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PubMed2002

Long-term disposition of a novel lipophilic platinum complex SM-11355 in dog after intrahepatic arterial administration: highly sensitive detection of platinum and radioactivity.

1. The disposition of SM-11355, an anticancer platinum complex for hepatocellular carcinoma, was investigated in dog by measuring platinum (Pt) and radioactivity levels following intrahepatic arterial administration of (14)C-SM-11355 suspended in Lipiodol, an oily lymphographic agent. Plasma and excretion profiles were monitored in six animals, with tissue distribution studied after 1 day, 4 and 13 weeks (n = 2/time point). 2. SM-11355 was released very slowly into the systemic circulation from Lipiodol, resulting in very low levels of Pt compounds in plasma, urine, faeces and organs. Plasma levels of Pt and radioactivity declined with apparent half-lives of 5-7 weeks. Excretion continued even at 3 months after the administration with proportions excreted for Pt and radioactivity up to 30-60% in urine and 8-10% in faeces. 3. The Pt and radioactivity in the liver accounted for 80-100% of the dose at 1 day and for 20-50% at 13 weeks after the administration, predominately as intact SM-11355. The concentrations were highest in the left lobe of the liver, the administration site, but levels in the remainder of the liver were also markedly higher than those in plasma and other tissues. 4. The results strongly support the concept that SM-11355 targets the liver with highly selectivity and sustained release of Pt compounds.

Animals↗
PubMed1987

A randomized study comparing platinum, doxorubicin, and VP-16 with platinum, 4'-epidoxorubicin, and VP-16 in patients with non-small-cell lung cancer.

Forty-four previously untreated patients with advanced non-small-cell lung cancer were treated in a randomized trial comparing platinum (60 mg/m2), doxorubicin (40 mg/m2), and VP-16 (150 mg/m2) (PAV) with platinum (60 mg/m2), 4'-epidoxorubicin (50 mg/m2), and VP-16 (150 mg/m2) (PEV). The overall response rate was 10%. Major response rates were quite similar for the 21 patients treated with PAV (5%) and the 23 patients treated with PEV (18%) (p = 0.2). Of the 23 patients with assigned to PEV, two (9%) achieved complete responses for a median duration of 20 weeks and 44+ weeks. There was no significant difference (p = 0.75) in the median survival among patients treated with PAV (24 weeks) and those treated with PEV (20 weeks). Toxicity was generally mild and tolerable. The lack of response found in both arms of treatment caused the study to be terminated early. Some benefit could be appreciated in patients with limited disease and good Karnofsky performance status.

Adenocarcinoma↗
PubMed2002

Biological availability of traffic-related platinum-group elements (palladium, platinum, and rhodium) and other metals to the zebra mussel (Dreissena polymorpha) in water containing road dust.

The uptake and bioaccumulation of 15 road dust metals by the zebra mussel (Dreissena polymorpha) were investigated in laboratory exposure studies with emphasis on the traffic-related platinum-group elements (PGEs) palladium (Pd), platinum (Pt), and rhodium (Rh). The biological availability of the metals may depend on water characteristics, so the mussels were maintained in two types of water: nonchlorinated tap water and humic water of a bog lake, both of which contained dust of a moderately frequented road. After an exposure period of 26 weeks, soft tissues of the mussels were freeze-dried and analyzed for the metals. The metal concentrations in the mussel soft tissue ranged from several hundred micrograms per gram (e.g., for iron [Fe]) to less than 10 ng/g (for PGEs). Metal uptake from the road dust by the mussels was found for the PGEs and silver (Ag), bismuth (Bi), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), Fe, lead (Pb), and antimony (Sb). After maintenance of mussels in road dust-contaminated tap water, bioaccumulation factors (BAF = (C(exposed mussels) - C(control mussels))/C(total metal, water), where c is concentration) decreased in the following order: Cu > Cd > Ag > Pd > Sb > Pb > Fe > Pt > Rh. The biological availability of most metals was enhanced by humic water as compared to tap water. Our results show a hitherto unrecognized high availability of Pd for the mussels. Thus, this metal should be monitored more intensively in the environment to assess its distribution in the biosphere.

Animals↗
PubMed1986

Cisplatin administered as a continuous 5-day infusion: plasma platinum levels and urine platinum excretion.

Total and filterable platinum in plasma were monitored for seven courses (five patients, 25 mg/m2/day) using continuous 5-day infusions and one 30-minute infusion at a similar dose level (120 mg/m2). Maximum filterable (non-protein-bound) platinum levels (0.1-0.3 mg/L) for the extended infusions were ten to 40 times lower than that for the short-term infusion (4.0 mg/L). Filterable drug exposure as measured by the area under the [Pt]filterable-time curve is greater for the extended infusions (9.6 mg X hr/L) than that for the short-term infusion (4.8 mg X hr/L). Renal excretion of cisplatin (% of dose excreted/24-hour period after the beginning of the infusion) was measured for four courses of continuous 5-day infusions and for the 30-minute infusion. Urine excretion rates were lower for the continuous infusion (5%-8% of dose/24-hour period during the infusion) compared to the short-term infusion (33% of dose/24-hour period after the beginning of the 30-minute infusion).

Cisplatin↗
PubMed1995

Antitumor activity of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2- isopropyl-1,3-dioxolane]platinum(II), a new platinum analogue, as an anticancer agent.

The in vitro and in vivo antitumor activity of a new antitumor platinum complex, cis-malonato[(4R, 5R)-4,5- bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI2053R, NSC D644591), were evaluated and compared with those of cisplatin (CDDP) and carboplatin (CBDCA) using murine tumors. SKI 2053R was highly active in vitro against both L1210 murine leukemia and its CDDP-resistant subline, L1210/DDP; the relative resistances were 20.0-, 14.5-, and 2.7-fold for CDDP, CBDCA, and SKI 2053R, respectively. SKI 2053R showed activity comparable with or superior to either CDDP or CBDCA in mice implanted with L1210. In mice implanted with L1210/DDP, as compared with CBDCA, SKI 2053R showed high values for the percentage of treated survivors relative to controls and for numbers of cured mice, whereas CDDP had virtually no activity. In mice implanted with P388, all three drugs were highly active, but the intensity of activity was shown to be ranked in the following order: SKI 2053R > CDDP > CBDCA. The antitumor activity of SKI 2053R against Lewis lung carcinoma was comparable with that of both CDDP and CBDCA. The antitumor activity of SKI 2053R was further investigated against two human tumor xenografts, KATO III (stomach adenocarcinoma) and WiDr (colon adenocarcinoma), implanted s.c. in nude mice and was compared with that of CDDP. In SKI 2053R-treated groups, the time required for a mean tumor weight of 1,000 mg was 33.1 days in KATO III xenografts and 35.0 days in WiDr xenografts as compared with 30.2 and 27.2 days in CDDP-treated groups, respectively. SKI 2053R achieved growth-inhibition rates comparable with those of CDDP against KATO III (65% versus 59%) and WiDr xenografts (64% versus 54%) on day 35. These results indicate that SKI 2053R is an attractive candidate for further development as a clinically useful anticancer drug.

Adenocarcinoma↗
PubMed1989

A comparison of cis-platinum-vindesine and cis-platinum-etoposide combined with radiotherapy for previously untreated localized inoperable non-small cell lung cancer.

Seventy-two previously untreated patients with localized inoperable non-small cell lung cancer were randomized to a study comparing the efficacy of cis-platinum-vindesine (P-VDS) and of cis-platinum-VP16 (P-VP16), both combined with split-course radiotherapy. Fifty-nine patients were evaluable for response after the minimum requirement of two chemotherapy cycles. Both arms were further randomized to two split intervals, 3 or 5 weeks. The response rate to chemotherapy only (three cycles) was 66% for P-VDS and 50% for P-VP16. Radiotherapy increased the response rates to 83 and 67%, respectively. A Karnofsky score of 80% or more and the 3-week split interval were significant positive prognostic factors. Of all patients, 66% had local or combined recurrences and 17% relapsed at a distant site only. Since the 2-year survival rates are not strikingly better than those obtained by radiotherapy alone, we feel that these regimens should be restricted to further investigations of the role of chemotherapy in the treatment of different clinical presentations of NSCLC.

Aged↗
PubMed2005

Induction of heat shock proteins (hsp70) in the zebra mussel (Dreissena polymorpha) following exposure to platinum group metals (platinum, palladium and rhodium): comparison with lead and cadmium exposures.

An increasing number of papers concentrate on the availability and uptake of platinum group elements (PGE) by different organisms. These metals are discharged into the environment from different anthropogenic sources, such as automobile catalytic converters, hospitals and other medical institutions. As the effects of these precious metals on organisms remain unclear, the induction of heat shock proteins (hsp70) in zebra mussels (Dreissena polymorpha) following exposure to soluble salts of platinum, palladium and rhodium was compared with the hsp70 induction in mussels following exposure to cadmium and lead. Mussels were sampled weekly during a period of 10 weeks and analyzed for their metal concentration and their hsp70 level. Highest metal uptake was found for Cd, followed by Pt, Pb and Pd. Rh demonstrated the lowest uptake rate. A clear time-dependent increase of hsp70 levels occurred in all exposed mussels. Concentrations of hsp70 started to rise between days 18 and 25, except for the Pt-exposed group, where the initial increase was between days 25 and 32. All groups reached maximal hsp70 concentrations at day 39. Subsequently, hsp70 levels decreased to initial levels for the remaining exposure period. Threshold metal levels for the hsp70 induction varied among the metals and increased in the order: Rh<Pd< or =Pb<Pt<Cd. Highest hsp70 values were found for mussels exposed to Pd, with a 25-fold higher level than in the controls, followed by Pt- and Rh-exposed mussels, which showed a 19-fold increase. The hsp70 levels of the mussels exposed to Cd and Pb were much lower, showing 6- and 12-fold higher values than the control, respectively. The clear induction of hsp70 due to exposure to Pt, Pd and Rh gives evidence for strong cellular effects of these metals, especially, when compared with lead and cadmium. Among the metals tested, Pd seems to have the highest potential as inducer for hsp70 production due to its low threshold level in combination with the strongest effect.

Animals↗
PubMed1997

Synthesis and antitumor activity of the metformin platinum (IV) complex. Crystal structure of the tetrachloro(metformin)platinum (IV) dimethylsulfoxide solvate.

The synthesis of (metformin) tetrachloroplatinum (IV) was investigated (metformin is N,N-dimethylbiguanide). It crystallizes with one dimethylsulfoxide molecule as solvate in the monoclinic system, space group P2(1)/n (No. 14) with Z = 4. The cell dimensions are: a = 13.136(7), b = 9.424(2), c = 14.009(8) A, beta = 111.96(4) degrees, V = 1608.4(2) A3. Of the 4269 independent nonzero reflections collected, 1979 with I > 3 sigma (I) were considered and used in the calculations. The structure was refined to R = 0.043 and wR = 0.045. The platinum coordination is octahedral, built up from four chloride anions and one bidentate chelating ligand via the two imine nitrogen atoms cis position. The distances and angles are typical of six-membered rings that have similar donor atoms. The complex was evaluated in vitro and in vivo on murine P388 leukemia. It was found to be as potent as cis-dichlorodiammine platinum (II), CDDP, in inhibiting the proliferation of the sensitive P388 cells. However the resistant P388/CDDP cells were threefold more sensitive to the compound than to CDDP. The two compounds induced a similar perturbation in the G2+M phases of the cell-cycle. The complex was less active than CDDP in vivo on P388 leukemia when administered i.p. (intra peritoneal) on day 1.

Animals↗
PubMed1987

Comparative antitumor studies on platinum(II) and platinum(IV) complexes containing 1,2-diaminocyclohexane.

The synthesis and characterization of a group of platinum(IV) compounds containing the various isomeric forms of 1,2-diaminocyclohexane (DACH) are described. Antitumor tests with the new complexes, as well as with other platinum(II) compounds containing the DACH ligand, revealed that trans,cis-PtIV(SS-DACH)(OH)2Cl2, 7, is more active than its mirror image, trans,cis-PtIV(RR-DACH)(OH)2Cl2, 6, against L1210 leukemia implanted in mice. However, activity is dependent on the tumor model, and against B16 melanoma implanted in mice, the activities of the two enantiomers are reversed, with 6 being more active than 7. The results of the tests are discussed in light of the mechanism by which Pt(IV) compounds are believed to express their antitumor effects.

Animals↗
PubMed1992

Stability of the new anticancer platinum analogue 1,2-diaminomethyl-cyclobutane-platinum(II)-lactate (lobaplatin; D19466) in intravenous solutions.

The chemical stability of the new anticancer platinum analogue 1,2-diaminomethyl-cyclobutane-platinum(II)-lactate (D19466) in infusion media was studied in an accelerated stability testing experiment with a selective HPLC-UV method. Variables were time, temperature, light, concentration, and infusion mixture. Mean reaction rate constants of decomposition were, respectively, 0.9555 *10(-2), 2.127 *10(-2), and 4.221 *10(-2) hr-1 at 37, 56, and 66 degrees C at a concentration of 200 mg/L in normal saline. From the Arrhenius equation, shelf lives (5% loss) at 4, 22, 37, and 121 degrees C were, respectively, calculated to be 41.6, 13.2, 5.7, and 0.15 hr. Mean reaction rate constant in 5% dextrose was 3.106 *10(-2) hr-1 (200 mg/L; 56 degrees C) and differed from that in normal saline (P less than 0.005). Mean reaction rate constant in Ringer lactate was 2.084 *10(-2) hr-1 (200 mg/L; 56 degrees C) (P greater than 0.05). There was no influence of normal daylight on the rate of decomposition. It is recommended to prepare D19466 infusions in normal saline. Chemical stability is then maximal 12 hr at room temperature or 24 hr at 4 degrees C. No protection against normal daylight is required. Sterilization by heat is not possible.

Antineoplastic Agents↗
PubMed1987

Platinum-DNA adducts in leukocyte DNA correlate with disease response in ovarian cancer patients receiving platinum-based chemotherapy.

Fifty-five ovarian cancer patients receiving platinum drug-based chemotherapy have been studied prospectively to determine the extent of formation of the bidentate intrastrand adducts of diammineplatinum covalently attached to the N7 positions of adenosine and/or guanosine in leukocyte DNA. Data for clinical response, obtained from medical records, were then correlated with the adduct values. Patients were treated with platinum-based single-agent or combination chemotherapy containing cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum on approved experimental protocols. Adduct measurements were performed by ELISA, and disease response to therapy was assessed by standard oncologic criteria. This study comprises a total of 101 blood samples obtained after intravenous cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum infusion from 55 individuals, and in each case the highest (or "peak") adduct level for each patient was chosen for statistical analysis. Values for median adduct levels in patients grouped by complete response, partial response, and no response were 212, 193, and 62 amol of adduct per microgram of DNA, respectively. Analysis of these data by Jonckheere's test (an extension of the Mann-Whitney test) shows that higher levels of adduct formation correlates with disease response with a two-sided P value of 0.030. Of eight patients on single-agent therapy whose buffy-coat samples did not have measurable adduct levels, none responded to therapy. Analysis of these data using the exact test for trend shows that the formation of adduct at a level of 160 amol/micrograms of DNA or greater correlates with disease response with a two-sided P value of 0.032. Thus in ovarian cancer patients, the formation of the intrastrand diammineplatinum adducts in leukocyte DNA is associated with favorable disease response to cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum chemotherapy.

Adult↗
PubMed1985

Prospective randomized trial in advanced malignant melanoma with cis-platinum, vindesine, and etoposide vs. cis-platinum, vindesine, and lomustine.

Thirty-seven consecutive patients with disseminated malignant melanoma and previously untreated with chemotherapy were randomly allocated to receive vindesine, cis-platinum, and etoposide (Regimen A) or vindesine, cis-platinum, and lomustine (Regimen B). In 31 evaluable patients, Regimen A induced an overall response rate of 31% and a complete response rate of 6%; with Regimen B the corresponding findings were 20% and 20%, respectively. The median duration of complete response was 12 months with both regimens and the comparative median total survivals were 8 and 6 months, respectively. In no case was toxicity so severe to require treatment discontinuation, and the major dose-limiting side effect was myelosuppression, especially in the patients treated with Regimen B. Present results confirm once more the limited activity of drugs and regimens presently utilized in the treatment of advanced malignant melanoma.

Adult↗
PubMed2003

Hexafluorophosphates of chlorotris(dimethyl sulfide)platinum(II) and bromotris(dimethyl sulfide)platinum(II).

The title compounds, chlorotris(dimethyl sulfide-kappaS)platinum(II) hexafluorophosphate, [PtCl(C(2)H(6)S)(3)]PF(6), and bromotris(dimethyl sulfide-kappaS)platinum(II) hexafluorophosphate, [PtBr(C(2)H(6)S)(3)]PF(6), are isomorphous and are composed of [PtX(dms)(3)](+) complex cations (X = Cl and Br, and dms is dimethyl sulfide) and PF(6)(-) anions. The Pt atom is coordinated by three S atoms and one X atom in a pseudo-square-planar coordination, with Pt-S distances in the range 2.293 (1)-2.319 (2) A. Two dms ligands have a staggered conformation with respect to the coordination plane, while the third is rotated by approximately 90 degrees compared with the orientation of the other two. The packing can be described as consisting of [PtX(dms)(3)](2)(PF(6))(2) units with a centre of symmetry. In this description, the Pt(II) atom has a pseudo-octahedral coordination, with four normal bonds and two long weak interactions. Density-functional theory calculations show that a conformation in which one dms ligand is not staggered is less favourable than having all three dms ligands staggered.

Journal Article↗
PubMed2000

Packing effects on the geometry of neutral platinum(II) complexes due to solvate molecules: the structures of trans-dichlorobis(triphenylarsine)-platinum(II)

A series of structures of trans-dichlorobis(triphenylarsine)platinum(II), recrystallized from four different solvents, have been characterized by X-ray crystallography and were shown to crystallize as different solvates (same metal complex, different crystallization solvents). Their geometric differences induced by packing and solvent molecules were analysed with half-normal probability plots and root-mean-square deviations. The recrystallization solvents used in the investigation were 1,1,1-trichloroethane, dichloromethane, 1,2-dichloroethane and benzene, and the following crystallization modes were obtained. From 1,1,1-trichloroethane the metal complex crystallizes without solvent as trans-[PtCl2(AsPh3)2] in P2(1)/n with Z = 2, a = 9.271 (2), b = 19.726 (4), c = 9.830 (2) A, beta = 111.83 (3)degrees, V = 1668.8 (6) A3, R = 0.0262, and from dichloromethane with two solvent molecules as trans-[PtC12(AsPh3)2].2CH2C12 in Pbca with Z= 4, a = 20.582 (4), b = 8.146 (2), c = 23.491 (5) A, V = 3938.5 (14) A3 and R = 0.0316. From dichloroethane it crystallizes with one solvent molecule as trans-[PtC12(AsPh3)2].C2H4C12 in P1 with Z = 1, a = 9.390 (2), b= 9.548 (2), c = 11.931 (2) A, alpha = 109.70 (3), beta = 108.26 (3), gamma = 98.77 (3) , V= 915.6 (3) A3, R = 0.0390, and from benzene with half a solvent molecule as trans- [PtC12(AsPh3)2].0.5C6H6 in P2(1)/n with Z = 4, a = 11.778 (2), b = 18.712 (4), c = 16.647 (3) A, beta = 104.78 (3) , V= 3547.3 (12) A3 and R = 0.0303. In all four compounds platinum(II) coordinates to triphenylarsine and chloride in a pseudo-square-planar trans configuration. The Pt-As distances are in the range 2.4104 (4)-2.3923 (4) A and the Pt-C distances are in the range 2.309 (2)-2.2839 (9) A. The solvents have a large influence on the packing, resulting in different space groups or different occupancies in the same space group. Half-normal probability plots show that the largest geometric differences, within the metal complex, are in the bond and torsion angles around the As-C bonds. Very similar torsion angles were observed around the Pt-As bond for all the structures, except for one AsPh3 ligand in the benzene solvate, which differs by about 10 from the others. The metal-donor bond distance varies by as much as 0.019 and 0.025 A (95% confidence interval) for Pt-As and Pt-C1, respectively. The variations are essentially caused by intermolecular interactions. Packing efficiency is expressed as the volume filled by each metal complex in the unit cell and is calculated by subtracting the sum of the solvent molecule volumes from the total volume of the unit cell and then dividing by Z. The efficiency is largest in the dichloroethane solvate and smallest in the non-solvated compound, with a difference of approximately 22 A3 per metal complex.

Journal Article↗
PubMed1992

Flow cytometric analyses of the characteristics of tumor cells treated with two platinum compounds: 1,1-cyclobutanedicarboxylato(2-aminomethylpyrrolidine)- platinum(II) and cisplatin.

In order to reduce the toxicities of cisplatin (DDP) and/or to improve antitumor efficacy, a large number of new platinum analogues have been synthesized. 1,1-Cyclobutanedicarboxylato(2-aminomethylpyrrolidine)platin um(II) (DWA2114R) is one of them. In this study, we characterized the action mechanism of DWA2114R flow-cytometrically in 3 human lung cancer cell lines by using bromodeoxyuridine (BrdUrd), rhodamine 123 (Rho) and Ki-67 antibody (Ab), and compared the results with those for DDP. We found that the actions of these 2 platinum analogues were characteristically different at the subcellular level. Our observations may be summarized as follows. a) Simultaneous exposure of cells to DDP and BrdUrd resulted in decreases in fluorescence intensity, i.e. in the amount of BrdUrd incorporated into single-stranded DNA. b) DDP appears to be approximately 20-fold more active than DWA2114R in producing cell cycle perturbation. c) In PC-6 small cell carcinoma cells, DDP induced decreases in S phase cells and accumulation of cells in the G2M phase, whereas in PC-10 squamous carcinoma and PC-3 adenocarcinoma cells DDP produced S phase cell accumulation. Weak but similar changes occurred with DWA2114R. d) The high Ki-67 antigen cell population was decreased by treatment with either DDP or DWA2114R, but DDP reduced the low Ki-67 antigen population more than DWA2114R. e) In PC-10 and PC-6 cells, DDP suppressed Rho incorporation into live mitochondria, whereas DWA2114R produced no change in Rho incorporation. PC-3 cells were not affected by either DDP or DWA2114R. It is likely that these differences reflect the biological activities of DDP and DWA2114R.

Antineoplastic Agents↗
PubMedDate not supplied

Interaction of cis-diamminedichloro-platinum(II) and its analogues cis-1,1- cyclobutanedicarboxylato(2R)-2-methyl-1,4-butanediammineplatinum(II) and cis-diammine(glycolato)platinum with hyperthermia in vivo.

The interaction of cis-1,1-cyclobutanedicarboxylato(2R)-2-methyl-1,4- butanediammineplatinum(II) (NK121) and cis-diammine(glycolato)platinum(II) (254-S), analogues of cis-diamminedichloroplatinum(II) (CDDP), with hyperthermia was examined in vivo. Antitumor activity of the platinum complexes at the maximum tolerated dose (MTD) with or without hyperthermia was evaluated by the tumor growth delay assay using B16F10 melanoma growing in the legs of C57BL/6J mice. MTD of CDDP, NK121 or 254-S at the single intraperitoneal injection with hyperthermia was 8, 50 or 30 mg/kg, respectively. Treatment of the tumor-bearing limb at 43 degrees C for 30 min resulted in a tumor growth delay of 1.1 days. A single dose of CDDP produced a 3.3-day tumor growth delay. When CDDP was injected just before hyperthermia (43 degrees C, 30 min), the growth delay increased to 5.5 days (1.7-fold increase). With NK121, there was a 1.5-day growth delay. In combination with hyperthermia, the tumor growth delay by NK121 was 3.2 days (2.1-fold increase). Injection of 254-S led to a growth delay of 3.5 days, and this delay was extended to 5.7 days (1.6-fold increase) when combined with hyperthermia. Changes in serum blood urea nitrogen (BUN) were determined 5 days after intraperitoneal drug administration with or without hyperthermia. A single administration of CDDP 8 mg/kg resulted in an elevated BUN level, and this was enhanced in combination with hyperthermia (66.3 mg/dl, 2.7-fold over control). NK121 50 mg/kg at 37 degrees C did not result in elevation of BUN, but mild nephrotoxicity was noted in combination with hyperthermia (40.3 mg/dl, 1.6-fold increase over control). The administration of 254-S 30 mg/kg resulted in an elevated BUN level, and this elevation was enhanced in combination with hyperthermia (48.6 mg/dl, 2.0-fold increase over control). Our data showed that NK121 and 254-S as well as CDDP produced greater tumor growth delay together with hyperthermia than did the drug alone. Though these new compounds were designed with reduced nephrotoxicity, attention should be paid to increased nephrotoxicity when combined with hyperthermia.

Animals↗