Antitumor activity of taxotere (RP 56976, NSC 628503), a new taxol analog, in experimental ovarian cancer

BACKGROUND:: The new cytostatic agent taxol has clearly demonstrated itseffectiveness in ovarian cancer patients. The synthesis of drugsrelated to taxol could overcome its limited natural supply andmay have additional benefits, such as greater efficacy or bettersolubility. Taxotere (RP 56976, NSC 628503) is such a compound.We investigated the drug for its antitumor activity in humanovarian cancer xenografts MATERIALS AND METHODS:: Five human ovarian cancer lines were selected with respect todifferences in histological subtypes, growth rates and chemosensitivityto conventional cytostatic agents. Tumors were implanted asfragments s.c. into both flanks of female nude mice (Hsd: athymicnude-nu). Treatment was started in groups of 5-8 mice at thetime mean tumor volume measured 50-150 mm³. Taxotere was injectedi.v. weekly x 2. Drug efficacy was expressed as the maximumpercentage of growth inhibition of treated tumors as comparedto control tumors. RESULTS:: At the maximum tolerated dose of 15-20 mg/kg for weekly i.v.x 2 injections, taxotere induced a mean weight loss of 10%–15%of the initial weight within 2 weeks after the first injection.The maximum percentage of growth inhibition obtained was     

Studies with RP 56976 (taxotere): a semisynthetic analogue of taxol.

RP 56976 (taxotere), a new semisynthetic analogue of taxol, is a potentially important chemotherapeutic agent for the treatment of cancer. We report here that this drug is a potent inhibitor of cell replication and, like taxol, promotes the in vitro assembly of stable microtubules in the absence of guanosine triphosphate and induces microtubule-bundle formation in cells. Compared with taxol, RP 56976 is slightly more active as a promoter of tubulin polymerization. As an inhibitor of cell replication, RP 56976 is 2.5-fold more potent than taxol in J774.2 and P388 cells and at least 5-fold more potent in taxol-resistant cells.     

The effect of pretreatment with docetaxel (taxotere; RP 56976) on irradiated subcutaneous MA 16/C murine tumors.

Docetaxel (taxotere; RP 56976) is twice as potent as taxol in the inhibition of microtubule depolymerisation and accumulates cells in their G2/M-phase, which is a highly sensitive phase of the cell cycle. The present study was designed to test the hypothesis that this property may lead to an enhanced effect of ionizing radiation on tumors. In a first experiment subcutaneous MA 16/C murine tumors, which are highly responsive to docetaxel, were treated intravenously with 45 mg/kg docetaxel and 6 hours later irradiated with 500 cGy (day 1). The pretreatment time of 6 hours resulted in a maximum mitotic index at the time of irradiation. On day 3 and 5, an additional 500 cGy was administered, without pretreatment with docetaxel. In a second experiment the radiation dose was given similarly, but pretreated with 15 mg/kg docetaxel. In both experiments, a prolonged increase of lifespan (%ILS) and a tumor growth delay (Td) was found among docetaxel treated mice and combinedly treated animals. Though a radiation dose of 1500 cGy on its own had no antitumoral effect on MA 16/C tumors, there was a marked tendency (but not statistically significant) to a better effect with the combined therapy in comparison with docetaxel alone (in experiment 1). Further studies with more radiosensitive tumors are warranted to determine the putative role of M-phase arrest on the radiosensitizing properties of docetaxel.     

Preclinical antitumor activity of an alpha-picoline derivative, penclomedine (NSC 338720), on human and murine tumors

Penclomedine, a synthetic alpha-picoline derivative, was identified as a potential antitumor agent in the P388 leukemia prescreen of the National Cancer Institute. Upon further evaluation in the National Cancer Institute in vivo tumor panel, the compound demonstrated good activity against two breast tumors. A single i.p. dose or five daily doses caused partial regressions of advanced-stage s.c. implanted mouse CD8F1 mammary adenocarcinomas. Also, penclomedine administered i.p. on Days 1,5, and 9 caused regression of the human MX-1 mammary carcinoma implanted under the renal capsule of athymic mice. In contrast, penclomedine demonstrated only marginal to moderate activity against the i.p. implanted L1210 leukemia and M5076 sarcoma and was inactive in three additional non-breast tumor models (i.p. B16 melanoma, i.v. Lewis lung carcinoma, and s.c. colon adenocarcinoma 38). Penclomedine administered p.o. and i.p. was equally effective against the subrenal capsule MX-1. Doses given p.o. every fourth day caused complete regression of 39 of 40 advanced-stage s.c. implanted MX-1 tumors but were much less effective against human H82 small cell lung carcinomas (13 of 80 complete regressions). Penclomedine p.o. also inhibited growth of the human MCF-7 and mouse 16/C breast adenocarcinomas. Further studies to support the development of penclomedine to clinical trial are in progress.     

Experimental antitumor activity of the amsacrine analogue CI-921

CI-921 is a di-substituted analogue of amsacrine currently in phase 1 clinical trial. CI-921 was developed to clinical trial largely on the basis of a series of studies at five cancer research laboratories that demonstrated its improved spectrum and degree of activity relative to those of amsacrine against murine tumor models. The tumor models studied included lung, colon, and mammary carcinomas and encompassed a wide range of biologic properties and chemosensitivities. CI-921 had significant activity against 16 of 19 (84%) tumor models examined. The activity of CI-921 was superior to that of amsacrine in 10 of 14 tumor systems that were sensitive to at least one of the agents and for which comparable data existed. In the remaining four systems, CI-921 and amsacrine were equivalent in activity. CI-921 was found to be roughly equipotent with amsacrine on a milligram-per-kilogram (body wt) basis and was found to have significantly higher activity when given orally.     

Cytotoxicity and antitumor activity of carzelesin, a prodrug cyclopropylpyrroloindole analogue.

The cyclopropylpyrroloindole analogues are DNA minor-groove binders containing a cyclopropyl group, which mediates N3-adenine covalent adduct formation in a sequence-selective fashion. Carzelesin (U-80244) is a cyclopropylpyrroloindole prodrug containing a relatively nonreactive chloromethyl precursor to the cyclopropyl function. Activation of carzelesin requires two steps, (a) hydrolysis of a phenylurethane substituent to form U-76073, followed by (b) ring closure to form the cyclopropyl-containing DNA-reactive U-76074. The formation of the DNA-reactive U-76074, via U-76073, from carzelesin was shown to proceed very slowly in phosphate-buffered saline (t1/2 greater than 24 h) but to occur rapidly in plasma from mouse, rat, dog, and human (initial t1/2 values ranging from 18 min for mouse to 52 min for rat) and in cell culture medium (t1/2 approximately 40 min). Although carzelesin was less potent in terms of in vitro cytotoxicity and in vivo optimal dosage and showed low affinity for binding to DNA, it was therapeutically more efficacious against mouse L1210 leukemia than was U-76074 or adozelesin (U-73975), another cyclopropylpyrroloindole analogue which is currently in phase I clinical trials. Carzelesin also proved to be more efficacious than U-76074 or adozelesin against mouse pancreatic ductal 02 adenocarcinoma, a system reported to be resistant to every agent tested. Carzelesin was highly effective against this tumor and produced 97% tumor growth inhibition. In addition, i.v. administered carzelesin showed significant activity (National Cancer Institute criteria) against i.v. or s.c. implanted Lewis lung carcinoma, i.p. or s.c. implanted B16 melanoma, s.c. implanted colon 38 carcinoma, and five s.c. implanted human tumor xenografts, including clear cell Caki-1 carcinoma, colon CX-1 adenocarcinoma, lung LX-1 tumor, ovarian 2780 carcinoma, and prostatic DU-145 carcinoma. Carzelesin treatment produced 100% complete remissions (no palpable tumor mass at the termination of the experiment) in mice bearing early-stage human ovarian 2780. Pharmacologically, carzelesin proved to be relatively schedule and route independent and was highly active against i.p. implanted L1210 leukemia, regardless of whether the analogue was given i.v., i.p., s.c., or p.o. These results, collectively, suggest that carzelesin is absorbed and distributed well. Both carzelesin and adozelesin caused marked tumor shrinkage in mice bearing human lung LX-1 or advanced-stage human ovarian 2780 carcinoma; however, tumor regrowth occurred shortly after the treatment with adozelesin was stopped. Little or no apparent tumor regrowth occurred after treatment with carzelesin.(ABSTRACT TRUNCATED AT 400 WORDS)     

Sequence-dependent antitumor activity of paclitaxel (taxol) and cisplatin in vivo

The established antitumor efficacy of paclitaxel and cisplatin as single agents and their distinctly different mechanisms of action have prompted laboratory and clinical research into their use in combination. Our in vivo study was performed to investigate the importance of sequence of administration and inter-agent interval. C3Hf/Kam mice bearing OCa-1 tumors received paclitaxel and cisplatin. The antitumor efficacy of the combination, measured as re-growth delay and expressed as the enhancement factor (EF), was determined for inter-agent intervals of I, 9, 24, 48 and 72 hr. Morphometric analysis was used to determine the contribution of induced apoptosis. Our findings showed an additive effect when cisplatin preceded paclitaxel by 1 and 24 hr, producing EF of 1.1 and 1.0, respectively, and a greater than additive effect for 9 and 48 hr, producing EF of 1.3 and 1.8, respectively. This sequence, however, was associated with significant morbidity and mortality. When paclitaxel preceded cisplatin the effect was greater than additive with the EF for I, 9 and 24 hr, being 1.2, 1.5 and 1.5, respectively, and increasing to a maximum of 1.9 at 48 hr. Thus, for this combination, the therapeutic ratio was improved when paclitaxel preceded cisplatin and was greatest when a 48 hr interval was allowed between drugs. We were unable to attribute the efficacy of the drug combination to increased induction of apoptosis and suggest other possible mechanisms. © 1995 Wiley-Liss, Inc.     

Comparison of antiangiogenic activities using paclitaxel (taxol) and docetaxel (taxotere)

Tumor growth requires a competent vascular supply and angiogenesis has been considered as a potential target for the treatment of several cancers. The two clinically approved taxanes, paclitaxel and docetaxel, are novel antimitotic agents that are under extensive investigation in clinical trials. Both taxanes have demonstrated significant activity against many solid tumors, but little is known about the effect of paclitaxel and docetaxel on endothelial cell function and angiogenic processes. The purpose of our study was to examine and compare the effects of these drugs on angiogenic processes in vitro and in vivo. These processes include: proliferation, migration and differentiation of cultured human umbilical vein endothelial cells (HUVEC) (in vitro), capillary sprouting of rat aortic ring explants (ex vivo) and HT1080 tumor growth in vivo. Our results demonstrate that endothelial cells are 10-100-fold more sensitive to these drugs than tumor cells. Additionally, comparison of the taxanes demonstrated that angiogenesis is blocked by both drugs primarily via inhibition of proliferation and differentiation (tube assay) and induction of cell death. Docetaxel, however, appears to be more potent at inhibiting angiogenesis, with an IC(50) concentration 10x less than that of paclitaxel. We conclude that these important findings should be taken in account in clinical trials where tumor angiogenesis is being targeted.     

Mechanism of action of 2,2'-(methylenediimino)bis-1,3,4-thiadiazole (NSC 143019), an antitumor agent.

The mechanism of action of 2,2'-(methylenediimino)bis-1,3,4-thiadiazole (NSC 143019) was clarified by studies on its effects on monolayer cultures of growing cells of the mouse cell line BALB/3T3. At concentrations below 50 muM, NSC 143019 specifically inhibited DNA and RNA syntheses without appreciably affecting protein synthesis. The syntheses of DNA and RNA were inhibited equally and concomitantly by the compound. The inhibition was reversed by removal of the compound and was prevented competitively by an equimolar amount of nicotinamide. It was also reversed completely by guanosine (0.1 mM) or deoxyguanosine (0.1 mM) and was reversed partially by xanthosine (1 mM). Other nucleosides did not influence the inhibition. The inhibition of DNA synthesis by NSC 143019 was not due to inhibition of RNA synthesis, and vice-versa. NSC 143019 inhibited the conversion of [8-14C]hypoxanthine to acid-soluble and -insoluble guanine nucleotides but not to adenine nucleotides. It was strongly suggested from these results that at concentrations of NSC 143019 below 50 muM the primary action of this compound might be due to the inhibition of GMP biosynthesis at the step of conversion of IMP to xanthosine 5'-phosphate.     

Cellular pharmacology and antitumor activity of N-(p-azidobenzoyl)-daunorubicin,a photoactive anthracycline analogue

Summary We have previously utilized N-(p-azidobenzoyl)daunorubicin (NABD), a photoactive analogue of daunorubicin (DNR), to identify unique anthracycline-binding polypeptides in rodent tissues and in tumor cells. Using cultured P388 tumor cells, we have now compared the cellular pharmacology and antitumor activity of NABD with that of DNR. Although rapidly accumulated by cells, the intracellular concentration of NABD was less than 20% that of DNR at steady-state levels. The cellular uptake of both drugs by P388 cells was dependent on extracellular drug concentration in the medium and on temperature. The rapid efflux of NABD and DNR from P388 cells in drug-free medium was reduced at lowered temperature (0 °C). Cytofluorescence microscopy demonstrated that NABD was predominantly localized in the cytoplasm, in contrast to the nuclear localization of DNR. NABD produced dose-dependent inhibition of [³H]thymidine (IC₅₀=10.0 M) and [³H]uridine (IC₅₀=1.60 M) incorporation in P388 cells to a lesser degree than DNR ([³H]thymidine, IC₅₀=0.15 M and [³H]uridine, IC₅₀=0.70 M). Continuous exposure to NABD inhibited P388 cell proliferation with an IC₅₀ of 0.27 M, compared with an IC₅₀ of 0.017 M for DNR. NABD is a pharmacologically active, photoactive analogue of DNR, which possesses properties different from those of the parent drug but similar to those of other anthracycline analogues. Photoaffinity labeling studies with NABD may identify important cytoplasmic constitutents which interact with this type of anthracycline and perhaps with the anthracycline antibiotics in general.Abbreviations used NABD N-(p-azidobenzoyl)daunorubicin - DNR daunorubicin - D₂ daunorubicinol - NABD₂ N-(p-azidobenzoyl)daunorubicinol - dDa 7-deoxydaunorubicin aglycone - dD_2a 7-deoxydaunorubicinol aglycone - TLC thin-layer chromatography - HPLC high-pressure liquid chromatography - THF tetrahydrofuran - PBS phosphate-buffered saline - DMSO dimethylsulfoxide     

Metabolism and murine pharmacokinetics of the 8-(N,N-dimethylcarboxamide) analogue of the experimental antitumor drug mitozolomide (NSC353451)

The in vitro cytotoxicity, stability, and metabolism of the 8-(N,N-dimethylcarboxamide) and 8-(N-methylcarboxamide) analogues of the experimental antitumor drug mitozolomide have been investigated in conjunction with their in vivo murine pharmacokinetics and metabolism. When tested against the TLX5 lymphoma in vitro the ID50 values for dimethylmitozolomide, methylmitozolomide, and mitozolomide were 14.6, 3.0, and 2.3 microM, respectively. The cytotoxicity of dimethylmitozolomide was dramatically increased when it was incubated with murine hepatic microsomes. There was no significant difference in the in vitro stabilities of dimethylmitozolomide and methylmitozolamide with half-lives of 43.5 and 45.8 min, respectively, in RPMI at 37 degrees C. The in vitro microsomal incubation of dimethylmitozolomide produced significant amounts of methylmitozolomide, which suggests that methylmitozolomide contributed to the cytotoxicity of dimethylmitozolomide in the presence of microsomes. The pharmacokinetics of both dimethylmitozolomide and methylmitozolomide, given i.p. at 10 mg/kg, were investigated in CBA/Ca mice bearing the s.c. solid TLX5 lymphoma. Methylmitozolomide was absorbed rapidly with maximum plasma and tumor concentrations of 10.66 mg/liter and 8.01 mg/kg, respectively, achieved 0.17 h following dosing. Dimethylmitozolomide was also rapidly absorbed with maximum plasma and tumor concentrations of 9.34 mg/liter and 5.00 mg/kg, respectively, achieved within 0.18 h of dosing. Following administration of dimethylmitozolomide, methylmitozolomide was found in both plasma and tumor tissue. The plasma and tumor area under the curves of methylmitozolomide were 87.7% and 120.8%, respectively, of those seen when mice were dosed with authentic methylmitozolomide. By comparison of the area under the curves and clearance values, it was demonstrated that 89% of the administered dimethylmitozolomide was metabolized via methylmitozolomide.     

Cyclophosphamide (NSC 26271) versus the combination of adriamycin (NSC 123127), 5-fluorouracil (NSC 19893), and cyclophosphamide in the treatment of metastatic prostatic cancer: a randomized trial.

Twenty-seven patients with a diagnosis of metastatic adenocarcinoma of the prostate were treated in a randomized, prospective trial with either Cyclophosphamide or a combination of Adriamycin, 5-Fluorouracil, and Cyclophosphamide. Doses were either Cyclophosphamide alone (800-1200 mg/m2 iv q 3 weeks) or Cyclophosphamide (150-200 mg/m2 po Day 3-6) plus 5-FU (400-500 mg/m2 iv Day 1, 8) plus Adriamycin (30-50 mg/m2 iv Day 1) given as a 4 week treatment cycle. Patients with compromised bone marrow reserve initially received the lower dose level. Objectively stable disease as defined by a modification of the National Prostatic Cancer Project criteria was seen in 53% of the 15 Cyclophosphamide treated patients and in 50% of the 12 combination treated patients. Survival was not significantly different in the two arms. However, the survival of patients responding to Cyclophosphamide was significantly longer than that of patients responding to the combination (median 18.6 months versus 8.1 months, p less than 0.05). Gastrointestinal and hematologic toxicity was moderate with both regimens. Therefore, in the present study, Cyclophosphamide alone was as effective as the combination of Cyclophosphamide, 5-FU and Adriamycin for patients with disseminated prostatic carcinoma. The moderate hematologic toxicity noted with both regimens suggests further evaluation of drug combinations utilizing higher dosages of active agents in this disease.     

Synergistic antitumor activity of taxol and immunotoxin SS1P in tumor-bearing mice.

PURPOSE: To investigate the combined antitumor activity in mice of immunotoxin SS1P and Taxol. Methods: Immunodeficient mice were implanted with A431/K5 tumors expressing mesothelin. Established tumors were treated i.v. with immunotoxin SS1P alone, i.p. with Taxol alone, or with the two agents together. SS1P was radiolabeled with (111)In and used to study the effect of Taxol on its uptake by A431/K5 tumors. RESULTS: Using doses at which either agent alone caused stabilization of tumor growth, the combination was synergistic causing long-lasting complete remissions in many animals. In contrast, synergy was not observed when the same cells were treated with these agents in vitro. Tumor uptake of (111)In-SS1P was not affected by treatment with Taxol. CONCLUSION: The combination of Taxol and SS1P exerts a synergistic antitumor effect in animals but not in cell culture. This effect is not secondary to increased tumor uptake of the immunotoxin. Synergy could be due to improved immunotoxin distribution within the tumor or could involve factors released by other cell types in the tumors.     

A late phase II study of RP56976 (docetaxel) in patients with advanced or recurrent breast cancer.

A late phase II clinical trial of RP56976 (docetaxel), derived from Taxus baccata was performed to evaluate anti-tumour activity, time to progression and clinical toxicity in patients with advanced or recurrent breast cancer. The patients, between 15 and 80 years old with performance status (PS) of 0-2, received at least two cycles of docetaxel 60 mg m-2 intravenously at 3-4 week intervals. Of the 81 patients enrolled, the 72 eligible for the study were given a total of 327 cycles, with a median of four cycles each. Five patients obtained a complete response (CR) and 27 a partial response (PR); the response rate (RR) was 44.4% (95% confidence interval 32.7-56.6%). A relatively high RR of 9/28 (32.1%) was observed in patients who had received prior chemotherapy involving anthracyclines. The dose-limiting toxicity was grade 3-4 leucocytopenia or neutropenia, found in 78.9% and 85.9% patients respectively. Other severe (grade > 3) toxicities included alopecia (38%), anorexia (18.3%), nausea/vomiting (11.3%), and fatigue (9.9%). Hypersensitivity reactions, oedema and skin toxicity were not severe and were reversible. One therapy-related death occurred 10 days after the initial dose was given. These findings indicate that docetaxel has potent activity against metastatic breast cancer, and that the dose of 60 mg m-2 is safe.     

SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 1: cellular pharmacology, in vitro and initial in vivo antitumor activity

SJG-136 (NSC 694501) is a rationally designed pyrrolobenzodiazepine dimer that binds in the minor groove of DNA. It spans 6 bp with a preference for binding to purine-GATC-pyrimidine sequences. The agent has potent activity in the National Cancer Institute (NCI) anticancer drug screen with 50% net growth inhibition conferred by 0.14 to 320 nmol/L (7.4 nmol/L mean). Sensitive cell lines exhibit total growth inhibition and 50% lethality after treatment with as little as 0.83 and 7.1 nmol/L SJG-136, respectively. COMPARE and molecular target analysis of SJG-136 data versus that of >60,000 compounds tested in the NCI 60 cell line screen shows that, although the agent has similarity to other DNA binding agents, the pattern of activity for SJG-136 does not fit within the clusters of any known agents, suggesting that SJG-136 possesses a distinct mechanism of action. Testing in the NCI standard hollow fiber assay produced prominent growth inhibition in 20 of 24 i.p. and 7 of 24 s.c. test combinations with 5 of 12 cell lines exhibiting cell kill. In addition, SJG-136 produced antitumor activity in mice bearing CH1 and CH1cisR xenografts, a cisplatin-resistant human ovarian tumor model, and also in mice bearing LS174T xenografts, a human colon tumor model. SJG-136 produces DNA interstrand cross-links between two N-2 guanine positions on opposite strands and separated by 2 bp. In human tumor cell lines, the cross-links form rapidly and persist compared with those produced by conventional cross-linking agents such as nitrogen mustards. In mice bearing the LS174T human colon xenograft, DNA interstrand cross-links can be detected in tumor cells using a modification of the single cell gel electrophoresis (comet) assay after administration of a therapeutic dose. Cross-links in the tumor increase with dose and are clearly detectable at 1 hour after i.v. administration. The level of cross-linking persists over a 24-hour period in this tumor in contrast to cross-links produced by conventional cross-linking agents observed over the same time period.     

Selective loss of mitochondrial DNA after treatment of cells with ditercalinium (NSC 335153), an antitumor bis-intercalating agent

Ditercalinium (NSC 335153), a bifunctional intercalating molecule with antitumor activity, is found to express its toxicity through a mechanism of action completely different from that of other monointercalating agents. Electron microscopic observation of ditercalinium-treated cells shows a drastic alteration of mitochondrial structure. Cells deficient in mitochondrial respiration (GSK3 cells) isolated by A. Franchi et al. (Int. J. Cancer, 27: 819-827, 1981) are about 25-fold more resistant than cells deficient in glycolysis (DS7 cells) isolated by J. Pouysségur et al. (Proc. Natl. Acad. Sci. USA, 77: 2698-2701, 1980). Revertants have been isolated from GSK3 cells. In these cells, the sensitivity to ditercalinium has been recovered with mitochondrial respiration. Ditercalinium treatment of L1210 leukemic mouse cells leads to a specific elimination of mitochondrial DNA detected by DNA-DNA hybridization. No measurable alteration of nuclear DNA is observed. In contrast, the monomeric analogue of ditercalinium only alters nuclear DNA and does not change the mitochondrial DNA content. The activity of cytochrome c oxidase, an enzyme which contains a subunit coded by the mitochondrial DNA, decreases exponentially in treated cells with a half-life of 24 h, corresponding to the turnover of the enzyme. These results suggest that ditercalinium exerts a specific cytotoxic effect at the level of mitochondrial DNA. This action could account for the delayed cytotoxicity induced by this compound.     

Flavone acetic acid (LM 975, NSC 347512) A novel antitumor agent

Summary Flavone acetic acid (FAA) is a synthetic flavonoid compound which has recently begun clinical trials as an antitumor agent based on its striking activity in solid tumor model systems. The pharmacologic behavior of FAA in animals appears to be predictive of both its cytotoxic efficacy and its toxicity to normal tissues (principally the central nervous system and gastrointestinal tract). The design and conduct of phase I studies in man are based upon these principles, with the goal of maximizing their safety and efficacy.This work was supported by NCI, NIH grant CA 38137, and the Ben Kasle Fund for Cancer Research     

SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 2: efficacy evaluations

Pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136 (NSC 694501) selectively cross-links guanine residues located on opposite strands of DNA, and exhibits potent in vitro cytotoxicity. In addition, SJG-136 is highly active in vivo in hollow fiber assays. In the current investigation, SJG-136 was evaluated for in vivo efficacy in 10 tumor models selected on the basis of sensitivity of cells grown in the hollow fiber and in vitro time course assays: LOX IMVI and UACC-62 (melanomas); OVCAR-3 and OVCAR-5 (ovarian carcinomas); MDA-MB-435 (breast carcinoma); SF-295 and C-6 (gliomas); LS-174T (colon carcinoma); HL-60 TB (promyelocytic leukemia); and NCI-H522 (lung carcinoma). SJG-136 was active against small (150 mg) and large (250-400 mg) xenografts with tumor mass reductions in all 10 models. In addition, significant growth delays occurred in nine models, cell kill in six models ranged between 1.9 and 7.2 logs, and there were 1 to 4/6 tumor-free responses in six models. SJG-136 is active following i.v. bolus injections, as well as by 5-day continuous infusions. Of all of the schedules tested, bolus administrations for 5 consecutive days (qd x 5) conferred the greatest efficacy. SJG-136 is active over a wide dosage range in athymic mouse xenografts: on a qd x 5 schedule, the maximum-tolerated dose was approximately 120 microg/kg/dose (total dose: 0.6 mg/kg = 1.8 mg/m2) and the minimum effective dose in the most sensitive model (SF-295) was approximately 16 microg/kg/dose (total dose: 0.08 mg/kg = 0.24 mg/m2). Results of this study extend the initial in vivo observations reported in the reference above and confirm the importance of expediting more detailed preclinical evaluations on this novel agent in support of phase I clinical trials in the United Kingdom and the United States, which are planned to commence shortly.     

Experimental antitumor activity of 5''-nor-anhydrovinblastine navelbine

The yield of N-nitrosodimethylamine (NDMA) has been studied in the nitrosation reaction in the presence or in the absence of ethanol. In the experiments in vivo the mice underwent intragastric administration of amidopyrin and sodium nitrite, and in the experiments in vitro dimethylamine (DMA) and sodium nitrite were used. It has been established that both in vivo (in the stomach of mice) and in vitro (in the medium of pure reagents and human gastric juice) ethanol inhibited the reaction of nitrosation by amines in acid media, thus decreasing the yield of NDMA.