title: Toxicity and anti-tumor activity of hydrophobic diammine and diaminocyclohexane platinum complexes entrapped in multilamellar vesicles.
abstract: The toxicity and anti-tumor activity of a lipophilic diaminocyclohexane (DACH) platinum complex entrapped in liposomes (liposomal-cis-bis-neodecanoato-trans-R, R-1, 2-DACH platinum II-L-NDDP) were compared with those of the liposomal preparation of the same compound without the DACH group (liposomal-cis-bis-neodecanoato-(diammine) platinum II-L-CNDP). Both liposomal preparations had the same liposome size distribution, drug entrapment efficiency (greater than 95%), and liposome stability (greater than 95%). Although no differences were observed in the mouse LD50 (60.2 mg/kg for L-NDDP vs 67.8 mg/kg for L-CNDP), the liposome entrapped non-DACH compound (L-CNDP) was more nephrotoxic than the liposome entrapped DACH compound (L-NDDP), but much less than cisplatin (CDDP) (mean BUN elevation 4 days after the administration of the LD50 dose 67 mg% for L-CNDP vs 30 mg% for L-NDDP vs 255 mg% for CDDP). L-NDDP was not cross-resistant with CDDP against L1210/CDDP leukemia while L-CNDP was cross-resistant (%T/C 200 for L-NDDP, 112 for CDDP, and 100 for L-CNDP). In addition, L-NDDP was slightly more active than L-CNDP against i.p. L1210/0 leukemia and i.v. M5076 reticulosarcoma. These studies suggest that the attachment of a cyclohexane group to the amino functions of lipophilic platinum complexes results in a decrease of the nephrotoxicity and a lack of cross-resistance with CDDP. The lack of cross-resistance is preserved when the compounds are entrapped and delivered in a liposomal carrier but not when they are delivered in a micellar suspension.
authors.affiliation: Department of Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston.
authors.forename: A R
authors.initials: AR
authors.lastname: Khokhar
authors.forename: S
authors.initials: S
authors.lastname: Al-Baker
authors.forename: R
authors.initials: R
authors.lastname: Perez-Soler
mesh_terms: D000818:Animals; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D007668:Kidney / Q000187:drug effects; D007939:Leukemia L1210 / Q000188:drug therapy; D008081:Liposomes; D051379:Mice; D008815:Mice, Inbred Strains; D012513:Sarcoma, Experimental / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D008081:Liposomes; D002945:Cisplatin