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Biomedical subjects

W C Rose

Publications and source records attributed to W C Rose.

At least 55 records · Page 3Linked to original sources
PubMed1990

In vivo antitumor activity of 9-[(2-phosphonylmethoxy)ethyl]-guanine and related phosphonate nucleotide analogues.

Phosphonylmethoxyalkylpurine analogues were evaluated for their antitumor activity in murine tumor models. Three compounds, (S)-9-[(3-hydroxy-2-phosphonylmethoxy)propyl]adenine (HPMPA), 9-[(2-phosphonylmethoxy)ethyl]adenine (PMEA), and 9-[(2-phosphonylmethoxy)ethyl]guanine (PMEG) were modestly active with treated versus control (T/C) values of 125%-175% versus intraperitoneal P388 leukemia, but were inactive versus intravenously implanted P388. The most active and most potent of the three was PMEG, which was also evaluated against subcutaneously (SC) implanted B16 melanoma. In confirmatory experiments, optimal therapy with PMEG yielded reproducible increases in life span (T/C values of 164%-170%) and delays in primary tumor growth (7.3- to 13.0-day T-C values). PMEG is representative of a new class of antitumor antimetabolites heretofore recognized only for their antiviral properties.

Animals↗
PubMed1990

Antitumor activity and toxicity in animals of N-7[2-(4-nitrophenyldithio) ethyl] mitomycin C (BMY-25067).

BMY-25067, N-7[2-(4-nitrophenyldithio)-ethyl] mitomycin C was selected from a number of disulfide derivatives of the highly active compound RR150, N-7(thioethyl) mitomycin C for further study. BMY-25067 had tumor inhibitory effects equivalent to mitomycin C (MMC) against ascitic P388 and L1210 leukemias and M109 lung carcinoma in mice with i.p. treatment. However, it demonstrated superior activity against B16 melanoma with a high percentage of cures when both tumors and drug were given i.p. Additionally, in separate tests against B16 melanoma implanted s.c. with treatment i.v., BMY-25067 was also consistently superior to MMC. This activity was observed when therapy was initiated either one day post-tumor implant or delayed until the ninth day post-tumor implant. Slight activity was seen against a line of L1210 partially resistant to MMC and none against a line of P388 completely resistant to MMC. Against s.c. M109, BMY-25067 inhibited tumor growth but did not prolong survival with the treatment schedule used. At their respective maximum non-lethal doses in mice, BMY-25067 was less neutropenic than MMC. This was confirmed in ferrets which were also examined for the compound's effects on platelets. BMY-25067 appeared to have much less effect on platelets than MMC; the nadir for BMY-25067 was 3.8 x 10(5) platelets/cmm compared to 7 x 10(4) platelets/cmm for MMC when the drugs were compared at a dose ratio of 2:1, BMY-25067:MMC (determined to represent their relative potencies). This initial evidence of superior antitumor effectiveness particularly to a solid tumor separated from site of treatment and reduced hematologic toxicity suggest that BMY-25067 may be a worthwhile candidate for clinical trial.

Animals↗
PubMed1990

Preclinical antitumor activity of a soluble etoposide analog, BMY-40481-30.

BMY-40481-30 is a new, water-soluble derivative and probable prodrug of etoposide characterized by the presence of a phosphate group in position 4' of the E ring of the etoposide molecule. The compound was only weakly cytotoxic in vitro and, consequently, an investigation of its antitumor activity was conducted in several murine and human tumor (xenograft) models. Etoposide was administered ip or po whereas BMY-40481-30 was given ip, po or iv. The potency of the derivative, when administered parenterally, as defined on the basis of maximum tolerated dose (MTD), was less than the parent compound on a weight (mg/kg) basis in some experiments but comparable to etoposide in other instances. Comparison at the MTD of the two compounds showed that BMY-40481-30 administered ip was as active as etoposide against ip P388 leukemia. BMY-40481-30 given iv was more active than etoposide given ip in two of five experiments versus iv P388 leukemia, but the two compounds were comparably active in the other three studies. Of particular interest was the finding that the derivative was more active than the parent compound at many of the comparable (on a mg/kg basis) dose levels of both evaluated po versus iv P388 leukemia; MTD levels were not achieved, and hence not compared, for either compound using the po route of administration. Both etoposide and BMY-40481-30 yielded comparable maximum effects against ic P388 leukemia, ic L1210 leukemia, and sc B16 melanoma, but etoposide was more efficacious versus sc M5076 sarcoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Experimental antitumor activity of BMY-28175 a new fermentation derived antitumor agent.

BMY-28175 is a novel antitumor antibiotic produced in fermentation by Actinomadura verrucosospora. The cytotoxic effects of BMY-28175 were determined using murine and human tumor cell lines in vitro. Following 72 hour exposure, the drug had IC50 values 1.5 to 13.5 ng/ml in a microtiter assay. BMY-28175 was evaluated for antitumor activity against several experimental murine and human tumor models. The drug administered ip was active against ip implanted P388 leukemia, L1210 leukemia, B16 melanoma, M109 lung carcinoma, C26 colon carcinoma, M5076 sarcoma and Lewis lung carcinoma. In addition, BMY-28175 administered iv was active against iv implanted P388 and L1210 leukemias. BMY-28175 was active against sc implanted B16 melanoma (increased lifespan and/or inhibition of primary tumor growth) in about 60% of the tests. The growth of sc implanted M109 was inhibited by BMY-28175 in a single experiment. BMY-28175 was also active against the MX-1 human mammary xenograft implanted in the subrenal capsule of nude mice. The optimal dose for BMY-28175 in these various studies ranged from 0.16 micrograms/kg per injection with consecutive daily (qd1-9) administration, to 51.2 micrograms/kg with single dose administration. The results of these studies indicate that BMY-28175 is one of the most potent antitumor agents yet observed, with a broad spectrum of activity against tumors of murine and human origin and activity against tumors located distal to the site of drug administration.

Aminoglycosides↗
PubMed1990

Synthesis of new nucleoside phosphoraziridines as potential site-directed antineoplastic agents.

With the aim of increasing the selectivity of the 2,2-dimethylphosphoraziridine type antitumor agents toward the intracellular site of DNA synthesis, a series of new compounds was synthesized in which the reactive bis(2,2-dimethyl-1-aziridinyl)phosphinyl (2,2-DMAP) group was linked through a carbamate or amide linkage to thymidine or cytosine nucleoside moieties. The 3'- and 5'-(2,2-DMAP)carbamates of thymidine (1 and 2) were found to be highly unstable, therefore the corresponding O-acetyl derivatives 5 and 6 were prepared by reacting 5'- and 3'-acetylthymidine, respectively, with dichloroisocyanatophosphine oxide followed by the addition of 2,2-dimethylaziridine and triethylamine. The 3'- and 5'-(2,2-DMAP)amides of thymidine 14 and 15 were prepared by reacting the appropriate thymidinylamines with bis(2,2-dimethyl-1-aziridinyl)phosphinyl chloride (17). The N4-(2,2-DMAP)amides of cytidine, 2'-deoxycytidine, and cytosine arabinoside (18, 19, and 20, respectively) were prepared by reacting the hydrochlorides of the O-peracetylated cytosine nucleosides with triethylamine and POCl3 and, subsequently, with 2,2-dimethylaziridine and triethylamine, to give the corresponding N4-(2,2-DMAP)cytosine nucleoside peracetates 21, 22, and 23, respectively, which were then deacetylated by aminolysis. However, the peacetate intermediates were found to be more stable and, probably for the same reason, also more active against P388 leukemia in mice than the deacetylated products. Particularly, 22 and 23 showed sufficient activity in this in vivo assay system to warrant further evaluation. The relationships between the antitumor activities, the chemical alkylating activities, and the cholinesterase inhibitory activities of these agents are discussed.

Alkylating Agents↗
PubMed1989

Experimental antitumor activity of BMY-28090, a new antitumor antibiotic.

BMY-28090 is a novel actinomycete fermentation derived antitumor agent. The cytotoxic effect of BMY-28090 was evaluated in two murine and eight human tumor cell lines in vitro. Following 72-hour exposures, BMY-28090 was cytotoxic for all of these cell lines with IC50 values of less than 0.02 to 3.25 micrograms/ml. BMY-28090 was evaluated for in vivo antitumor activity in a variety of experimental murine tumor and human tumor xenograft models. Initial testing against the murine tumor models was performed using BMY-28090 as the water insoluble free base whereas subsequent antitumor tests were performed using water soluble lactate or succinate salts. BMY-28090 administered ip demonstrated good, reproducible antitumor activity against ip implanted P388 leukemia, L1210 leukemia, B16 melanoma and M5076 sarcoma. The water soluble preparations of BMY-28090 were active iv against sc implanted B16 melanoma and M5076 sarcoma as well as subrenal capsule (src) M5076 sarcoma; activity against src implanted B16 was marginal. BMY-28090 lactate was also evaluated for activity against src implanted MX-1 human mammary tumor xenografts in nude mice and the HCT116 human colon tumor xenografts in immune-suppressed BDF1 mice. At maximum tolerated doses administered ip, BMY-28090 was active against the MX-1 xenograft in two of three tests, causing greater than 90% inhibition of tumor growth. BMY-28090 administered iv at maximally tolerated doses had marginal activity against the HCT116 xenografts, producing 61% and 68% inhibition of tumor growth in two tests. The results of these studies demonstrated that BMY-28090 has a broad spectrum of in vitro cytotoxicity against both murine and human tumor cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoglycosides↗
PubMed1985

Preclinical antitumor and toxicologic profile of carboplatin.

Carboplatin, an analog of the antitumor drug Platinol, was selected for clinical evaluation on the basis of its experimental antitumor and toxicologic profile in animal models. Described in this review is a detailed summary of selected preclinical data accumulated on carboplatin as well as data obtained concomitantly using Platinol. The predominant result gleaned from the experimental antitumor data is that of comparability between the two compounds, a finding which we feel best reflects the emerging clinical data. With respect to the preclinical toxicology, carboplatin was found to be less nephrotoxic and less emetic than Platinol. This pattern of toxicity for carboplatin appears to be substantiated in the clinical setting.

Animals↗
PubMed1985

Reductive amination of 3-ketoanguidin and antitumor activity of the products.

Amine-containing trichothecanes were prepared by reductive aminations of 3-ketoanguidin. In in vivo tests against P388 leukemia, most of them showed an improved activity compared to anguidin though their potency was decreased. 3-Ketoanguidin also produced some unexpected structures: oxazoline 5, dioxalane 7, and alpha-amino nitrile 13.

Amines↗
PubMed1985

Synthesis and properties of bis(2,2-dimethylaziridinyl)phosphinic amides: a series of new antineoplastic agents.

In continuation of efforts to improve the antitumor selectivity of the 2,2-dimethylaziridine class of alkylating agents, a series of N-substituted bis(2,2-dimethyl-1-aziridinyl)phosphinic amides has been synthesized and evaluated. All of these compounds (3-15) were tested in vivo against leukemia P-388 in mice, where most of them caused significant increase of survival time at nontoxic dose levels. Some of the most active compounds were also tested against leukemia L1210, B16 melanoma, and colon 26 carcinoma; in the latter tests, the parent unsubstituted amide 3 appeared to show the highest antitumor activity. Since the dose-limiting toxicity of the clinically tested prototypes of this class of anticancer agents AB-132 (1) and AB-163 (2) had been found to be CNS toxicity attributable mainly to the inhibition of cholinesterase, the compounds were tested in vitro against the cholinesterases from horse serum, electric eel, and bovine erythrocytes, as well as in vivo for the inhibition of the cholinesterase present in the whole blood of mice. In all of these assays, the various members of the present series showed a wide range of anticholinesterase activities, ranging from almost zero (for 3) to even higher potency than that of the prototype 2. A similarly wide range of stability was observed toward hydrolytic ring opening of the 2,2-dimethylaziridine moieties. Several of the compounds, particularly 3, deserve further study.

Animals↗
PubMed1985

Bicyclic and tricyclic analogues of anthramycin.

As analogues of pyrrolo[2,1-c][1,4]benzodiazepine antitumor antibiotics, such as anthramycin and tomaymycin, several benzo[1,4]diazepine imines and carbinolamine ethers were prepared and tested in vivo against P388 leukemia. Two different synthetic approaches, namely, a reduction of an aromatic nitro group with a concomitant cyclization and a reduction of a lactam, were employed to generate an imine or a carbinolamine moiety. Bicyclic analogues 6a', 6f, and 6g were found to be active, indicating that the pyrroline ring of anthramycin is not an absolute necessity for the antitumor activity. Compound 6g, 3,4-dihydro-9-hydroxy-4-propargyl-5H-1,4-benzodiazepin-5-one, was at least as active as neothramycin although it was 5 times less potent. Among the tricyclic analogues, compounds 5, 7a, and 8b were active against P388 leukemia, and they generally appear to be more potent than bicyclic analogues.

Animals↗
PubMed1985

Antitumor activity and toxicity in animals of BMY-25282, a new mitomycin derivative.

BMY-25282, 7-N-(dimethylamino methylene)mitomycin C, is one of a novel series of amidino mitomycin derivatives. Some of these were discovered as intermediates in a synthetic program being conducted to find improved procedures for modifying the structure of mitomycin C (MMC). Markedly superior in vivo antitumor effects have been observed with BMY-25282 compared to MMC in initial tests against i.p.-implanted P388 leukemia and B16 melanoma. When administered i.v. to mice bearing s.c. B16 melanoma, BMY-25282 was also superior to MMC. The derivative was fully active against a line of L1210 leukemia which was partially resistant to MMC treatment but had little or no activity against a line of L1210 fully resistant to MMC. It is also 2 to 4 times more potent than MMC based on a comparison of doses required to achieve optimum antitumor effects. The superior antitumor efficacy of BMY-25282 over MMC against both i.p. and s.c. B16 melanoma was maintained when the drug was given in pluronic acid formulation. Against P-388 leukemia, however, the efficacy of the drugs was equivalent when BMY-25282 was administered in the pluronic vehicle. In an in vitro clonogenic assay involving freshly explanted human tumors, BMY-25282 was consistently more potent in cytotoxic effects than MMC. With human colorectal carcinoma samples, BMY-25282 was 13.8 times more potent than MMC. The i.v. 50% lethal dose values of BMY-25282 and MMC in C57BL/6 X DBA/2 F1 mice were 2.1 mg/kg and 8.6 mg/kg, respectively. Leukopenic effects of the drugs in mice were comparable at doses up to their respective 50% lethal dose values. Hematology studies in ferrets revealed a similar pattern of depression and recovery of lymphocytes, neutrophils, and platelets for BMY-25282 and MMC; however, with BMY-25282 there was earlier recovery of platelet counts. BMY-25282 is being further developed toward possible clinical trial.

Animals↗
PubMed1984

Tallysomycin S10b: experimental antitumor activity and toxicity.

Tallysomycin S10b (TLM S10b), a structural analog of bleomycin (BLM), was evaluated and compared with BLM for antitumor activity in several murine tumor systems and for toxic effects in mice and rats. Neither TLM S10b nor BLM was effective against IP P388 and L1210 leukemias, whereas both drugs were active against IP P388/J leukemia (a BLM-sensitive subline). TLM S10b and BLM were both active against murine solid tumors, including SC B16 melanoma, IV Lewis lung carcinoma, SC Madison 109 lung carcinoma, SC CD8F1 mammary carcinoma and SC Colon 38 carcinoma. In human tumor xenograft models, TLM S10b was active against a colon tumor and had slight activity against breast and lung tumors. Compared with TLM S10b, BLM had less activity against the colon tumor, comparable activity against the breast tumor, and no effect against the lung tumor. A consensus of the antitumor data indicated that compared with BLM, TLM S10b had comparable or greater activity and was about twice as potent. TLM S10b and BLM had approximately equivalent LD50 values in mice. TLM S10b had minimal effects on WBC counts, blood urea nitrogen levels, and serum glutamic pyruvic transaminase levels in mice during the time periods monitored. These effects were comparable to or less pronounced than those of BLM. Both drugs caused dose-related increases in the whole-lung hydroxyproline content in mice, but the dose-response curves were not parallel. TLM S10b caused a larger increase than BLM at the lower doses and a smaller increase than BLM at the highest doses. In rats, TLM S10b and BLM caused comparable, significant decreases in lung mechanics; however, histopathological examination of the lungs indicated that TLM S10b caused less evidence of pulmonary toxicity than did BLM at comparable dose levels. TLM S10b was, therefore, generally comparable to BLM in causing pulmonary toxicity in mice and showed possibly less pulmonary toxicity in rats, while demonstrating approximately equivalent to four-fold greater potency, depending on the test system. It also appeared that TLM S10b caused less pulmonary toxicity than BLM in both mice and rats at doses approaching maximally tolerated levels. TLM S10b is currently undergoing phase I clinical evaluation.

Animals↗
PubMed1984

cis-4-[[[(2-Chloroethyl)nitrosoamino]carbonyl]methylamino] cyclohexanecarboxylic acid, a nitrosourea with latent activity against an experimental solid tumor.

cis-4-[[[(2-Chloroethyl)nitrosoamino]carbonyl]methylamino] cyclohexanecarboxylic acid (N-Me-cis-CCCNU) was synthesized in five steps from cis-4-aminocyclohexanecarboxylic acid via an N-tosylated intermediate. N-Me-cis-CCCNU, which is incapable of the facile decomposition that characterizes the clinically useful nitrosoureas, effected a significant cure rate of both early and established murine Lewis lung carcinoma, even though its in vitro half-life was approximately 5.5 times that of the unmethylated parent compound. This is the first observation of latent activity of a nitrosourea against an experimental solid tumor.

Animals↗
PubMed1984

Antitumor activity and toxicity in animals of RR-150 (7-cysteaminomitosane), a new mitomycin derivative.

The experimental antitumor activity of a new mitomycin derivative, 7-cysteaminomitosane (RR-150), was evaluated in mice. When administered i.p. to mice bearing i.p.-implanted tumors, RR-150 was superior to mitomycin C (MMC) in increasing the life span of animals bearing P388 leukemia, B16 melanoma, and a line of L1210 leukemia partially resistant to MMC. RR-150 appeared comparable to MMC in increasing life span of mice bearing Madison 109 lung carcinoma, Colon 26 carcinoma, or parental (nonresistant) L1210 leukemia. Mice immunosuppressed with 550 rads whole-body irradiation prior to i.p. implantation of B16 still benefited (e.g., 40% cure rate) following optimal RR-150 therapy when compared to nonirradiated, B16-implanted mice given RR-150 (e.g., 70% cure rate). RR-150 had inconsistent activity in the treatment of s.c.-implanted tumors. In toxicity evaluations, RR-150 was comparable to MMC in suppression of total while blood cell counts but appeared to be less neutropenic. RR-150 also caused less cumulative leukopenia than did MMC in a weekly chronic dose experiment. Based on serum chemistries, RR-150 did not have significant nephrotoxicity, but there was evidence of possible liver toxicity at doses near the 50% lethal dose. Because of the balance of favorable antitumor and toxicity properties of RR-150, work is under way to prepare a more bioavailable form for advanced evaluation.

Animals↗