Preclinical antitumor activity of CI-973,[SP-4-3-(R)]-[1,1-cyclobutanedicarboxylato(2-)] (2 methyl-1,4-butane-diamine-N,N′)platinum

Summary The antitumor activity of [SP-4-3-(R)]-[1,1-cyclobutanedicarboxylato-(2-)](2 methyl-1,4-butanediamine-N,N)platinum (CI-973) was characterized in a number of preclinical model systems. CI-973 retained substantial activity in cisplatin resistant murine leukemia cell lines, in vitro and in vivo; in L1210 leukemia resistant to cisplatin in vivo, CI-973 retained as much activity as was found in animals bearing sensitive L1210 leukemia. When compared in five solid murine tumors in vivo, both CI-973 and cisplatin were approximately equivalent in activity. In one human colon tumor and one human non-small cell lung carcinoma tested as xenografts in immunodeficient mice, cisplatin and CI-973 were ineffective. In two other human non-small cell lung carcinomas tested in the same fashion, cisplatin did possess activity. CI-973 has entered phase I clinical trials.A portion of this work was reported in a preliminary form at the 79th Annual Meeting of the American Association for Cancer Research, Proc. AACR 29:344, 1988.     

Anticancer activity in murine and human tumor cell lines of bis(platinum) complexes incorporating straight-chain aliphatic diamine linker groups.

The biological activity of a series of dinuclear bis(platinum) complexes of formula [(cis-PtX2-(NH3)]2(NH2(CH2)nNH2)] (X = Cl, n = 4-9, compounds 6-11; X2 = malonate, n = 5 or 6, compounds 12 and 13) is described in selected murine leukemia, murine solid tumor, and human tumor cell lines and in murine leukemia cell lines rendered resistant to cisplatin (cis-[Pt(NH3)2Cl2]). The bis(platinum) compounds showed greater activity in vitro against murine tumor cell lines resistant to either cisplatin or DACH ([Pt(DACH)Cl2]). The resistance factor is dependent on chain length of the diamine, and the structural feature of a dinuclear complex is of general use in reducing cross-resistance with cisplatin. In vivo [(cis-PtCl2(NH3)]2(NH2(CH2)5NH2)] (7) showed a % T/C of 204 against murine L1210 leukemia resistant to cisplatin compared to a % T/C of 104 for cisplatin itself at optimal doses. The complex [(Pt(mal)(NH3)]2(NH2(CH2)6NH2)] (13) was highly active in the colon 26 tumor line with 3/10 tumor-free survivors (dose of 186 mg/kg, ip D1,5,9); however, 13 was subject to substantial cross-resistance in the cisplatin resistant L1210 leukemia (% T/C 139 versus % T/C of 223 in the sensitive line). In four selected human tumor lines in vitro, compounds 6-11 were uniformly more potent than cisplatin. In the corresponding xenografts, compound 7 showed greater activity in the HCT-8 (coloadenocarcinoma) and H23 (nonsmall cell lung), but diminished potency in AH125 and H520 (both nonsmall cell lung) lines in comparison to cisplatin. Retention of activity against cisplatin-resistant cell lines and a different spectrum of activity compared to cisplatin in some human tumor cell lines suggest that this class of complexes is mechanistically different from mononuclear complexes and worthy of further development toward clinical trials.     

Cross-resistance of drug-resistant murine leukemias to deoxyspergualin (NSC 356894) in vivo

Deoxyspergualin, the 15-deoxy derivative of the antibiotic spergualin, is a novel guanidino analog structurally related to spermine. Deoxyspergualin has significant activity in selected experimental tumor models, and clinical trials have been initiated. Described here are in vivo evaluations of the therapeutic activity of deoxyspergualin against murine leukemia lines specifically resistant to eight clinically useful antitumor drugs. These were P388 lines resistant to doxorubicin, vincristine, L-phenylalanine mustard, cisplatin, ara-C, and methotrexate and L1210 lines resistant to 5-FU, L-phenylalanine mustard, and cyclophosphamide. Sensitivity to deoxyspergualin was evaluated in parallel comparisons of each resistant leukemia to the sensitive line from which it had been derived. All experiments were repeated at least once for confirmation of results. Responses were quantitated in terms of the change in tumor cell numbers from the beginning of treatment to the end of treatment as estimated from the median survival times of dying mice. The results indicated that P388 leukemia resistant to cisplatin (P388/DDPt) was cross-resistant to deoxyspergualin. No cross-resistance was observed in leukemias resistant to doxorubicin, vincristine, ara-C, methotrexate, or cyclophosphamide. L1210 resistant to 5-FU (L1210/5-FU) was collaterally sensitive to deoxyspergualin. Although cross-resistance was also observed in P388/L-PAM, L1210/L-PAM retained sensitivity to deoxyspergualin. Total glutathione concentrations in P388/L-PAM and L1210/L-PAM provided no apparent explanation for this unexpected result. It may be tentatively concluded that resistance to cisplatin, L-PAM, or other DNA alkylators or cross-linkers may increase the potential for cross-resistance to deoxyspergualin. This conclusion requires verification with additional alkylating agents, with drug-resistant human tumor cell lines, and with prospective clinical studies.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis and antitumor activity of cyclotriphosphazene-(diamine)platinum(II) conjugates

A new class of water-soluble cyclotriphosphazene-(diamine)platinum(II) conjugate drugs [NP(Am-Li2)(Am.PtA2)]3 (Am: dicarboxylic amino acid; A2: diamine) has been synthesized and characterized by means of elemental analysis, multinuclear (1H, 31P, 13C, 195Pt) NMR and IR spectroscopies. All the title compounds were subjected to both in vitro and in vivo assays against the murine leukemia L1210 cell line and selected human tumor cells. Most of the title compounds have shown higher in vivo antitumor activity than cisplatin and carboplatin, and, in particular, [NP(L-Glu-Li2)(L-Glu.Pt(-dach)]3 (Glu=glutamate, dach=trans(+/-)-1,2-diaminocyclohexane) showed extraordinary high activity (ILS>500%) equally against both parent and cisplatin-resistant leukemia L1210 cell lines. Furthermore, this candidate compound (KI 60606) exhibited a wider spectrum of in vitro activity by showing higher cytotoxicity against all the selected human tumor cells than cisplatin and, therefore, was subjected to preclinical studies which are now near completion.     

Heterocyclic quinones. 17. A new in vivo active antineoplastic drug: 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione

A series of heterocyclic quinones, 6-substituted and 6,7-disubstituted 4-(alkylamino)-5,8-quinazolinediones, have been synthesized in order to evaluate their in vitro cytotoxicity on L1210 leukemia cells. Among 14 derivatives that have been prepared and studied for the structure-activity relationship, the most potent cytotoxic compound on L1210 leukemia cells was the 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione (24). This compound has been tested with the use of a cell-image processor on MCF-7 human mammary and HBL human melanoma cell lines. The results show that compound 24 influences cell proliferation and blocks both cells lines in the S phase. In vivo antineoplastic activity of compound 24 has been demonstrated on a broad spectrum of murine experimental models, but it was found highly toxic and produced long-delayed deaths.     

Specific metabolic activation of FK973, a new antitumor antibiotic, in L1210 leukemia cells

FK973 (11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11- diazatetracyclo[7.4.1.O2,7O10,12]tetradeca-2,4,6-trien -6,9-diyl diacetate), a new substituted dihydrobenzoxazine, has potent cytotoxic and antitumor effects on murine and human tumors in vivo and in vitro, and forms interstrand DNA-DNA and DNA-protein cross-links after being activated in the cytoplasm. In this study, the mechanism(s) by which FK973 is activated in the cytoplasm of in vitro cultured murine L1210 leukemia cells were studied using compounds that affect monoamine oxidase. When the cells were incubated with an antitumor drug and the compounds, tranylcypromine, benzylamine, phenylethylamine and tyramine of the many compounds tested reduced the cytotoxicity of FK973, but not that of mitomycin C or cisplatin. These compounds also suppressed the formation of interstrand DNA-DNA cross-links with FK973 in the cells, but did not suppress cross-links with mitomycin C or cisplatin. The incorporation of 14C-FK973 into the cells was not affected by these compounds. The results suggest that FK973 is activated by some drug-metabolic system(s) in the cytoplasm to form interstrand DNA-DNA cross-links, and induces cytotoxicity against the cells. This activation of FK973 in the cytoplasm is discussed in connection with the drug-metabolic system(s) in relation to the structures of the compounds.     

PTT.119, p-F-Phe-m-bis-(2-chloroethyl)amino-L-Phe-Met ethoxy HCl, a new chemotherapeutic agent active against drug-resistant tumor cell lines

PTT.119 [p-F-Phe-m-bis-(2-chloroethyl)amino-L-Phe-Met ethoxy HCl], a new synthetic tripeptide, was highly effective against the L-phenylalanine mustard (L-PAM) resistant (L1210/L-PAM and P388/L-PAM) tumor lines, as well as the sensitive L1210 leukemia. Cytolytic activity of PTT.119 against all three leukemias was significantly greater than equimolar doses of L-PAM. These in vitro results paralleled the significant increases in mean survival times of hosts and, in some cases, abrogations of tumor formation observed in the in vivo bioassays of PTT.119-treated L1210 and L1210/L-PAM cells. Dose-response studies failed to demonstrate cross-resistance to the tripeptide by L-PAM resistant cells. Doses of PTT.119 required to reduce the viable fraction by 50% (tissue culture dose 50, TCD50) or 100% (TCD100) were 1.3- to 3-fold lower for the L-PAM resistant cells than for the L1210 leukemia. In comparison, L-PAM was unable to completely eliminate cell survival; 0.2 to 3% of the cells in all three leukemias remained viable even at doses of 75 and 163 microM. In similar studies, L1210 leukemia cells made resistant to methotrexate (L1210 MTX) and cisplatin (L1210DDP) were also completely susceptible to PTT.119; TCD50 values of the two resistant lines were 1.94 microM for L1210 MTX and 0.525 microM for L1210DDP compared to 2.38 microM for the susceptible parent L1210S leukemia. Continuous low-dose PTT.119 treatment of MJY-alpha mammary tumor cells for 8 months and exposure of L1210 leukemia to escalating levels of tripeptide for over 100 passages failed to select or induce drug-resistant phenotypes in either cell line. PTT.119 appears to be a poor mutagen and is unlikely to readily increase the probability of drug-resistant mutants in the tumor cell populations.     

Synthesis and antileukemic activity of new 3-(1-phenyl-3-methylpyrazol-5-yl)-2-styrylquinazolin-4(3H)-ones

3-(1-Phenyl-3-methylpyrazol-5-yl)-2-styrylquinazolin-4(3H)-ones 14a-q and 15a-q were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 12 and 13 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 14a-q and 15a-q were tested in vitro for their antileukemic activity against L1210 (murine leukemia), K562 (human chronic myelogenous leukemia) and HL60 (human leukemia) cell lines showing in some cases good activity.     

Triapine (3-aminopyridine-2-carboxaldehyde- thiosemicarbazone): A potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity

Previous studies from our laboratories have shown that (a) Triapine() is a potent inhibitor of ribonucleotide reductase activity and (b) hydroxyurea-resistant L1210 leukemia cells are fully sensitive to Triapine. In an analogous manner, Triapine was similarly active against the wild-type and a hydroxyurea-resistant subline of the human KB nasopharyngeal carcinoma. Triapine was active in vivo against the L1210 leukemia over a broad range of dosages and was curative for some mice. This agent also caused pronounced inhibition of the growth of the murine M109 lung carcinoma and human A2780 ovarian carcinoma xenografts in mice. Optimum anticancer activity required twice daily dosing due to the duration of inhibition of DNA synthesis which lasted about 10 hr in L1210 cells treated with Triapine in vivo. DNA synthesis in normal mouse tissues (i.e. duodenum and bone marrow) uniformly recovered faster than that in L1210 leukemia cells, demonstrating a pharmacological basis for the therapeutic index of this agent. Triapine was more potent than hydroxyurea in inhibiting DNA synthesis in L1210 cells in vivo, and the effects of Triapine were more pronounced. In addition, the duration of the inhibition of DNA synthesis in leukemia cells from mice treated with Triapine was considerably longer than in those from animals treated with hydroxyurea. Combination of Triapine with various classes of agents that damage DNA (e.g. etoposide, cisplatin, doxorubicin, and 1-acetyl-1,2-bis(methylsulfonyl)-2-(2-chloroethyl)hydrazine) resulted in synergistic inhibition of the L1210 leukemia, producing long-term survivors of tumor-bearing mice treated with several dosage levels of the combinations, whereas no enhancement of survival was found when Triapine was combined with gemcitabine or cytosine arabinoside. The findings demonstrate the superiority of Triapine over hydroxyurea as an anticancer agent and further suggest that prevention by Triapine of repair of DNA lesions created by agents that damage DNA may result in efficacious drug combinations for the treatment of cancer.     

Syntheses and antiproliferative activities of new rebeccamycin derivatives with the sugar unit linked to both indole nitrogens

The synthesis of new rebeccamycin derivatives, in which the carbohydrate moiety is attached to both indole nitrogens, is described. The newly synthesized compounds were tested for their abilities to block the cell cycle of murine leukemia L1210 cells and their in vitro antiproliferative activities against four tumor cell lines (murine L1210 leukemia and human HT29 colon carcinoma, A549 non-small-cell lung carcinoma, K-562 leukemia). Their biological activities are compared with those of the parent compound rebeccamycin. Some of the new compounds exhibit potent antiproliferative activities, either against the four cell lines or mostly the two leukemias (L1210 and K-562 cell lines). The 3,9-diformyl analogue 9 was selective toward L1210 cells, whereas the 3,9-dibromo 16 was strongly cytotoxic toward the four cell lines tested. Nonselective compound 16 and 3,9-dinitro 13, which exhibited selectivity toward leukemia tumor cell lines, were selected for in-depth evaluation, including in vivo experiments.     

Synthesis and antileukemic activity of new 3-(5-methylisoxazol-3-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones

3-(3-Methylisoxazol-5-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones 8a-l and 9a,c-e,h-l were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 6 and 8 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 8a-l and 9a,c-e,h-l were tested in vitro for their antileukemic activity against L-1210 (murine leukemia), K-562 (human chronic myelogenous leukemia) and HL-60 (human leukemia) cell lines showing in some cases good activity.     

Induction of apoptosis by a novel copper-based anticancer compound, casiopeina II, in L1210 murine leukaemia and CH1 human ovarian carcinoma cells.

The activity of casiopeina II [Cu(1,4-dimethyl-1, 10-phenanthroline)(glycine)NO(3)], a novel anticancer agent, was tested in two cell lines, L1210 murine leukaemia, CH1 human ovarian carcinoma, cisplatin-resistant and sensitive. Exposure of the cells to a range of concentrations of casiopeina II indicates that this copper complex kills cells by apoptosis and necrosis. Condensed chromatin and nuclear fragmentation were observed after exposure to casiopeina II. The caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethylketone (Z-VAD-FMK) almost completely inhibited apoptosis induced by cisplatin; however, casiopeina II-induced apoptosis was inhibited only by 50-70%. These data are consistent with caspase activation (measured by Z-Asp-Glu-Val-Asp-7-amino-4-trifluoromethylcoumarin; Z-DEVD-AFC) by casiopeina II and cisplatin and confirm that caspases are activated in the apoptotic cell death induced by casiopeina II. DNA fragmentation was observed in L1210 cells, but not in CH1 cells. No difference in susceptibility to induction of apoptosis by casiopeina II was found between sensitive and cisplatin resistant cells. In this work we show that the novel copper-based antineoplastic agent casiopeina II is highly active against murine and human cancer cell lines, including cell lines resistant to cisplatin.     

Biochemical and antitumor activity of tiazofurin and its selenium analog (2-beta-D-ribofuranosyl-4-selenazolecarboxamide)

2-beta-D-Ribofuranosyl-4-selenazolecarboxamide (selenazofurin, CI-935), the selenium analog of tiazofurin (CI-909), was 3- to 10-fold more cytotoxic to murine or human tumor cells in vitro than tiazofurin and was also more active against P388 mouse leukemia in vivo. In vitro cytotoxicity could be reversed by guanosine or guanine but not by other purine nucleosides or bases. Three human tumor cell lines selected for selenazofurin or tiazofurin resistance showed cross resistance between selenazofurin and tiazofurin. Treatment with tiazofurin, selenazofurin, or mycophenolic acid decreased guanylate pools and caused an accumulation of IMP in WIL2 human lymphoma cells. The decrease in guanylate pools was accompanied by inhibition of RNA and DNA synthesis. The NAD analogs of tiazofurin and selenazofurin were inhibitors of L1210 IMP dehydrogenase (IMP:NAD oxidoreductase, EC 1.2.1.14), and both showed uncompetitive inhibition with respect to NAD having Kii values of 5.7 X 10(-8)M and 3.3 X 10(-8)M respectively.     

Antitumor spectrum of deoxyspergualin and its lack of cross-resistance to other antitumor agents

Antitumor activities of 15-deoxyspergualin (NKT-01), an analogue of spergualin (SGL), were examined in cultured tumor cells, transplantable murine tumors, and human tumor xenografts in nude mice. NKT-01 exhibited strong antitumor activity specifically against leukemias both in vitro and in vivo. Moreover, it also showed activity against AH66F hepatoma, M5076 fibrosarcoma and MH134 hepatoma. However, antitumor activity of NKT-01 against other non-leukemic tumors was marginal. Effective dose range of NKT-01 in sensitive tumors was so wide that the largest chemotherapeutic indexes were produced by NKT-01 in P388 and L1210 leukemias among 15 antitumor agents examined. The efficacy of NKT-01 against doxorubicin- and cytosine arabinoside-resistant P388 leukemias was comparable to that against parental sensitive P388 leukemia. NKT-01 also retained activity against other p388 leukemia sublines resistant to cisplatin, 5-fluorouracil or nimustine, although the effect was slightly decreased. In addition, in the in vitro and in vivo experiments using NKT-01-resistant P388 and SGL-resistant L1210(IMC) leukemias, no cross-resistance was observed. Moreover, collateral sensitivity was observed especially to alkylating agents in animal study.     

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.     

Antitumor activities of (2"R)-4'-O-tetrahydropyranyl-adriamycin (THP) and its combination with other antitumor agents on murine tumors

(2'R)-4'-O-Tetrahydropyranyladriamycin (THP) is a new derivative of doxorubicin (adriamycin, ADM). The concentrations of THP and ADM required to inhibit by 50% the growth of a cultured L1210 cells was 0.003 microgram/ml and 0.016 microgram/ml, respectively. Various therapeutic designs of combinations of THP with other antitumor agents were investigated in vivo using the L1210 murine leukemia. The combination of THP with cytosine arabinoside (Ara-C), cyclocytidine hydrochloride (Cyclo-C), 6-mercaptopurine (6-MP) and cyclophosphamide (EX) showed a great effectiveness following daily intraperitoneal treatment from days 1 to 10. High therapeutic effects were also obtained with the combinations of THP with Ara-C, Cyclo-C, vincristine (VCR) and EX following intravenous combination therapy one day following implantation of L1210 leukemia. Schedule dependency and its therapeutic efficacy of THP were examined. THP showed almost the same antitumor activity on the solid-type sarcoma-180 or solid-type Ehrlich carcinoma as ADM by intraperitoneal or intravenous treatment. THP showed some superior activity to ADM in the advanced stage of L1210 leukemia. High antitumor activity of THP on murine leukemia L1210 has been reported by Tsuruo et al. (Cancer Res. 42: 1462-1467, 1982) and was also confirmed. THP gave many mice cures, especially in the intravenous treatment.     

8,11-dihydroxy-6-[(aminoalkyl)amino]-7H-benzo[e]perimidin-7-ones with activity in multidrug-resistant cell lines: synthesis and antitumor evaluation.

The synthesis of dihydroxybenzoperimidine derivatives, which are chromophore-modified dihydroxyanthracenediones with an additional pyrimidine ring incorporated into the chromophore, is reported. These derivatives are structurally related to the antitumor agent mitoxantrone. Their synthesis was carried out by the reaction of 6-amino-8,11-dihydroxy-7H-benzo[e]perimidin-7-one (5) or 6,8, 11-trihydroxy-7H-benzo[e]perimidin-7-one (10) with a number of respective (alkylamino)alkylamines. The dihydroxybenzoperimidine derivatives exhibited in vitro cytotoxic activity against murine leukemia L1210 and human leukemia HL60 cell lines comparable to that of mitoxantrone. These compounds also exhibited a range of in vitro activity against the human MDR-type resistant leukemia K562R cell line with the MDR phenotype. The most active compound of this series, namely 6a, exhibited potent in vitro cytotoxic activity against a panel of human cell lines. Furthermore, in contrast to both mitoxantrone and doxorubicin, it displayed little cross-resistance in cell lines characterized by a MDR phenotype. Cell cycle analysis in the sensitive HT-29 and mitoxantrone-resistant HT-29/Mx (not identified resistance mechanism) cell lines has revealed that both mitoxantrone and 6a induce a G2/M block. However, while the proportion of apoptotic cells after mitoxantrone treatment is similar for both sensitive and resistant cell lines, it is much lower for 6a. Compound 6a tested against P388 murine leukemia in vivo displayed a significant antitumor effect (%T/C 196 at an optimal dose of 10 mg/kg). The property of overcoming the cross-resistance was maintained also in in vivo efficacy studies, where no difference was observed in the antitumor activity of compound 6a against the A2780 human tumor xenograft and its MDR A2780/Dx subline. We conclude that benzoperimidines, if properly substituted, constitute a novel class of compounds that can overcome multidrug resistance.     

Synthesis of new 1-phenyl-6H-pyrido[4,3-b]carbazole derivatives with potential cytostatic activity

A number of new 1-substituted-6H-pyrido[4,3-b]carbazole derivatives have been synthesized. Nine of the newly obtained compounds were subjected to preliminary in vitro cytostatic activity screening against murine leukemia (L1210), human lung cancer (A549) and human colon cancer (HT29) cell lines. One particular compound 6f exhibited over 20 times better activity against L1210 tumor cell line than the reference ellipticine.     

Murine anti-tumor activity of new water soluble platinum(II) complexes with reduced toxicity

A series of new water soluble sugar and non-sugar containing platinum(II) complexes was synthesized and evaluated for effects of the sugar moiety on water solubility, anti-tumor activity, and acute leukopenia. When tested in vivo against the murine P388 and L1210 leukemias at LD10/maximally effective doses, the compound cis-[(gluconylamino)malonato-O,O'](1R,2R-cyclohexanediami ne-N,N')platinum (II), R,RG-AMP produced comparable or superior anti-tumor activity to cisplatin, carboplatin, and tetraplatin. Efficacy was also demonstrated for the L1210/DDP (cisplatin-resistant) leukemia. Further, R,R-G-AMP is non-nephrotoxic and produces less leukopenia than cisplatin, carboplatin, and tetraplatin.     

Chemical and biological properties of a new series of cis-diammineplatinum(II) antitumor agents containing three nitrogen donors: cis-[Pt(NH3)2(N-donor)Cl]+

A series of 32 cationic platinum(II) complexes of the form cis-[PtA2(Am)Cl]+, where A is a monodentate (NH3 or i-PrNH2) or A2 is a bidentate (ethylenediamine or 1,2-diaminocyclohexane) amine and Am is either a heterocyclic amine based on a pyridine, pyrimidine, purine, piperidine, or a saturated amine (RNH2) ligand, was prepared and screened against in vivo murine tumor models. Each compound was tested against Sarcoma 180 ascites (S180a) in mice, with 20 members of the series showing activity (ILS greater than 50%). Antitumor activity also was demonstrated in 4 of 16 compounds tested in the L1210 murine leukemia model (ILS greater than 25%) and in 3 of 3 tested in the P388 murine leukemia model (ILS greater than 30%). The most active and potent analogues of the series were obtained when A was NH3 and Am was N1-pyridine, N1-4-methylpyridine, N1-4-bromopyridine, N1-4-chloropyridine, N3-cytosine, or N7-2'-deoxyguanosine. Complexes containing chelating and saturated amine ligands (A), as well as two trans isomers of active cis analogues (trans-[Pt(NH3)2(Am)Cl]+, where Am = N1-pyridine or N1-4-methylpyridine), were inactive in the S180a screen. All complexes were characterized by means of elemental analysis, HPLC, and 195Pt NMR spectroscopy, and the structure of one analogue, cis-[Pt(NH3)2(N3-cytosine)Cl](NO3), was determined by using single-crystal X-ray diffraction methods. While members of this series of compounds demonstrate antitumor activity in vivo, these new agents are not classical analogues of cisplatin (i.e. cis-[PtA2X2] complexes), as they contain three nitrogen donors and only one leaving group. The results of these studies suggest that further work should be conducted to better define the limits of the structure-activity relationships among platinum(II) complexes.