In vitro comparative studies of the myelotoxicity and antitumor activity of 6-[bis-(2-chloroethyl)-amino]-6-deoxy-D-glucose versus melphalan utilizing the CFU-C and HTSCA assays

Summary 6-[Bis-(2-chloroethyl)-amino]-6-deoxy-D-glucose (C-6) is a new glucose-containing nitrogen mustard that has significant activity for murine P388 leukemia with relative sparing of bone marrow in mice. The in vitro myelotoxicity of C-6 compared with that of melphalan, a clinically active, myelosuppressive nitrogen mustard, was determined in the CFU-C assay in human bone marrow samples obtained from normal volunteers. There was no significant difference between the myelosuppressive actions of C-6 and melphalan at any of the concentrations used except for 4.0 M, at which C-6 was significantly (P0.05) more toxic than melphalan. Both agents decreased the number of bone marrow cell colonies to approximately 12% of control at 6.6 M (1 h incubation), which is a good approximation of melphalan's CxT (concentration by time) in man.We used the human tumor stem cell assay (HTSCA) to investigate in vitro antitumor activity. We obtained two specimens of malignant melanoma and two of malignant ovarian carcinoma from patients not previously treated with chemotherapy. The antitumor activity of melphalan was either similar to or greater than that of C-6 at all concentrations utilized against any of the four tumor specimens, except at 1.3 M for tumor I. In particular, there was no significant difference in the antitumor activities of the two agents at 6.6 M. These results suggest that C-6 will not be less myelosuppressive than melphalan at doses that produce equivalent antitumor activity in man.In addition, C-6 did not demonstrate increased myelotoxicity for normal human bone marrow cells incubated in glucose-deficient medium as against medium containing 300 mg% glucose at any of the concentrations used. This suggests that C-6 is not transported into normal human bone marrow cells via the glucose transport system, despite the presence of a glucose moiety within the molecale.Supported by Grant RO1 CA28984, a grant from the National Cancer Institute of Canada, a private contribution from Mr Schiff     

Alkylating derivatives of 2-amino-2-deoxysugars and 1-methylamino-1-deoxypolyols (synthesis and experimental study)

A number of derivatives of 2-amino-2-deoxysaccharides and 1-methylamino-1-deoxypolyols acylated by cytotoxic phenylalkanic and amino acids were synthesized and experimentally tested for antitumor activity. Some compounds showed a high antitumor activity against plasmacytoma MOPC-406: a 2-fold increase in experimental animals survival and a 80--100% cure rate were observed. Physicochemical properties, particularly, stability in aqueous solution and antitumor activity of one of the most potent compounds--1-methylamino-1-deoxy-1-N[p-di(2-chloroethyl) aminophenylacetyl]-D-glucitol (Agluphen)--are described in detail.     

Isophosphoramide mustard, a metabolite of ifosfamide with activity against murine tumours comparable to cyclophosphamide.

Isophosphoramide mustard was synthesized and was found to demonstrate activity essentially comparable to cyclophosphamide and ifosfamide against L1210 and P388 leukaemia. Lewis lung carcinoma, mammary adenocarcinoma 16/C, ovarian sarcoma M5076, and colon tumour 6A, in mice and Yoshida ascitic sarcoma in rats. At doses less than, or equivalent to, the LD10, isophosphoramide mustard retained high activity against cyclophosphamide-resistant L1210 and P388 leukaemias, but was less active against intracerebrally-implanted P388 leukaemia while cyclophosphamide produced a 4 log10 tumour cell reduction. It was also less active (one log10 lower cell kill) than cyclophosphamide against the B16 melonoma. Metabolism studies on ifosfamide in mice identified isophosphoramide mustard in blood. In addition, unchanged drug, carboxyifosfamide, 4-ketoifosfamide, dechloroethyl cyclophosphamide, dechloroethylifosfamide, and alcoifosfamide were identified. The latter 4 metabolites were also identified in urine from an ifosfamide-treated dog. In a simulated in vitro pharmacokinetic experiment against L1210 leukaemia in which drugs were incubated at various concentrations for various times, both 4-hydroxycyclophosphamide and isophosphoramide mustard exhibited significant cytoxicity at concentration times time values of 100-1000 micrograms X min ml-1, while acrolein was significantly cytotoxic at 10 micrograms X min ml-1. Treatment of mice with drug followed by L1210 cells demonstrated a shorter duration of effective levels of cytotoxic activity for isophosphoramide mustard and phosphoramide mustard in comparison with cyclophosphamide and ifosfamide. Isophosphoramide mustard and 2-chloroethylamine, a potential hydrolysis product of isophosphoramide mustard and carboxyifosfamide, were less mutagenic in the standard Ames test than the 2 corresponding metabolites of cyclophosphamide [phosphoramide mustard and bis(2-chloroethyl)amine].     

Antitumor activity of 2-chloroethyl (methylsulfonyl)methanesulfonate (clomesone, NSC 33847) against selected tumor systems in mice

Clomesone was evaluated for antitumor activity against a spectrum of animal tumor models. Clomesone exhibited significant antitumor activity against the murine L1210 leukemia implanted i.p., s.c., and intracerebrally (i.c.). Activity against s.c.-implanted tumor was largely independent of schedule and route of administration. Therapeutically optimal single-dose treatment (for tumored mice) was less toxic to nontumored mice than therapeutically optimal prolonged treatment. Clomesone also exhibited activity against other murine tumors (P388 leukemia, B16 melanoma, Lewis lung carcinoma, and M5076 sarcoma). It was active against P388 leukemia sublines resistant to cyclophosphamide, L-phenylalanine mustard, and cis-diamminedichloroplatinum(II). No activity was observed against a P388 subline resistant to N,N'-bis(2-chloroethyl)-N-nitrosourea or against Ridgway osteogenic sarcoma, a nitrosourea-resistant murine solid tumor. Clomesone is generally as effective as the chloroethylnitrosoureas against experimental tumor models. Since clomesone does not have the hydroxyethylating and carbamoylating activities of the chloroethylnitrosoureas (which do not appear to contribute to antitumor activity), it would likely be a more toxicologically selective compound. It may prove to be less carcinogenic than the chloroethylnitrosoureas, and it may contribute less target organ toxicity and less interference with the actions of other drugs when used in combinations.     

6-[Bis(2-chloroethyl)amino]-6-deoxygalactopyranose hydrochloride (C6-galactose mustard), a new alkylating agent with reduced bone marrow toxicity

We have previously reported that chloroethyl nitrosourea and nitrogen mustard bone marrow toxicity can be selectively reduced by placement of the cytotoxic group on specific positions of a glucose molecule. We have now synthesized and evaluated a new drug in which the mustard cytotoxic group is attached to the carbon-6 position of galactose (C6-GLM). C6-GLM, administered i.p. as a single 10% lethal dose of 15.5 mg/kg, produced a 121% increase in life span (ILS) in mice bearing the ascitic P388 leukemia, compared to a 60% ILS with a 10% lethal dose of nitrogen mustard (P less than 0.01). A single p.o. dose of C6-GLM, 16 mg/kg, produced an ILS of 58%. Against i.p.-implanted B-16 melanoma, i.p. C6-GLM produced a 56% ILS compared to 30% with an equitoxic dose of nitrogen mustard (P less than 0.01). The activity of the two drugs for Ehrlich ascites was comparable, with 60% survivors with the galactose mustard. A single 10% lethal dose of C6-GLM reduced the white blood cells to 74% of control; circulating granulocytes remained at 91% of initial values. With nitrogen mustard, the nadir white blood cell count was 57% of control with an absolute granulocyte count of 70% of initial values (P less than 0.01). The toxicity of melphalan was considerably greater, with a lower and more protracted while blood cell nadir and an absolute neutrophil count nadir of 49% of control. These findings paralleled the relative decrements in bone marrow DNA synthesis produced by the three drugs. Measurement of human bone marrow granulocyte-macrophage colony-forming units, following in vitro exposure to graded concentrations of the three mustards, confirmed the bone marrow sparing properties of C6-GLM. At the highest concentration, 1 X 10(-2) mM, the latter drug produced only a 33% reduction in colonies compared to a 75% reduction with nitrogen mustard and a virtual elimination of activity of colony-forming units with melphalan. The demonstration of antitumor activity, at least equivalent to nitrogen mustard, without the necessity of significant bone marrow toxicity supports the development of C6-GLM for clinical trials in humans.     

Modulation by taurine of the toxicity of taumustine, a compound with antitumor activity

The antitumor activity of 2-[bis-(2-chloroethyl)-amino]ethanesulfonic acid (also referred to here as "taurine mustard" or "taumustine") was evaluated in the murine P388 and L1210 lymphocytic leukemias and in the pigmented and nonpigmented B16 melanoma systems. Treatment with a single ip dose of taumustine (40 mg/kg) resulted in a 130% increase in life-span for mice bearing P388 (intraperitoneal), a 93% increase for mice bearing L1210 (intraperitoneal), and an approximately 80% increase for mice bearing B16 melanoma (intraperitoneal). Repeated low doses (10 mg/kg) of taumustine promoted a 250% increase in life-span for mice bearing P388 (intraperitoneal), the absence of ascitic fluid from day 4 onward, and the presence of pulmonary emboli from day 5 onward. The inclusion of taurine (5 mM) in the culture medium of P388 cells in primary culture for 45 hours did not alter the cytotoxicity of taumustine, and pretreatment of the tumor-bearing host with taurine (250 mg/kg) in daily treatments with taumustine for up to 8 days did not interfere with antitumor activity (140-160% increased life-span). However, treatment of tumor-bearing mice with taurine abrogated neurotoxicity, intestinal necrosis, pulmonary emboli formation, and tail vein necrosis due to the administration of taumustine. The modulation by taurine of taumustine activity suggests that the combination of these agents offers an advantage of selectivity and host protection during chemotherapy.     

Cytostatic effect of homo-aza-steroidal esters in vivo and in vitro. Structure-activity relationships.

The p-[N,N-bis (2-chloroethyl)amino]phenylacetate esters of 3 beta-hydroxy-N-methyl-17 alpha-aza-D-homo-5 alpha-androstan-17-one and 3 beta-hydroxy-17 alpha-aza-D-homo-5 alpha-androstane have been prepared and their antitumor activity evaluated against L1210 leukemia, P388 leukemia, Ehrlich ascites tumor (EAT) and Lewis Lung Carcinoma (LLC). The results are compared with those of the p-[N,N-bis (2-chloroethyl)amino]phenylacetate of 3 beta-hydroxy-17 alpha-aza-D-homo- 5 alpha-androstan-17-one. The above compounds were also tested in vitro against L1210, P 388, EAT and BHX cell cultures. All compounds were found to be active and their structure-activity relationship is discussed.     

Biological and biochemical properties of 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (NSC D 254157), a nitrosourea with reduced bone marrow toxicity.

1-(2-Chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (GANU), a water-soluble nitrosourea, differs from 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose (chlorozotocin) by the placement of the cytotoxic group on C-1 of glucose. Its biological and biochemical properties are compared with those of chlorozotocin. At a 10% lethal dose (10 mg/kg i.p.), GANU demonstrates minimal myelosuppression. This dose failed to depress normal bone marrow DNA synthesis, in contrast to a 96% inhibition in L1210 DNA synthesis. In L1210 cell suspension, equimolar doses of GANU and chlorozotocin produced equivalent degrees of inhibition in DNA synthesis. GANU has significant L1210 activity in BALB/c X DBA/2 F1 mice treated on Day 2 of tumor growth. A 117% increased life-span and 15% 45-day survivors are atained with 15 mg/kg i.p., a 50% lethal dose. However, in concurrent studies using randomly selected littermate groups of mice, GANU proved less active than chlorozotocin which produced a 306% increased life-span (15 mg/kg i.p.). GANU and chlorozotocin have similar in vitro alkylating activity but the in vitro carbamoylating activity of GANU is sevenfold that of chlorozotocin. On a molar basis, the lethal toxicity of GANU is twice that of chlorozotocin. The significant carbamoylating activity of GANU may contribute to its greater toxicity and therefore limit the mumoles of alkylating agent that can be administered to the tumor. These structure-activity studies further confirm that the addition of a glucose carrier to a cytotoxic nitrosourea moiety can selectively reduce bone marrow toxicity while retaining antitumor activity.     

Antitumor activity of a nitrosourea derivative,CNUA, on murine tumors

Summary The antitumor activity of a new derivative of nitrosourea, 3-[3-(2-chloroethyl)-3-nitrosoureido]-3-deoxy-d-allose (CNUA), against murine tumors was studied. CNUA showed significant antitumor activity against L1210 leukemia, Lewis lung carcinoma, B-16 melanoma and autochthonous lung tumor induced by 1-ethyl-1-nitrosourea. The effect of CNUA, chlorozotocin, and ACNU on the peripheral white blood cell count (WBC) in normal CDF₁ mice was examined. The lowest WBC count occurred 3 days after administration at the therapeutic dose level and the decreased value returned to the normal level 7–14 days following administration of CNUA and chlorozotocin. CNUA also exerted a depressive action on both humoral and cell-mediated immune response to sheep red blood cells determined by the serum hemagglutinin titer, plaque-forming cells in the spleen, and delayed-type hypersensitivity reaction, while the suppression was almost the same or less than that obtained with chlorozotocin when compared at the dose resulting in similar antitumor activity. These findings suggest that the antitumor activity of CNUA was not at all inferior to those of other nitrosoureas. The bone marrow toxicity was moderate and did not last long.     

DNA repeat length in chromatin from murine bone marrow and L1210 leukaemia cells

Previous studies have suggested that 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3-(2-chloroethyl) -3-nitrosoureahydrochloride (ACNU) and 1,(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) bind specifically to the nucleosomal DNA of murine bone marrow and L1210 leukaemia cells whereas the glucose nitrosoureas, 2-(3-(2-chloroethyl)-3-nitrosoureido)-2-deoxy-D-glucopyranose, (chlorozotocin, CLZ) and 1-(2-chloroethyl)-3-(-D-glucopyranosyl)-1-nitrosourea (GANU), bind preferentially to the linker DNA of bone marrow but not tumour cell chromatin. In order to provide an explanation for this differential, the DNA repeat and linker lengths in murine bone marrow and L1210 leukaemia cells were measured using electrophoresis of micrococcal nuclease-digested DNA. The linker length of bone marrow chromatin was approximately 22% longer than that in L1210 leukaemia cells from mouse ascites. The linker length of L1210 cells maintained in suspension culture was 27% less than in those from ascites fluid. The tissue-specific toxicity of sugar nitrosoureas and the differential binding of these drugs to chromatin does not appear to correlate quantitatively with differences in DNA linker length.     

Biological and biochemical properties of the 2-hydroxyl metabolites of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

The lethal and bone marrow toxicity and antitumor activity of the cis- and trans-2-hydroxylated metabolites of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) have been correlated with their relative in vitro alkylating and carbamoylating activities. Both the isomers have considerably greater alkylating activity and shorter chemical half-lives than the parent compound and on a molar basis have greater antitumor activity against i.p. L1210 leukemia. However, in terms of molar doses resulting in the death of 10% of normal mice, the cis- and trans-2 isomers were 2- and 3-fold more toxic than was CCNU in normal mice. In comparing the antitumor activity produced by a maximum nonlethal dose for each compound, we found that the trans isomer had activity identical to that of CCNU (413 and 410% increased life span compared to control), and the cis isomer had considerably less (152%). Like chlorozotocin, both isomers possess low carbamoylating activity and increased water solubility, two features that have been considered possible contributors to the bone marrow-sparing character of chlorozotocin. However, in the murine model the human bone marrow colony formation (CFU-C) assay neither hydroxylated metabolite of CCNU was associated with reduced myelotoxicity.     

Effects of 1-methyl-3-propyl-7-butylxanthine (MPBX) on idarubicin-induced antitumor activity and bone marrow suppression.

The effects of 1-methyl-3-propyl-7-butylxanthine (MPBX), a xanthine derivative, on idarubicin (IDA)-induced antitumor activity against P388 leukemia cells (P388) and bone marrow suppression were examined. In P388 tumor-bearing mice, the combination of MPBX with IDA increased the antitumor activity of IDA. The IDA concentration in the tumors in the MPBX combination group increased by 2.0-fold compared to the level in the IDA-alone group. On the other hand, as regards IDA-induced bone marrow suppression, the combination of MPBX with IDA reduced the decrease in the bone marrow cell number by 30% compared to that in the IDA-alone group. In addition, the IDA concentration in the bone marrow cells was decreased by the combination of MPBX with IDA. An in vitro experiment showed that MPBX facilitated IDA influx and suppressed IDA efflux in P388 cells. In conclusion, the combination of MPBX with IDA increased the antitumor activity and decreased the bone marrow suppression. Therefore, we expect that the combination of MPBX with IDA will be useful for leukemia chemotherapy.     

Chemical structure of carbamoylating groups and their relationship to bone marrow toxicity and antiglioma activity of bifunctionally alkylating and carbamoylating nitrosoureas

Although the antitumor effects of chloroethylnitrosoureas have been shown to be due primarily to DNA-DNA cross-linking by the alkylating moieties of these agents, the basis of the often accompanying bone marrow toxicity has been more controversial. We report on the relative bone marrow toxicity of four model nitrosoureas with different alkylating and carbamoylating activities: 1,3-bis(2-chloroethyl)-1-nitrosourea; 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea; chlorozotozin, (2-[3-(2-chloroethyl)-3 -nitrosoureido]-2-deoxy-D-glucopyranose); and -3-(beta-D-glucopyranosyl)-1-nitrosourea. Inhibitions of DNA, RNA, and protein synthesis in murine bone marrow cells and of colony growth of myeloid precursor cells (granulocyte-macrophage colony-forming units) were used as in vitro end points of myelotoxicity. Further, we determined the antiglioma activity of the four nitrosoureas on two human gliomas in a clonogenic tumor cell assay and studied the effect of the non-nitrosourea carbamoylators potassium cyanate, chloroethyl isocyanate, cyclohexyl isocyanate, ethyl isocyanate, and ethyl isothiocyanate on granulocyte-macrophage colony-forming units. The results show that, at equivalent drug exposures, clonogenic glioma cell kill was significant and comparative for 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea, and chlorozotocin; 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea showed little activity. In contrast, granulocyte-macrophage colony-forming unit toxicity was low with chlorozotocin and 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea and very high with 1,3-bis(2-chloroethyl)-1-nitrosourea and 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea. Of the isocyanates, bone marrow toxicity was highest with chloroethyl isocyanate and cyclohexyl isocyanate, intermediate with ethyl isocyanate, and lowest with KOCN and ethyl isothiocyanate. Our results indicate that (a) bifunctional alkylation is essential for antiglioma activity of nitrosoureas and (b) myelosuppression is at least partly linked with carbamoylation but that structural entities in the carbamoylating isocyanate rather than a quantitative degree of carbamoylation determine the degree of potential myelotoxicity.     

Antitumor quinolones with mammalian topoisomerase II mediated DNA cleavage activity.

Ninety quinolones were evaluated to determine whether their ability to induce mammalian topoisomerase II mediated DNA cleavage in vitro correlated with their antitumor activity in vivo. Ten quinolones generated linear DNA at a yield of more than 10% of substrate supercoiled DNA in the mammalian topoisomerase II mediated DNA cleavage assay. All of these compounds showed a significant increase in life span (greater than 20%) in the murine leukemia P388 model. These antitumor quinolones have closely related structures: two halogens at C-6 and C-8; and cyclopropyl at N-1 of quinolone skeleton. In contrast, many analogues of the above quinolones, as well as new quinolones used clinically as an antibacterial drug, did not induce the cleavable complex in vitro or show antitumor activity in vivo. These findings indicate that quinolone derivatives can be a promising new class of antitumor agent targeting mammalian topoisomerase II.     

Potentiation by squalene of antitumor effect of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-nitros ourea in a murine tumor system

The effect of squalene (SQ) on the antitumor activity of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitros our ea (ACNU) was studied in a murine tumor system. SQ at 4.2 g/kg exhibited a significant potentiating effect on the activity of 10 mg/kg of ACNU against lymphocytic leukemia P388 and resulted in some long-term survivors without toxicity to the host. Simultaneous administration of SQ and ACNU was most effective.     

1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino)carbonylhydrazine (101M): a novel sulfonylhydrazine prodrug with broad-spectrum antineoplastic activity

Our laboratory has synthesized and evaluated the anticancer activity of a number of sulfonylhydrazine DNA modifying agents. As a class, these compounds possess broad spectrum antitumor activity, demonstrating significant activity against a variety of experimental murine tumors, including the P388 and L1210 leukemias, B16 melanoma, M109 lung carcinoma, and M5076 reticulum cell sarcoma, as well as against the human LX-1 lung carcinoma xenograft. The current report describes the activity of a more recently synthesized member of this class, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino)carbonylhydrazine (101M). 101M was active in mice against the i.p. implanted L1210 leukemia over a wide range of doses and produced long-term survivors when administered as a single i.p. bolus of 10, 20, 40, 60, or 80 mg/kg, demonstrating a wider margin of safety than the nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Curative therapy was achieved with doses of 101M that did not produce depression of the bone marrow. 101M was also highly effective against the L1210 leukemia when administered by the oral route. The ability of 101M to penetrate the blood-brain barrier and eradicate leukemia cells in the brain was remarkable (>6 log kill). This agent was also curative against L1210 variants resistant to cyclophosphamide, BCNU, or melphalan. Mice implanted with the murine C26 colon carcinoma were also cured by two injections of 10 or 20 mg/kg of 101M. Administration of 101M by two different well-tolerated regimens caused complete regression of established human glioblastoma U251 xenografts in 100% of treated mice, and significant responses were also obtained with 101M against advanced murine M109 lung carcinomas in mice. The broad spectrum of anticancer activity of the sulfonylhydrazine prodrug 101M coupled with the wide range of therapeutic safety exhibited by this agent, makes 101M particularly attractive for further development and clinical evaluation.     

联合应用新城疫病毒及其 HN基因对小鼠黑色素瘤抑制效应的研究

背景与目的:尽管新城疫病毒( Newcastle disease virus, NDV)对多种肿瘤具有抑制作用 ,但其抑瘤机制尚不完全清楚.以前的研究结果表明,该病毒的血凝素神经氨酸酶( hemagglutinin-neuraminidase,HN)基因在该病毒的抗肿瘤作用上发挥重要作用且 HN蛋白表达后能够定位于肿瘤细胞膜上,以 HN蛋白作为肿瘤细胞的外源抗原来研究其抑瘤作用尚未见报道.本研究拟探讨 HN蛋白作为外源抗原在新城疫病毒抗肿瘤的作用以及二者联合应用对小鼠黑色素瘤的抑制效应.方法:在 C57BL/6小鼠右后肢皮下接种 B16黑色素瘤细胞 2× 105个.荷瘤第 2天,左后肢肌肉注射含新城疫病毒 HN基因的重组质粒,荷瘤第 7天,瘤内注射新城疫病毒 2× 109pfu;同时设单独 HN基因或 NDV治疗组及注射 PBS的对照组.通过抑瘤率观察动物体内的抑瘤效果;通过特异性细胞毒 T淋巴细胞( cytotoxic T lymphocyte,CTL)实验, ICAM Ⅰ、 CD48及新城疫病毒 HN蛋白在肿瘤细胞表面表达检测,探讨 HN蛋白所介导的抑瘤作用.结果:联合应用新城疫病毒及该病毒 HN基因对肿瘤的抑制效果明显好于单独 HN基因及新城疫病毒,抑瘤率达 82.8%,特异性 CTL反应增强,对靶细胞的杀伤率为 18.4%;单独 HN基因及新城疫病毒治疗组的抑瘤率分别为 56.6%、 41.0%,特异性 CTL活性分别为 4.4%、 10.1%;瘤内注射 NDV的肿瘤细胞表面检测到 HN分子的表达, ICAM Ⅰ、 CD48分子表达上调.结论:定位于肿瘤细胞表面的 HN蛋白介导机体对肿瘤细胞的特异性杀伤,联合应用新城疫病毒及该病毒 HN基因显著增强了机体对肿瘤细胞的杀伤效应.     

ANTITUMOR PRINCIPLES OF STELLERA CHAMAEJASME L.

lnthestudiesol1novelantilumoragentstYomtraditionalChineseMedicinalherbs,wehavereportedthata111cthanolextractofStelleracl]ulII'Iqj`lsnJeL.(j;ffjL1lli)showedsignit1cantal1titumoractivityagail1stmLlrineIeuken1iaP388invivo.IFromthemethanolextract,sixantitumoractivecompoundsinc1udi11ganovelcompoundnan1edsteIleramacrinhavebeenis()Iatedt()bediterpene(compounds).:(inidil11acrin,then,ostactiyecompoundwastbundto111anitbsthighbutalsosolidtumorsinvivoandstrongcelIgrowthinhibitoryactivityagainsthuman…     

Antitumor Effect in Cyclosporine A- or FK506-Treated Mice After Syngeneic Bone Marrow Transplantation

We investigated the possibility for induction of graft-versus-tumor (GVT) effects in cyclosporine A (CsA)- or FK506 (FK)-treated DBN2 mice after syngeneic bone marrow transplantation (BMT). For in vitro assays of spleen cells, the CsA-treated mice had more enhanced cytotoxic activity against YAC1 and P388, while the FK-treated animals had more against P815, YAC1, and P388. IL-4 mRNA expression was detected in spleen cells of the FK-treated mice and IL-6 mRNA expression was clearly detected in both the treated groups. Concerning GVT effects, FK had more pronounced immunostimulatory potential than CsA in this experimental setting using DBA/2 mice. In tumor-loading in vivo experiments, we could not show any antitumor effect on survival. However, this immunostimulation could be expected to eradicate the minimal residual disease after autologous BMT and autologous peripheral blood stem cell transplantation.     

Anticancer activity of new 3-amino-pyrrolidinedione-nitrogen mustard derivatives on murine sarcoma 180

A 2,5-pyrrolidinedione linked nitrogen mustard derivative, (R,S)3-[N,N-bis(2-chloroethyl)]-amino-1-(2'-methoxyphenyl)pyrrolidine- 2,5-dione hydrochloride (I) showed a marked antiproliferative effect on mouse Sarcoma 180. Since (I) is also active against L1210 and P388 leukaemias, its toxicity in mice was evaluated. A study of acute toxicity revealed focal liver cell necrosis. Another derivative, (R,S)3-[N,N-bis-(2-chloroethyl)]amino-1-(4'-n-butoxyphenyl)pyrrolidine- 2,5-dione dihydrate (II), which also possessed significant anticancer effect on P388 and L1210 leukaemias, was inactive against Sarcoma 180.