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.     

Comparison of the cytotoxicity of amsacrine and its analogue CI-921 against cultured human and mouse bone marrow tumour cells

Human and mouse bone marrow cells were cultured for 1 h in the presence of either the antileukaemia drug amsacrine or its 4-methyl,5-[N-methyl]carboxamide disubstituted analogue CI-921, before being plated in methylcellulose medium to determine the survival of granulocytemacrophage colony forming units (CFU-GM). The drug concentration required for 50% reduction in survival was approx. 0.4 μM for both drugs and was similar for both human and mouse cells. A comparison of the two drugs was then made, at an added drug concentration of 0.5 μM, using cultured mouse L1210 and P388 leukaemia, Lewis lung carcinoma cell lines LLAK and LLTC, human Jurkat leukaemia, human histiocytic lymphoma U937 and human colon carcinoma SW620. The sensitivity of the mouse lines for amsacrine was in the order L1210 > P388 > LLAK > LLTC, similar to the in vivo sensitivity. The selectivity of CI-921 for L1210 versus bone marrow, and for LLAK versus L1210 or P388, was greater than that of amsacrine, again in keeping with its in vivo properties. The sensitivity of the human Jurkat and U937 lines for amsacrine was intermediate between that of L1210 and P388, while SW620 was resistant. The selectivity of CI-921 for Jurkat and U937 versus bone marrow was greater than that of amsacrine, suggesting that CI-921 could have additional advantages over amsacrine in the treatment of some tumours.     

Pharmacological characterization of teroxirone, a triepoxide antitumor agent, in rats, rabbits, and humans

Teroxirone is an experimental triepoxide antitumor agent currently undergoing evaluation in clinical trials. We have developed an assay based on derivatization with diethyldithiocarbamate followed by normal-phase high-performance liquid chromatographic analysis. When 14C-labeled teroxirone is administered to rabbits by rapid i.v. infusion, plasma disappearance of parent drug is very rapid (t1/2 less than 5 min), while plasma 14C-labeled drug equivalents are eliminated at a much slower rate (t1/2 greater than 60 min). Twenty-four-hr urinary recovery of parent drug is less than 1%, while recovery of 14C total radioactivity is 60 to 70%. Rapid plasma elimination (t1/2 less than 5 min) and total body clearance (greater than 5 liters/min) are observed following rapid i.v. administration of teroxirone to humans. When teroxirone is administered to humans at constant rates of infusion, plateau concentrations are rapidly achieved and maintained during infusion. Plasma concentrations rapidly decrease upon cessation of infusion. Less than 1% parent drug is recovered in 24-hr urine. Teroxirone is relatively stable in fresh human plasma and whole blood. Teroxirone is metabolized by rat liver, but not lung, microsomal preparations by an NADPH-independent pathway. Epoxide hydrolysis metabolites are detected in microsomal incubations, and cyclohexene oxide inhibits teroxirone metabolism, suggesting that epoxide hydrase may be responsible for teroxirone biotransformation. Cytotoxicity of teroxirone against continuous human tumor cell lines is abolished in the presence of 9000 X g rat liver supernatant preparations but partially restored when cyclohexene oxide is added to incubation mixtures.     

Disposition of amsacrine and its analogue 9-([2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4- acridinecarboxamide (CI-921) in plasma, liver, and Lewis lung tumors in mice

9-([2-Methoxy-4-[(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4- acridinecarboxamide (CI-921), an analogue of the clinical antileukemia drug amsacrine with improved solid tumor activity in mice, is currently being evaluated in patients. In order to determine whether CI-921 possesses any advantages over amsacrine in terms of tissue delivery, the pharmacokinetics of amsacrine and CI-921 were determined following i.v. injection in male B6D2F1 mice. Plasma kinetics in normal mice were measured following administration of 14.4, 28.9, and 57.7 mumol/kg. The kinetics in s.c. Lewis lung tumors, and in plasma and livers of normal and tumor-bearing mice were measured following administration of 57.7 mumol/kg. CI-921 and amsacrine were quantitated by high-performance liquid chromatography after extraction from plasma and from liver and tumor homogenates. In experiments with appropriate 3H-labeled compounds, both total and covalently bound radioactivity (determined after precipitation and washing with acetonitrile) were measured in plasma and in liver homogenates. Over this dose range, nonlinear kinetics were observed in plasma for unchanged CI-921 and amsacrine, and a reasonable fit was obtained with Michaelis-Menten kinetics to a one-compartment model for CI-921 (Km 3.7 mumol/liter; Vmax 18 mumol/h/kg; V ss 3.3 liter/kg) and a two-compartment model for amsacrine (Km 3.6 mumol/liter; Vmax 76 mumol/h/kg; Vss 4.8 liter/kg). The area under the concentration-time curve (AUC) for plasma following a dose of 57.7 mumol/kg was 31 mumol.h/liter for CI-921 and 6.3 mumol.h/liter for amsacrine. However, equilibrium dialysis measurements indicated high plasma protein binding with free drug fractions for CI-921 and amsacrine of 0.63 and 6.7%, respectively. In the liver, unchanged drug concentrations and total radioactivity for both compounds were approximately 10-fold those in plasma, and the tissue half-life of CI-921 was approximately 4-fold longer for CI-921 than for amsacrine. Plasma and liver kinetics in mice with s.c. Lewis lung tumors were similar to those in normal mice. Tumor half-lives of unchanged CI-921 and amsacrine were 3.9 and 2.7 h, respectively, considerably longer than those for plasma (1.2 and 0.30 h respectively) or liver (1.2 and 0.28 h, respectively). Tumor AUC values for CI-921 and amsacrine were 68 and 37 mumol.h/liter, respectively, as compared to the calculated AUC values for free drug in plasma of 0.19 and 0.42 mumol.h/liter, respectively. It is concluded that the uptake into tumors from the plasma free drug fraction is more efficient for CI-921 than for amsacrine.     

Phase I trial of the amsacrine analogue 9-[( 2-methoxy-4-[(methylsulfonyl)amino]-phenyl]amino)-N,5-dimethyl-4- acridinecarboxamide (CI-921)

CI-921, an analogue of amsacrine with superior activity against in vivo and in vitro experimental tumor models, has been studied in 16 patients with solid tumors refractory to chemotherapy or for which conventional therapy does not exist. Thirty-nine cycles were given and doses escalated from 39 to 810 mg/m2. This total dose was divided over 3 consecutive days and administered by 15-min infusion each day, repeated three times weekly. Neutropenia (Eastern Cooperative Oncology Group) Grade greater than or equal to 3 occurred at Day 8 (range, 7-13) in 10/13 courses at 648 mg/m2 and in 2/2 courses at 810 mg/m2 with recovery in 10 (range, 4-20) days. At 810 mg/m2 Grade 2 mucositis and phlebitis were noted. Mild nausea and venous irritation occurred in some patients at doses greater than or equal to 288 mg/m2. No objective response was seen. Pharmacokinetics were evaluated following 65 infusions on Days 1 and 3 with plasma concentrations of CI-921 measured by high performance liquid chromatography. Peak plasma concentrations ranged from 3.36 to 85.6 mumol/liter and were significantly correlated with dose. Mean (range) model-independent pharmacokinetic parameters were: distribution half-life, 0.46 h (0.24-1.08); elimination half-life, 2.63 h (1.08-4.98); mean residence time, 2.0 h (1.05-3.35); plasma clearance, 158 ml/h/kg (95-290); and steady-state volume of distribution, 319 ml/kg (219-614) with no significant difference between Day 1 and 3. Toxicity as defined by absolute granulocyte count nadir was significantly correlated with dose, area under concentration-time curve, and peak plasma concentration. The recommended dose for Phase II studies in this schedule is 648 mg/m2 (216 mg/m2 daily for 3 days) repeated every three weeks.     

A combined pharmacokinetic model for the hypoxia-targeted prodrug PR-104A in humans, dogs, rats and mice predicts species differences in clearance and toxicity

Background

PR-104 is a phosphate ester that is systemically converted to the corresponding alcohol PR-104A. The latter is activated by nitroreduction in tumours to cytotoxic DNA cross-linking metabolites. Here, we report a population pharmacokinetic (PK) model for PR-104 and PR-104A in non-human species and in humans.

Methods

A compartmental model was used to fit plasma PR-104 and PR-104A concentration?Ctime data after intravenous (i.v.) dosing of humans, Beagle dogs, Sprague?CDawley rats and CD-1 nude mice. Intraperitoneal (i.p.) PR-104 and i.v. PR-104A dosing of mice was also investigated. Protein binding was measured in plasma from each species. Unbound drug clearances and volumes were scaled allometrically.

Results

A two-compartment model described the disposition of PR-104 and PR-104A in all four species. PR-104 was cleared rapidly by first-order (mice, rats, dogs) or mixed-order (humans) metabolism to PR-104A in the central compartment. The estimated unbound human clearance of PR104A was 211?L/h/70?kg, with a steady state unbound volume of 105?L/70?kg. The size equivalent unbound PR-104A clearance was 2.5 times faster in dogs, 0.78 times slower in rats and 0.63 times slower in mice, which may reflect reported species differences in PR-104A O-glucuronidation.

Conclusions

The PK model demonstrates faster size equivalent clearance of PR-104A in dogs and humans than rodents. Dose-limiting myelotoxicity restricts the exposure of PR-104A in humans to approximately 25% of that achievable in mice.     

Pharmacokinetic determinants of the activity and toxicity of antitumour agents

Pharmacokinetic-pharmacodynamic relationships in cytotoxic cancer chemotherapy are reviewed. In all classes of established cytotoxic drugs there is now good evidence that pharmacokinetics are a major determinant of drug toxicity and, in some instances, activity. Attempts are now being made to exploit these relationships to improve the therapeutic utility of established cytotoxic drugs and initial results are promising. In addition, there is evidence that the early clinical evaluation of new drugs may benefit from the application of pharmacokinetic information.     

Pharmacokinetic analysis and antitumor efficacy of MKT-077, a novel antitumor agent

MKT-077 (1-ethyl-2-{[3-ethyl-5-(3-methylbenzothiazolin-2-yliden)]-4-oxothiazolidin-2-ylidenemethyl} pyridinium chloride), a novel rhodacyanine dye in phase I/II clinical trials, may provide a new approach to cancer therapy based on the accumulation in the mitochondria of the cells of certain carcinomas, for example, those of the colon, breast and pancreas. To support the development of MKT-077 for clinical application as an intravenous (i.v.) therapy, we investigated the metabolic fate of [¹⁴C]MKT-077 in BDF1 mice as well as the distribution of MKT-077 in experimental LS174T tumor-bearing mice using a high-performance liquid chromatography (HPLC) method. The plasma levels of ¹⁴C after i.v. administration of [¹⁴C]MKT-077 declined in a triphasic manner. In the first distribution phase, the levels of ¹⁴C decreased with a T_1/2 of ∼5 min. In the second and terminal phase, the T_1/2 of ¹⁴C was 2.8–4.6 h and 16.2 h, respectively. C_max (1 min after injection) increased from 0.3 to 1.5 μg/ml linearly, but less than proportionately between the doses. The AUC_(0–∞) at 0.3, 1 and 3 mg/kg were 0.030 ± 0.002, 0.60 ± 0.12 and 1.73 ± 0.25 μg · h/ml, respectively. Plasma clearance was ∼1.8 l/h per kg (at doses of 1 and 3 mg/kg). The steady state volume of distribution (6.8 and 25.1 l/kg) indicated that MKT-077 distributed as a lipid-soluble molecule. The mean residence time (MRT) was 4.1 (at a dose of 1 mg/kg) and 14.1 h (at a dose of 3 mg/kg). In the first rapid phase (5 min after dosing), ¹⁴C radioactivity was detected in most of the tissues and organs, most strongly in the kidney cortex, and not in the central nervous system and testes. In the terminal phase (24 h after dosing), ¹⁴C contents increased in the intestinal tract, and in the kidney and liver were nearly to the background level. After i.v. bolus administration at a dose of 3 mg/kg of [¹⁴C]MKT-077, the predominant route of elimination of the radioactivity was via the feces, and recoveries of total radioactivity in urine and feces corresponded to 33.5% and 61.1%, respectively. More than 60% was recovered within 24 h and 95% within 1 week. MKT-077 was primarily excreted in unmetabolized form with five unidentified metabolites found in the urine and plasma. Intact MKT-077 was retained in the tumor tissue longer than in plasma and kidney in LS174T tumor-bearing mice receiving MKT-077 at an i.v. therapeutic dose (10 mg/kg). This accumulation decreased very slowly, suggesting that the high membrane potentials of tumor cell mitochondria may help retain the drug in tumors. Received: 4 February 1998 / Accepted: 29 June 1998     

Comparison of the pharmacokinetics and protein binding of the anticancer drug,amsacrine and a new analogue,N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino)phenyl-amino]-4-acridinecarboxamide in rabbits

Summary Amsacrine (NSC 249992) is a new anticancer drug which, although effective for the treatment of various disseminated tumors, has shown disappointing activity against most solid tumors. A new analogue, N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino)phenylamino]-4-acridine-carboxamide (CI-921, NSC 343499) has been identified, which might offer a broader clinical antitumor spectrum. This analogue is more lipophilic (0.5 log p units) and is also a considerable weaker base (pKa 6.40) than amsacrine (pKa 7.43). This study compared the pharmacokinetics of total and unbound amsacrine and CI-921 in plasma after equimolar dose infusions (12.7 mol/kg) in a balanced crossover design in six rabbits. Drug concentrations were determined by high-pressure liquid chromatography and the unbound fraction by equilibrium dialysis. Three fold higher total plasma concentrations were achieved with CI-921 than with amsacrine. However, the unbound fraction was significantly less for CI-921 (0.33%±0.04) than for amsacrine (2.78%±0.53). There was no significant difference between distribution and elimination half-life and mean residence time, but the apparent volume of distribution (means, 121 vs 45 l/kg) and clearance (means, 46.6 vs 16.3 l h^-1 kg^-1) of unbound CI-921 were threefold greater than the corresponding parameters for unbound amsacrine. We suggest that despite higher binding in plasma, the greater distribution or tissue uptake of CI-921 may be partly responsible for its greater anticancer activity in vivo.The work described in this paper was supported by a grant from the Medical Research Council of New Zealand. It was reported on at the 18th Annual Meeting of the Australasian Society of Clinical and Experimental Pharmacologists, Melbourne, Australia, December 1984     

Pharmacokinetic approach to the improvement of clinical predictability in the preclinical test for antitumor agents

Clinical predictability of preclinical test for antitumor agents has not been significantly improved even after the use of a human tumor/nude mouse model. Such different antitumor activities between preclinical and clinical tests probably due to the fact that therapeutic used in both tests usually each maximum tolerated dose (MTD), are pharmacokinetically not equivalent. Therefore, we introduced a new concept of "clinically equivalent dose (CED)", which can reproduce in the nude mouse the blood level of a given drug observed with human patients received its therapeutic dose. Treatment of human tumors implanted in the nude mice with CEDs of several drugs exhibited much better correlation with their clinical efficacies than those with MTDs. The feasibility of use of CED predicted by animal scale-up procedure as a therapeutic dose in the preclinical test was discussed.     

Ruboxyl, a new nitroxyl derivative of daunorubicin - acute toxicity and antitumor effect in animals

Ruboxyl (RBX), a new nitroxyl derivative anthracycline, showed an interesting cytotoxic effect on in vitro established human cell lines and an antitumor activity in tumor-bearing animals. In this study, we further investigated the antitumor effect of this drug compared to Doxorubicin (DX) in four in vivo systems of experimental murine tumors. Our data demonstrate that RBX had little effect on the growth of primary tumor, and on the survival, in mice bearing Lewis lung carcinoma (3LL), while the drug showed a higher effect on the growth of B 16 melanoma. In both the experimental murine systems the activity of RBX was similar to that exerted by DX. As regards the leukemia models, RBX induced a significant increase on survival in mice bearing both L1210 or L5178Y leukemias. However, the effect on survival and the number of long-term survivors (LTS) were lower than that observed following DX treatment.     

Tintelnotia,a new genus in Phaeosphaeriaceae harbouring agents of cornea and nail infections in humans

Phaeosphaeriaceae is a family in the order Pleosporales containing numerous plant pathogens, endophytes, lichenised fungi, and environmental saprobes. A novel genus, Tintelnotia is introduced containing two species, one of which caused an eye infection and several nail infections in humans. All species of Tintelnotia produce conidia in soft pycnidia with a wide ostiole. The generic type species is T. opuntiae causing necrotic spots on cactus plants. The isolates of the human opportunist T. destructans showed variable susceptibility pattern to a panel of common antifungal agents. The MICs of amphotericin B, voriconazole, posaconazole and itraconazole were 1 μg/mL, complemented by an in vitro MEC of 16 μg/mL against caspofungin; the MIC of terbinafine was 0.125 μg/mL. The latter compound contributed to the successful therapy in the ocular mycosis refractory to standard antifungal therapy, the benefit of terbinafine should be highlighted as a therapeutic option especially in difficult‐to‐treat fungal keratitis.     

Extraction and partial purification of a hepatic stimulatory substance in rats, mice, and dogs

A factor has been isolated from weanling rat liver which stimulates in vivo hepatic DNA synthesis in a dose dependent manner when injected into 40% hepatectomized rats. The factor has been partially purified by successive steps, involving ethanol precipitation, ultrafiltration through an Amicon PM 30 membrane, and finally fast protein liquid chromatography, resulting in a 38,000-fold increase in specific activity over that in the original cytosol. The factor contains a few bands in the molecular weight range of 14,000-50,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Active fractions from fast protein liquid chromatography (F150), when injected into 40% hepatectomized rats, increased hepatic DNA synthesis 3-fold over the background stimulation due to the hepatectomy. The response was dose dependent over a range from 1.76 micrograms to 6.8 micrograms per 200-g (body weight) rat. Mitotic and labeling indexes confirmed that F150 stimulates both replicative DNA synthesis and cell proliferation. The factor is heat and neuraminidase resistant, trypsin sensitive, organ specific, but not species specific.     

Effect of a high-protein-low-carbohydrate diet on toxicity and antitumor activity of 5-fluorouracil in mice

The effect of different levels of dietary protein on 5-fluorouracil (FUra) toxicity and antitumor activity was assessed in female (BALB/c X DBA/2Ha)F1 (CDF1) and BALB/c mice bearing the P1798 lymphosarcoma. In the toxicity experiments, CDF1 mice were fed diets containing 5% [low protein (LP)], 20% [normal protein (NP)], or 60% [high protein (HP)] casein for 22 days and were then given a single ip injection of 275 mg FUra/kg. As determined by effects on the white blood cell count and by changes in body weight, FUra was least toxic in mice fed the HP diet. Moreover, mortality was 77.0, 42.9, and 11.4% for mice fed the LP, NP, and HP diets, respectively. In the antitumor studies, BALB/c mice bearing the P1798 lymphosarcoma were fed one of the 3 diets starting 5 days after transplant. Mice were given injections of 50 mg FUra/kg or the vehicle control on days 14 and 15 after transplant. As measured by tumor weights on day 16, FUra was least effective in mice fed the LP diet and most effective in mice fed the NP and HP diets. Survival time of mice given injections of FUra on days 14 and 15 was increased when compared to the survival time of control mice, but no difference in the percent increase in survival time was noted among the 3 dietary groups. If mice were given two cycles of FUra therapy (days 14 and 15 and days 20 and 21), mice fed the HP diet survived significantly longer than did mice fed the LP or NP diet. These data demonstrate that the feeding of an HP diet markedly decreases the toxicity of FUra while preserving or actually enhancing the antitumor effect.     

Evaluation of toxicity of beta-tethymustine, a new anticancer compound, in mice.

The toxicity of beta-tethymustine, a potential anticancer compound 1 ((Cancer Lett., 119 (1997) 7-12) was assessed in normal as well as in Ehrlich ascites carcinoma (EAC), Sarcoma-180 (S-180) and Dalton' s Lymphoma (DL) tumour-bearing Swiss male mice by measuring drug-induced changes in haematological parameters, femoral bone marrow cellularity and splenic cellularity on days 9, 15 and 21 following drug treatment at the optimum dose of 8.0 mg/kg body weight from days 1 to 7. Detailed studies were also made by noting sequential changes in the above parameters in normal and EAC-bearing mice on days 12 and 18, respectively. The results indicate that the compound did not adversely affect haematopoiesis as it was observed that no significant decrease in haematological parameters and femoral marrow cellularity occurred in treated groups. Initial hyposplenic activity was, however, noted in EAC and normal treated groups on day 9 which soon reached normal count within 7-10 days after termination of drug therapy. Drug-induced hepatotoxicity and nephrotoxicity were also sequentially evaluated in normal and tumour-bearing mice on days 9, 15 and 21 but no such toxicities were detected. Also, body weight, skin and hair texture, and behavioural pattern (food and water intake and activity) did not reflect any toxic reaction in host mice at this optimum dose.     

Development of a radioimmunoassay for the anthrapyrazole chemotherapy agent CI-937 and the pharmacokinetics of CI-937 in rats

The anthracyclines daunorubicin and doxorubicin are cancer chemotherapy agents that complex DNA and are widely utilized clinically. Cumulative cardiotoxicity, however, limits their prolonged use. The novel anthrapyrazole agent, CI-937, which has shown exceptional in vivo anticancer activity and reduced cardiotoxicity in preclinical models has been developed at the Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co. Due to an inability to extract CI-937 reproducibly from biological fluids, high-performance liquid chromatography is not a feasible analytical method. We developed a radioimmunoassay by conjugating CI-937 to porcine thyroglobulin to elicit rabbit antibody which was used with a radioiodinated derivative. The assay was validated for rat plasma using 50 microliters of sample with a resulting limit of quantitation of 100 pg/ml. By dilution of samples the assay can quantitate CI-937 levels up to 16 micrograms/ml. The antiserum is very specific as evidenced by cross-reactivities of less than 0.4% for structural analogues and less than 0.004% for any of the commonly used cancer chemotherapy agents. Analysis of plasma samples from rats treated with a single 5 mg/kg i.v. dose indicated that CI-937 is rapidly cleared from plasma and is extensively bound to tissues.     

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)     

Effect of vitamin E on toxicity and antitumor activity of adriamycin in mice

The use of vitamin E as a protective agent against adriamycin-induced toxicity in CDF1 and BDF1 mice resulted in potentiation of the chemotherapeutic index of adriamycin. A single dose of 15 mg of adriamycin per kg body weight produced a significantly reduced mean survival time. A dosage of adriamycin of 15 mg per kg body weight was employed in the following experiments. In P388 ascites tumor-bearing mice, four consecutive injections of several doses of vitamin E before injection of adriamycin produced a significant prolongation of the mean survival. In concomitant studies of serum tocopherol content, 7 to 10 micrograms/ml appeared to be an appropriate serum concentration, in accordance with the result of our previous report on its immunopotentiation effect. alpha-tocopherol seemed to have a two- to three-fold greater physiological activity than alpha-tocopheryl acetate. Dietary vitamin E treatments offered no protection against adriamycin toxicity, because the serum tocopherol content reached only 4.39 micrograms/ml in mice given the vitamin E-sufficient feed in this study. The results suggested that an increase of the serum tocopherol level to about two to three times the untreated control would be required before the adriamycin treatment to reduce its toxicity.