Tumor inhibition by titanocene complexes. Activity against B16 melanoma and colon 38 carcinoma

In the present study, the antitumor activity of some titanocene derivatives (C5H5)2TiX2 (I, X = Cl; II, X = Br; III, X = cis-OOCCH = CHCOOH; IV, X = p-SC6H4NH3+Cl-) was investigated against B16 melanoma and colon 38 carcinoma. Both tumors grew subcutaneously as solid tumors in mice. Substances were applied intraperitoneally either as single, triple or 5-fold injections. Against both tumors, satisfactory results were observed for the chloro, bromo and aminothiophenolato derivatives I, II and IV, resp. They reduced tumor growth by 60-80% to 40-20% of control values. These effects underline the antitumor potency of titanocene complexes and show that titanocene dihalides as well as titanocene derivatives containing hydrophilic ligands X are able to inhibit the growth of various solid experimental tumors.     

Synthesis and antitumor activity of fused tetracyclic quinoline derivatives. 1

Several fused tri- and tetracyclic quinolines (I and II) with [2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino or [3-(N,N-dimethylamino)propyl]amino side chains were prepared, and their DNA intercalative properties, KB cytotoxicity, antitumor activity (P388 leukemia), and ability to induce topoisomerase II dependent DNA cleavage were investigated. Some compounds having both intercalative ability and KB cytotoxicity were found to be inactive in vivo. However, a positive correlation was seen between the ability to induce topoisomerase II dependent DNA cleavage and antitumor activity in vivo. The indeno- (13a), benzofuro- (21a), and benzothieno- (22a) quinoline derivatives exhibited potent antitumor activities in vitro and in vivo, comparable to those of m-AMSA. They also intercalate DNA and induce topoisomerase II dependent DNA cleavage. Extended screening of 13a showed it to be active against solid tumors such as M5076 sarcoma, B16 melanoma, and colon 38 carcinoma.     

Antitumor activity of an ionic titanocene tetrachloroferrate derivative against some solid experimental tumors

The metallocene complex bis(cyclopentadienyl)acetonitrilechlorotitanium(IV) tetrachloroferrate(III) [(C5H5)2Ti(Cl)NCCH3]+[FeCl4]- was investigated for antitumor properties against three solid experimental animal tumors (B16 melanoma, colon 38 adenocarcinoma, Lewis lung carcinosarcoma). The growth of all three tumors was inhibited significantly by the titanocene complex. Colon 38 carcinoma and Lewis lung carcinoma revealed to be more sensitive to the titanocene tetrachloroferrate derivative than solid B16 melanoma, whereby the growth development of the aforementioned tumors was suppressed by 70-76% of control tumor size to T/C ratios amounting to 24-30%. Bis(cyclopentadienyl)acetonitrilechlorotitanium(IV) tetrachloroferrate(III) is representative of ionic titanocene complexes which are generally distinguished by improved water solubility in comparison to neutral metallocene compounds.     

Nitrogen analogues of 1,4-benzoquinones. Activities against the ascitic sarcoma 180 of mice

Compounds having the basic structure N-(R)-substituted ring-substituted 4-iminocyclohexadienone have been synthesized and tested as antitumor agents against the ascitic sarcoma 180 tumor in Swiss mice. Among these compounds, the dimethylindoanilines [R = 4-(CH3)2NC6H4] are most stable in water at pH 7.0 and at 25 degrees C, the oximes (R = oh) are less stable, and the N-halo compounds (R = Br and Cl) are least stable. The N-halo derivatives have the highest redox potentials under the conditions used, the greatest effect against ascitic sarcoma 180 in Swiss mice, and the greatest acute toxicity when injected ip in the Swiss mice. Discriminant analysis of the results indicates that substituents with positive values of F and negative values of pi increase the antitumor activities, whereas those with positive values of sigma and R should lower the toxicity. The redox potential, a molecular parameter, is the best single variable for discriminating between the groups based on antitumor activities.     

Comparative antitumor activities of 7-N-(p-hydroxyphenyl)mitomycin C (M-83) and mitomycin C

The antitumor activity of 7-N-(p-hydroxyphenyl)mitomycin C (M-83) against 7 kinds of ascitic tumors and 4 kinds of solid tumors was compared with that of mitomycin C (MMC). M-83 showed more potent activities than MMC against ascites sarcoma 180, fibrosarcoma Meth 1, sarcoma Meth A, melanoma B-16, leukemia P388 and lymphoma EL4, by a single intraperitoneal injection. Furthermore, M-83 gave markedly higher chemotherapeutic ratio than MMC in these tumor systems. M-83 was also markedly effective against solid tumors of sarcoma 180, Meth 1, Meth A and Lewis lung carcinoma, by a single intravenous injection. M-83 gave lower myelo-suppression than MMC at the doses which gave almost equal inhibition on the tumor growth of solid Meth 1. M-83 and MMC significantly inhibited the growth of HeLa S3 cells. Cell growth was observed at 24 hours after addition of 3 X 10(-3) mM of drugs, but no growth was shown thereafter. M-83 inhibited more strongly the incorporation of the radioactive precursor into DNA than that into RNA or protein at the concentration of 3 X 10(-3) mM.     

Antitumor effects of a podophyllotoxin derivative, VP 16-213

Single and combination chemotherapies of VP 16-213, a new antitumor agent were evaluated for its antitumor effect against several murine tumors. Dose-dependent antitumor effects were observed when VP 16-213 was administered via any of the three routes, i.p., i.v. and orally, on days 1 and 5 after i.p. or s.c. inoculation of Ehrlich carcinoma and sarcoma 180. The drug also proved effective against i.v. inoculated EL-LP-12 (subline of Ehrlich carcinoma), i.p. or s.c. inoculated P388 and B16 melanoma, i.p. inoculated colon 26, and s.c. inoculated colon 38 and Lewis lung carcinoma. However, oral administration of the drug was not effective against B16 melanoma, colon 26 and Lewis lung carcinoma despite the fact that the doses employed for this route was higher than those employed for i.v. and i.p. routes. The optimum dosing schedule was also investigated with oral administration of the drug against s.c. inoculated Ehrlich carcinoma. A single dose (day 1) or two doses (days 1 and 5) were more effective than three doses (days 1, 3 and 5) or five consecutive daily doses. VP 16-213 showed additive and more than additive effects in combination with the antitumor agents, cyclophosphamide, BCNU, mitomycin C or cisplatin against s.c. inoculated Ehrlich carcinoma and i.v. inoculated EL-LP-12.     

白桦三萜类物质抗黑色素瘤B16、S180肉瘤作用及其机制的实验研究

目的　研究白桦三萜类物质 (triterpenesofbetulaplatyphyllasuk .TBP)抗黑色素瘤B16、S180肉瘤及其诱导细胞调亡作用和对细胞周期的影响。方法　建立小鼠体内荷黑色素瘤B16和腹水型S180肉瘤模型 ,测定TBP的抑瘤率和生命延长率。用形态学检测方法 (Giemsa染色法 )和流式细胞光度术检测TBP诱导的细胞调亡和对细胞周期的影响。结果　TBP具有明显的抗肿瘤作用 ,1 2 g·kg-1TBP对黑色素瘤B16的抑瘤率为 5 1 40 % ,对荷S180肉瘤小鼠生命延长率为 41 0 4%。可诱导B16和S180肿瘤发生细胞调亡 ,G0 /G1期细胞比例增加 ,S期细胞比例下降。结论　TBP可明显抑制黑色素瘤B16和S180肉瘤生长 ,其机制与诱导细胞调亡和阻断细胞生长于G0 /G1期有关。     

Antitumor activity of trienomycin A on murine tumors

The antitumor activity of a novel ansamycin antibiotic, trienomycin A, against various murine tumors was studied with two treatment schedules. The intraperitoneal injection of the antibiotic showed remarkable antitumor activity on sarcoma 180 and P388 leukemia at doses of 160 or 320 mg/kg, showing 151% and 100% increase in life span, respectively. Trienomycin A inhibited the growth of Ehrlich and Meth A cells in vitro at doses of 0.1-0.4 microgram/ml when the cells were exposed to the antibiotic for 72 hours. The incorporation of [3H]thymidine into acid precipitable material in HeLa cells was slightly more marked than that of [3H]uridine and [3H]leucine when the cells were exposed to 0.04 or 0.08 microgram/ml of trienomycin A for 4 hours. It appeared that trienomycin A showed antitumor activity by direct cytotoxic action.     

Antitumor efficiency of novel fluoro-substituted 6-amino-2-phenylbenzothiazole hydrochloride salts in vitro and in vivo

The purpose of this study was to investigate antitumor activity of novel fluoro-substituted 6-amino-2-phenylbenzothiazole hydrochloride salts in vitro and in vivo. A novel series of hydrochloride or dihydrochloride salts of the novel 2-(fluoro-substituted phenyl)-6-aminobenzothiazoles (5-7) have been prepared in multistep synthesis starting from 3- or 4-fluorobenzaldehydes and 2-amino-5-nitrothiophenol and evaluated for their antiproliferative activity against human cervical (HeLa), breast (MCF-7), colon (CaCO-2), and laryngeal (Hep-2) carcinomas and against fibroblast cell lines (WI-38). Also, antitumor activity of these compounds was evaluated in vitro and in vivo against murine melanoma (B16-F10), fibrosarcoma (FsaR), and squamous cell carcinoma (SCCVII). The tested compounds were found to exert good cytotoxic activity in vitro. The cytotoxic effect was selective, cell specific, and dose dependent, between 33 microM for MCF-7 and 110 microM for WI-38. Benzothiazoles reduced de novo protein and DNA synthesis up to 75%. All examined benzothiazoles had significant antitumor activity in vivo against melanoma B16-F10, fibrosarcoma, and squamous cell carcinoma. The best therapeutic results were achieved when therapy started 7 days after tumor cell implantation and when benzothiazoles were given repeatedly five times every 2 days, i.e., on day 7, 9, 11, 13, and 15 after transplantation of tumor cells.     

Preclinical efficacy of thioxanthone SR271425 against transplanted solid tumors of mouse and human origin

A highly active and broadly active thioxanthone has been identified: N-[[1-[[2-(Diethylamino)ethyl]amino]-7-methoxy-9-oxo-9H-thioxanthen-4-yl] methylformamide (SR271425, BCN326862, WIN71425). In preclinical testing against a variety of subcutaneously growing solid tumors, the following %T/C and Log₁₀ tumor cell kill (LK) values were obtained: Panc-03 T/C = 0, 5/5 cures; Colon-38 (adv. stage) T/C = 0, 3/5 cures, 4.9 LK; Mam-16/C T/C = 0, 3.5 LK; Mam-17/0 T/C = 0, 2.8 LK; Colon-26 T/C = 0, 1/5 cures, 3.2 LK; Colon-51 T/C= 0, 2.7 LK; Panc-02 T/C = 0, 3.1 LK; B16 Melanoma T/C = 13%, 4.0 LK; Squamous Lung-LC12 (adv. stage) T/C = 14%, 4.9 LK; BG-1 human ovarian T/C = 16%, 1.3 LK; WSU-Br1 human breast T/C = 25%, 0.8 LK. The agent was modestly active against doxorubicin (Adr)-resistant solid tumors: Mam-17/Adr T/C =23%, 0.8 LK; and Mam-16/C/Adr T/C = 25%, 1.0 LK, but retained substantial activity against a taxol-resistant tumor: Mam-16/C/taxol T/C = 3%, 2.4 LK. SR271425 was highly active against IV implanted leukemias, L1210 6.3 LK and AML1498 5.3 LK. The agent was equally active both by the IV and oral routes of administration, although requiring approximately 30% higher dose by the oral route. Based on its preclinical antitumor profile, it may be appropriate to evaluate SR271425 in clinical trials.     

Activity of batracylin (NSC-320846) against solid tumors of mice

Summary Batracylin (NSC 320846) is a water insoluble, solid tumor active compound discovered by the Developmental Therapeutics Program of the National Cancer Institute (NCI). In vivo, the NCI found this compound to be highly active [median treated tumor mass/median control tumor mass (T/C) = 0 to 20%] both orally and intraperitoneally against colon 38. In a disk diffusion, soft agar colony formation assay (500 ug/disk), we found solid tumor selectively (compared to leukemia L1210) against colon adenocarcinoma 38 (0–170 zuL1210 leukemia; > 950 zuC8), colon adenocarcinoma 9 (0–170 zuL1210; > 950 zuC9), colon adenocarcinoma 7/A (0–170 zuL1210; 250–400 zuC7), and pancreas ductal carcinoma 03 (0–170 zuL1210;>950 zuPanc 03 (200 zone units [zu] = 6.5 mm zone of inhibition of cultured tumor colonies from drug disk). In vivo we have tested batracylin against mammary adenocarcinoma 16/C, colon 9, colon 38, colon 51, Panc 03, and hepatoma 129. Upon oral administration, batracylin was effective against colon 9 (T/C = 2.4%) and marginally active against colon 38 (T/C = 39%). Batracylin was orally ineffective against Panc 03 (T/C > 100%), colon #51 (T/C = 77%) and hepatoma 129 (T/C > 100%). Upon subcutaneous administration, batracylin was effective against colon #9 (T/C = 0%), and Panc 03 (T/C = 15%) but ineffective against mammary 16/C (T/C > 100%). At efficacious doses, delayed neurotoxicity, hepatic toxicity and a significant host weight loss was noted (with slow recovery). Both our in vitro data and the NCI in vivo data confirm its scant activity against L1210 (%ILS = 8 to 16%). Although showing activity against selected murine solid tumors, it lacked curative potential with early stage disease [C38, C9, Panc 03] and has shown relative inactivity in vitro against human solid tumor cell lines (H-125, CX-1, HCT-8, HCT-116). Batracylin has entered large animal toxicology trials at the NCI, anticipating phase I clinical evaluation.     

Cytotoxicity and antitumor activity of some tetrahedral bis(diphosphino)gold(I) chelates

We report the cytotoxicity toward B16 cells and antitumor activity in three transplantable tumor models of a series of ionic, tetrahedral, bischelated gold diphosphine complexes of the type [Au1(R2PYPR2')2]X, where Y = (CH2)2, (CH2)3, or cis-CH = CH. The anion (X = Cl, Br, I, CH3SO3, NO3, PF6) had little effect upon activity. The R = R' = phenyl complexes 1, 7, and 8 [Y = (CH2)2, (CH2)3, cis-CH = CH, X = Cl] were the most active against P388 leukemia, with an increase in lifespan ranging from 83 to 92% and were also active against M5076 sarcoma and B16 melanoma. Complexes with pyridyl or fluorophenyl substituents had reduced activities. For the latter, 19F and 31P NMR were used to verify the formation of bischelated gold(I) complexes in solution. The reduced activity of the complex with R = Et and R' = Ph and inactivity with R = R' = Et are discussed in terms of their increased reactivity as reducing agents. 31P NMR studies show that [AuI(Et2P(CH2)2PPh2)2]Cl readily reacts with serum, albumin, and Cu2+ ions to give oxidized ligand.     

Antitumor activity of intoplicine (RP 60475, NSC 645008), a new benzo-pyrido-indole: evaluation against solid tumors and leukemias in mice

Summary Intoplicine (RP 60475, NSC 645008) is a new 7H-benzo[e]pyrido[4,3-b] indole derivative which interacts with DNA and inhibits both topoisomerases I and II.In vitro it was found cytotoxic against various cell types with greater cytotoxicity towards solid tumor cells. We report here the anticancer activity of RP 60475 against a variety of transplantable tumors of mice, and also its cross-resistance profile in leukemias. The end points used were % T/C (median tumor weight of the Treated over the Control × 100) and logCK (log₁₀ cell kill total). RP 60475 administered i.v. was found schedule-independent with a peak plasma level problem. It had a good therapeutic index and host recovery usually occurred 7.5 days post last treatment. RP 60475 was found to be highly active against early stage colon 38 (T/C=0%, 2.9 logCK) and could induce 5/5 complete regressions of advanced stage tumor. It was found active against colon adenocarcinoma 51 (T/C=3.6%, 1.9 logCK) and colon carcinoma 26 (T/C=11.7%, 1.2 logCK). Most of the mammary adenocarcinomas were found very responsive, MA16/C (T/C=0%, 2.8 logCK), MA14/A (T/C=0%, 1.4 logCK), MA13/C (T/C=0%, 3.1 log CK) and MA44 (T/C=34%). Excellent activity was also observed against early stage pancreatic ductal adenocarcinoma 03 (T/C=0%) and RP 60475 could achieve 5/5 complete regressions of upstaged tumor. Activity was also obtained on Glasgow osteogenic sarcoma (T/C=0%, 3.3 logCK), on B16 melanoma (T/C=14%, 1.3 logCK) and to a lesser extent on Lewis lung carcinoma (T/C=33.2%). Evaluation of RP 60475 against leukemia sublines with acquired resistance, revealed that L1210/cisplatin and L1210/BCNU were not cross-resistant to RP 60475 whereas P388/vincristine was partially cross-resistant to RP 60475 and P388/doxorubicin was cross-resistant to RP 60475. Based on RP 60475 broad activity against transplantable tumors of mice, its effectiveness against some resistant sublines, its original mechanism of action and its acceptable toxicological profile, this compound was selected for clinical trials.     

Synthesis and antitumor properties of pyrazolo [3,4-D] pyrimidine derivatives

Several new 5-substituted 1-phenylpyrazole [3,4-d] pyrimidine derivatives were synthesized and tested for antitumor activity. Compound 17, which has 3,4-dichlorophenyl moiety at N5 of the pyrazole pyrimidine ring, shows a strong activity against L-1210 leukemia (152%). On the other hand, compounds 15, 17 and 21 were the most active against sarcoma Sa-180. It was observed that many derivatives of pyrazole [3,4-d] pyrimidine possess different biological, especially antitumor properties [1-6, 9, 10].     

Antineoplastic natural products and the analogues V. Antitumor activity of skullcapflavon II

The effect of skullcapflavon II, 5, 2′-dihydroxy-6, 7, 8, 6′-tetramethoxyfiavone, on the growth of transplantable L1210 and sarcoma 180 tumors in mice was studied. Intraperitoneal treatment of skullcapflavon II caused a significant (T/C=166%) and a moderate (T/C=122%) prolongations of the life spans of ICR and BDF₁ mice respectively, which had been intraperitoneally inoculated with sarcoma 180 and L1210 cells. Peritumoral injection of skullcapflavon II on the solid form of sarcoma 180 in mice inhibited the tumor growth strongly (Inhibition rate=71%).     

Tallysomycin, a new antitumor antibiotic complex related to bleomycin. III. Antitumor activity of tallysomycins A and B.

The antitumor activity of tallysomycins A and B was determined in five experimental tumor systems in mice. Tallysomycins A and B were highly active against B16 melanoma, sarcoma 180 ascites tumor and Lewis lung carcinoma, and moderately active against P388 leukemia but were without effect on lymphoid leukemia L1210. The antitumor activity of tallysomycin A was 2 to 3 times that of tallysomycin B and 3 to 17 times that of bleomycin. Tallysomycin A was about 1.5 and 4 times more toxic for mice than tallysomycin B and bleomycin, respectively, in terms of subacute LD50 values.     

丹酚酸A抑制核苷转运并增强化疗药物的抗肿瘤作用丹酚酸A抑制核苷转运并增强化疗药物的抗肿瘤作用

目的观察丹酚酸A(SAA)的抑制核苷转运活性及其抗肿瘤作用。方法用3H-TdR和3H-UR转运测定法,克隆生成测定法以及小鼠移植性肉瘤180模型。结果SAA抑制艾氏腹水癌细胞的胸苷和尿苷的转运,其IC₅₀分别为18.1和17.1 μmol·L^-1。SAA能明显增强5-FU、丝裂霉素C、MTX对KB细胞、肝癌BEL-7402细胞的细胞毒性。体内试验,SAA 200 mg·kg^-1和5-FU 10 mg·kg^-1单独使用的抑瘤率分别为41%和27%;SAA和5-FU联合使用的抑瘤率为63%(CDI=0.86)。结论SAA有抑制肿瘤细胞核苷转运的活性,可增强5-氟尿嘧啶等药物的抗肿瘤作用,有可能用于肿瘤联合化疗。     

Antitumor activity of echinosporin

Echinosporin isolated from a Streptomyces culture showed antitumor activity against rodent tumor models such as leukemia P388, P388/VCR, and fibrosarcoma Meth 1. It was marginally active against melanoma B16 and sarcoma 180. It was not active against Lewis lung carcinoma and xenograft MX-1. It inhibited the colony formation of HeLa S3 cells with a wide shoulder at low dose ranges. DNA, RNA, and protein synthesis were inhibited by echinosporin. It depressed WBC with nadir on day 3, but the recovery to the normal level after echinosporin injection was more rapid than that after mitomycin C.     

一些植物成分对实验肿瘤的作用

观察了18个植物成分对S180、Lewis肺癌、B16黑色素瘤、Ehrlich腹水癌、白血病P388、L1210和L615等小鼠肿瘤的疗效。以白血病P388和L1210最为敏感,L615最不敏感。此外,试验了高三尖杉酯碱、美登素、羟基喜树碱和长春新碱对Friend白血病的疗效,仅高三尖杉醋碱有明显疗效。部分样品还观察了对~3H标记的前体参入肿瘤细胞核酸和蛋白质的影响。     

Carbamoyl mycophenolic acid ethylester, an oral antitumor agent.

Several derivatives of mycophenolic acid (MA) were tested for their antitumor activity against leukemia L-1210 when administered orally and carbamoyl mycophenolic acid ethylester (CMAE) was selected as the most active antitumor agent in these tests. An oral administration of CMAE also inhibited the growth of Ehrlich solid carcinoma, NF sarcoma, myeloma X-5563 and sarcoma 180 in mice. In comparison with antitumor activity of MA, the improvement in activity of CMAE against leukemia L-1210 and Ehrlich solid carcinoma was indeed remarkable, CMAE seems to be less immunosuppressive than MA.