were three times lower in animals treated with liposomal doxorubicin. Following treatment with the liposomal form, the cumulative urinary excretion of doxorubicin at 8 h was 38 times lower. In good correlation with these findings, liposomal doxorubicin (2.35 mg/kg on day 7) was more effective than free doxorubicin against liver W256 tumors as measured by tumor-growth inhibition at 5 days after treatment (16% for liposomal doxorubicin versus -53.7% for free doxorubicin, P < 0.05) and increased life span (ILS; 108% for liposomal doxorubicin versus 27% for free doxorubicin, P < 0.05). These results demonstrate that as compared with free doxorubicin, the administration of liposomal doxorubicin into the hepatic artery results in higher drug levels in the liver tumor and enhanced antitumor activity while maintaining the cardioprotective effect of the liposome carrier as suggested by the decreased peak drug levels measured in the heart tissue.

Animals↗

PubMed1993

Organ distribution and tumor uptake of annamycin, a new anthracycline derivative with high affinity for lipid membranes, entrapped in multilamellar vesicles.

Annamycin (Ann) is a lipophilic, non-cross resistant anthracycline antibiotic that is easily amenable to formulation in a wide variety of liposomal carriers. We studied the organ distribution and tumor uptake of Ann entrapped in multilamellar vesicles (L-Ann), free annamycin (F-Ann), and doxorubicin (DOX) in C57BL/6 mice bearing advanced subcutaneous B16 melanoma tumors. L-Ann was composed of DMPC: DMPG: Ann at a molar ratio of 7:3:0.7. Mean particle size was 1.88 +/- 0.89 microns, and the entrapment efficiency was 93.08% +/- 2.96%. F-Ann was prepared as a suspension (particle size < or = 0.2 microns) in 10% DMSO. Drug levels were measured by fluorescence spectrometry after extraction with chloroform. The extraction ratio ranged between 60% and 90% for both drugs in most tissues. Compared with those of DOX, organ AUCs of L-Ann were threefold higher in plasma and brain, twofold higher in liver and kidney, sixfold higher in lung, ninefold higher in spleen, and tenfold higher in B16 tumors. Compared with F-Ann, organ AUCs of L-Ann were twofold higher in plasma, liver, and B16 tumors and were twofold lower in brain. Heart AUCs were similar with all three drugs. Higher tumor uptake was associated with a faster penetration and more prolonged retention of Ann in tumor tissue compared with those of DOX. The results obtained indicate significant differences in organ distribution between L-Ann and DOX as a result of the higher affinity of Ann for lipid membranes and the use of the liposomes as a delivery system. The potential clinical relevance of the increased uptake of L-Ann in B16 tumors, lung, and brain is being investigated.

Animals↗

PubMed1993

Design and tumor targeting of anthracyclines able to overcome multidrug resistance: a double-advantage approach.

A novel, 'double-advantage approach' to developing more effective chemotherapies will be reviewed. This approach is based on a presumption that analogs designed on a sound hypothesis, and combined with a rationally selected drug delivery system, will optimize antitumor activity by creating drugs that are more active and that can be more specifically targeted to tumors. In the design of drugs superior to doxorubicin, we have focused on typical multidrug resistance and new anthracycline analogs, whose uptake is not affected by P-glycoprotein. Analysis of structural elements of anthracyclines affecting activity against multidrug resistant tumors and affinity for liposomes will be discussed. Annamycin, a lipophilic anthracycline analog, was selected for further preclinical development as a liposomal formulation and demonstrated, in the initial biological evaluation, high activity against tumors resistant to doxorubicin.

Animals↗

PubMed1993

Removal of the basic center from doxorubicin partially overcomes multidrug resistance and decreases cardiotoxicity.

Hydroxyrubicin, a synthetic doxorubicin analog in which the basic amino group at C-3' is replaced by a hydroxyl group, was used as a prototype compound to study the effects of basicity of the sugar moiety on the toxicity and antitumor activity of anthracycline antibiotics. Compared with doxorubicin, hydroxyrubicin showed similar or superior in vitro cytotoxicity against P388, L1210, and M5076 cells, as determined by an MTT assay, and against 8226 and CEM cells, as determined by a growth inhibition assay. Hydroxyrubicin was 5 and 13 times more effective than doxorubicin in inhibiting the growth of multidrug-resistant CEM (CEMvbl) and 8226 (8226R) cells, respectively. Hydroxyrubicin was not cross-resistant with doxorubicin in a cytotoxicity assay against KB 3-1 and KB V1 cells (resistance index 1.1 for hydroxyrubicin versus > 15.6 for doxorubicin). Cellular uptake and retention of hydroxyrubicin were studied by flow cytometry in parent and multidrug-resistant 8226 cells, and compared with those of doxorubicin. In 8226 sensitive cells, 2 h uptake and retention of doxorubicin were similar or higher than those of hydroxyrubicin. In 8226R cells, uptake and retention of hydroxyrubicin were about 3-fold higher than those of doxorubicin. In mice, the acute LD50 of hydroxyrubicin was about 3-fold higher than that of doxorubicin (79.1 versus 25.7 mg/kg). At equitoxic doses, hydroxyrubicin was as myelosuppressive as doxorubicin but less cardiotoxic, as assessed by the Bertazzoli test. In contrast to doxorubicin, hydroxyrubicin, due to the lack of basic amine function, showed no selective interaction with negatively-charged cardiolipin (CL). The observed decrease of affinity to CL might be responsible for the reduced cardiotoxicity of hydroxyrubicin. In in vivo antitumor activity studies, hydroxyrubicin at the optimal dose (37.5 mg/kg, i.p., on day 1) had significant activity against intraperitoneal P388 leukemia resistant to doxorubicin, whereas doxorubicin (10 mg/kg, i.p., on day 1) was inactive (%T/C 163-200 versus 118-120). These studies indicate that: (i) the amino group at position 3' is not essential for doxorubicin to exert its biological activity, (ii) removal of the basic center (deamination at the C-3') results in an increased cellular uptake and retention, (iii) the increased cellular uptake and retention of hydroxyrubicin in multidrug-resistant cells correlate with a partial or total lack of cross-resistance of this analog with the parent compound, doxorubicin, and (iv) deamination at position 3' confers a reduced cardiotoxicity and diminished affinity for CL.

Animals↗

PubMed1992

Lipophilic cisplatin analogues entrapped in liposomes: role of intraliposomal drug activation in biological activity.

cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (NDDP), a lipophilic cisplatin analogue containing two branched leaving groups of 10 carbon atoms, is undergoing clinical evaluation in a liposomal formulation. In previous studies, NDDP entrapped in multilamellar vesicles composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) at a 7:3 molar ratio was non-nephrotoxic in humans, not cross-resistant with cisplatin in different in vitro and in vivo systems, and more active than cisplatin against murine models of experimental liver metastases whereas free NDDP was devoid of in vivo antitumor activity at the optimal dose of L-NDDP and barely active at higher doses. To elucidate the mechanisms by which the liposomal carrier enhances the biological properties to this class of antitumor agents, we studied the effect of the liposome composition, size of the branched leaving groups of the platinum compound, and pH and composition of the aqueous phase on the entrapment efficiency, drug leakage, drug stability, and in vivo toxicity and antitumor activity of different liposomal formulations of these agents. In experiments using normal saline as aqueous phase, the presence of DMPG in the lipid bilayer resulted in a decreased stability and an increased biological activity of NDDP, whereas NDDP entrapped in liposomes composed of DMPC alone (not containing DMPG) was stable but devoid of antitumor activity. In studies with structurally related analogues with branched leaving groups of 5, 6, 7, and 9 carbon atoms, similar trends were observed. In addition, the number of carbon atoms in the leaving groups was directly and inversely related to the entrapment efficiency and stability of the analogues, respectively, independently of lipid composition; increasing the size of the branched leaving groups resulted in an increased in situ degradation of the platinum compound and enhanced biological activity and potency. These results suggest that this class of platinum compounds exerts its biological activity through the formation of active intermediates in situ within the lipid bilayers and that the activation reaction is highly dependent on the presence of DMPG and the size of the lipophilic leaving group.

Animals↗

PubMed1992

Targeting liver tumors by administering liposomal doxorubicin into the hepatic artery.

The plasma levels, organ distribution, and in vivo anti-tumor activity of liposomal doxorubicin administered i.v. or i.a. (hepatic) in rats bearing W256 liver tumors were studied. I.a. administration of liposomal doxorubicin resulted in 4-fold and 1.3-fold higher liver tumor and liver parenchyma doxorubicin levels, respectively, than i.v. administration, thus suggesting a more preferential distribution of liposomal doxorubicin into the liver tumor with i.a. administration. By contrast, the heart, spleen, and plasma AUCs were decreased 3.8-, 3.2-, and 16-fold, respectively, after i.a. administration. Cumulative urinary excretion at 8 hr was also 14 times lower in animals that received liposomal doxorubicin i.a. In good correlation with these findings, i.a. administration markedly enhanced the anti-tumor effect of liposomal doxorubicin against liver W256 tumors as measured by tumor growth inhibition 5 days after treatment (-16% for i.a. administration vs. +89% for i.v. administration, p less than or equal to 0.05) and prolongation of survival (ILS: 108% for i.a. administration vs. 26% for i.v. administration, p less than or equal to 0.05). Our results show that i.a. administration of liposomal doxorubicin results in preferential distribution of the anti-tumor agent into the tumor tissue and increased anti-tumor activity, while increasing the cardioprotective effect of the liposome carrier by decreasing the plasma peak and heart-tissue levels of the drug.

Animals↗

PubMed1992

Liposomal formulation and antitumor activity of 14-O-palmitoyl-hydroxyrubicin.

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.

Animals↗

PubMed1992

Pharmacokinetics of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) and cisplatin given i.v. and i.p. in the rat.

The pharmacokinetics of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (L-NDDP) and cisplatin (CDDP) were studied after i.v. and i.p. administration of an equimolar dose (11 and 5 mg/kg for L-NDDP and CDDP, respectively) in the rat. The systemic absorption following i.p. administration was faster in rats receiving CDDP than in those receiving L-NDDP. Peak serum platinum (Pt) levels were observed at 30 min and 12 h after the i.p. administration of CDDP and L-NDDP, respectively. Administration by the i.v. route did not significantly alter the serum Pt levels for either compound. However, serum Pt levels were 2-3 times greater in animals treated with L-NDDP than in those treated with CDDP. The estimated pharmacokinetic parameters for each drug were independent of the route of administration, except for the clearance (Cl) of CDDP, which increased 2-fold following i.p. administration. In addition, significant differences in pharmacokinetic parameters were observed between drug-treatment groups that were independent of the route of administration: the serum Pt area under the concentration-time curve (AUC) was higher and the volume of distribution at steady state (Vdss) was lower in rats receiving L-NDDP. Pt levels measured at 6 h in the peritoneal fluid, peritoneal tissue, and intestine of rats receiving i.p. L-NDDP were higher than those observed in rats receiving either i.v. L-NDDP or CDDP by either route. Pt levels measured in the liver and spleen of rats receiving L-NDDP were independent of the route of administration and were significantly higher than those determined in rats treated with CDDP. In contrast, kidney Pt levels were lower in rats receiving L-NDDP than in rats receiving CDDP by either route. These results suggest that the prolongation of the mean retention time of L-NDDP in the peritoneum achieved after i.p. administration without compromising the systemic distribution of the drug may result in a significant enhancement of the therapeutic efficacy of L-NDDP against malignancies confined to the peritoneal cavity as compared with that of i.p. CDDP.

Animals↗

PubMed1992

Synthesis and biological studies of new lipid-soluble cisplatin analogues entrapped in liposomes.

A series of highly lipophilic platinum(II) complexes of the type cis-[(RNH2)2PtX2] have been synthesized, where R = ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclopentyl, or neopentyl and X = either long-chain carboxylate, such as decanoate (C10), laurate (C12), myristate (C14), heptadecanoate (C17), stearate (C18), nonadecanoate (C19), or 2,2,3,3-tetramethylcyclopropylcarboxylate, or branched-chain carboxylate, such as neopentanoate, neohexanoate, neoheptanoate, neononanoate, or neodecanoate. These complexes have been characterized by elemental analysis, IR, and 13C and 195Pt NMR spectroscopic techniques. The platinum complexes were entrapped in multilamellar vesicles composed of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) at a 7:3 molar ratio and tested for antitumor activity. The entrapment efficiency of liposomal platinum (L-Pt) complexes ranged from 60 to 100%. The percentage of T/C obtained after a single i.p. injection of the optimal dose of L-Pt complexes tested against L1210 leukemia ranged from 90 to 125%. These L-Pt preparations did not show significant antitumor activity in mice.

Animals↗

PubMed1992

Liposomes in the treatment of malignancy: a clinical perspective.

Technological advances in liposomal preparation and efficient drug entrapment, along with supportive preclinical studies, have led to a number of recent clinical trials utilizing liposomes as drug carriers in the treatment of human malignancy. Although the results of these trials must be considered preliminary, it is clear that liposomal delivery of chemotherapeutic agents is safe at the doses administered. Aside from minor constitutional symptoms, virtually all toxicity could be attributed to release of the incorporated drug. Myelosuppression tends to be the dose-limiting toxicity with free drug, whereas constitutional symptoms are more likely to occur with encapsulated biologic therapy. Prior to human trials, there was fear that intravenous injection of liposomes could result in pulmonary emboli. No cases of pulmonary embolism secondary to liposome therapy have been recorded. The objective response rate in the patients studied appears to be minimal. This is not surprising, since the overwhelming majority of patients studied had disease that was advanced and previously shown to be refractory to therapy. Subgroups of patients that appear to benefit most include those with breast cancer who were treated with liposomal doxorubicin and those with advanced melanoma treated with liposomal tumor vaccines. Additional phase II and III clinical trials will better define the effectiveness of treatment modalities incorporating liposomes. VI-A. Future directions One of the earliest applications of liposomes may be in the amelioration of drug toxicity. Although not yet proven, the clinical studies reviewed suggest that liposomal delivery of doxorubicin reduces cardiotoxicity without sacrificing antitumor effect. Although similar claims have been made in support of continuous infusion doxorubicin [11], one can avoid unnecessary hospitalization or the bulk and expense of portable infusion devices by a single administration of the liposomal preparation. Liposome encapsulation can markedly alter the biodistribution and pharmacokinetics of well-known chemotherapeutic agents. The effectiveness of liposomal drug delivery in human trials thus far has probably been more closely related to altered pharmacokinetics rather than enhanced drug delivery to tumor or increased tumor responsiveness. As demonstrated by Gabizon [19], increased liposome circulating time in the murine model can be achieved by using small unilamellar vesicles containing a phosphatidylcholine of high phase-transition temperature and a small molar fraction of monosialoganglioside or hydrogenated phosphatidylinositol.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1992

Toxicity and efficacy studies on a series of lipid-soluble dineodecanoato(trans-R,R- and trans-S,S-1,2-diaminocyclohexane) platinum (II) complexes entrapped in liposomes.

A number of highly lipophilic dineodecanoato(trans-R,R- and trans-S,S-1,2-diaminocyclohexane) platinum (II) complexes were entrapped in multilamellar vesicles composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidyl-glycerol at a molar ratio of 7:3. The entrapment efficiency and stability of liposomal platinum (L-Pt) preparations was greater than 90%. The subacute mouse LD50 of L-Pt preparations tested ranged from 60 to 104 mg/kg. All L-Pt preparations tested had no significant nephrotoxicity at the LD50 dose except for L-Pt 5, which caused renal dysfunctions (as evidenced by elevated blood urea nitrogen levels) at the LD50 dose. L-Pt preparations had shown good in vivo antitumor activity against i.p. L1210 leukemia when an optimal dose was administered i.p. to mice on days 1, 5 and 9 (% T/C 230-300; cisplatin 220). L-Pt preparations were also markedly active, by the i.p. route, against L1210 leukemia resistant to cisplatin (% T/C 237-355; cisplatin 112). All L-Pt preparations exhibited significant antitumor activity against B16 melanoma when administered i.p. on day 1 (% T/C 144-155; cisplatin 161). L-Pt 1, 3 and 5 were all tested by the i.v. route on days 4, 8 and 12 against M5076 reticulosarcoma, but none of these preparations showed any significant antitumor activity against this tumor system (% T/C 120-127; cisplatin 173). Current studies aimed at optimizing the liposomal formulation of these compounds should result in the selection of a single isomeric L-Pt formulation for clinical development.

Animals↗

PubMed1991

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.

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.

Animals↗

PubMed1990

Anthracycline antibiotics with high liposome entrapment: structural features and biological activity.

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.

Animals↗

PubMed1990

Phase I clinical and pharmacological study of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II).

cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ +(II) (NDDP) is a liposome dependent cisplatin analogue since the liposome carrier is required for its i.v. administration and for its biological activity. A Phase I study of liposome entrapped NDDP (L-NDDP) was performed using a single i.v. injection every 4 weeks. L-NDDP was prepared and characterized at M. D. Anderson Cancer Center. The maximum tolerated dose of L-NDDP was 312.5 mg/m2. The dose-limiting toxicity was myelosuppression, affecting all three blood cell lineages. The granulocyte nadir occurred on days 14-18, and the platelet nadir consistently earlier (days 11-12). The median day of recovery of blood cell counts was day 21 (range, 18-32). Other toxicities included grade 2 nausea and vomiting, fever consisting of a single temperature spike in most patients, grade 1 diarrhea after 60% of courses, and grade 1-2 malaise lasting for 5-10 days after the infusion in 73% of courses. Transient alanine aminotransferase elevations without clinical relevance were common. No signs of renal dysfunction or ototoxicity were observed. One patient with a preexisting peripheral neuropathy showed some progression of the neuropathy after a cumulative dose of 1605 mg/m2. Except for fever and transient liver dysfunction, no liposome related side effects were observed in spite of the high doses of lipid administered. The blood clearance of L-NDDP fits a two-compartment model at lower doses and a single-compartment model at the maximum tolerated dose, suggesting that saturation of the reticuloendothelial organs occurs at the maximum tolerated dose. Two minimal responses were observed. L-NDDP has a toxicity profile similar to that of carboplatin. Phase II studies to address the issue of how the therapeutic index of platinum compounds is affected by liposome entrapment are being planned.

Antineoplastic Agents↗

PubMed1990

3'-Hydroxyesorubicin. Synthesis and antitumor activity.

A novel route to 4'-deoxy anthracycline analogues has been developed starting from previously unavailable, optically active 4,6-dideoxy-hex-1-enitol 9. Coupling of daunomycinone (11) or 14-O-tert-butyldimethylsilyladriamycinone (12) with glycosyl chloride 10 in Koenigs-Knorr condition gave mainly alpha anomers, which were successfully deblocked to final 3'-deamino-4'-deoxy-3'-hydroxydaunorubicin (7) and 3'-deamino-3'-hydroxyesorubicin (8). Analogues were evaluated in vitro against P388 and L1210 leukemia and M5076 cells and in vivo against P388 leukemia. Compared with doxorubicin (1), 3'-hydroxyesorubicin (8) showed in vitro similar cytotoxic potential and in vivo higher antitumor activity.

Animals↗