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F A Schmid

Publications and source records attributed to F A Schmid.

At least 19 recordsLinked to original sources
PubMed1990

Preferential selection during therapy in vivo by edatrexate compared to methotrexate of resistant L1210 cell variants with decreased folylpolyglutamate synthetase activity.

Acquired resistance of the L1210 leukemia in mice developed with less rapidity during therapy with edatrexate (10-ethyl-10-deazaaminopterin, EDX) than with MTX. Since this was explained only partially by the somewhat greater antitumor activity of EDX, this result may also reflect a difference in biochemical phenotypes selected in each case. Among 20 sublines selected for resistance to MTX, a reduction in influx, an elevation of DHFR, and a reduction of DHFR inhibition by MTX were all delineated. Among 14 sublines selected for resistance to EDX, both a reduction in influx and an elevation in level of DHFR were also commonly found. In addition, however, 7 of 14 EDX-resistant sublines exhibited a reduction in the level of folylpolyglutamate synthetase (FPGS) activity. Clonal derivatives of these 7 EDX-resistant cell lines exhibited 2- to 28-fold reductions in FPGS activity and a commensurate reduction in [3H]-MTX polyglutamate formation in situ following exposure to [3H]-MTX during growth in mice. An analysis of the kinetics and relative substrate preferences for FPGS from variant and parental L1210 cells revealed that the various changes in FPGS activity were at the level of the Vmax rather than Km. These results derived from an in vivo tumor model provide further evidence for a role of FPGS as a determinant of cytotoxicity and acquired resistance to classical folate analogs. They also provide evidence in the same pharmacologic model for a manifestation of resistance to 4-aminofolates in vivo that involves all of the alterations of its primary target, transport, and metabolism that have ever been associated with acquired resistance in cell culture systems.

Aminopterin↗
PubMed1989

Intracavitary therapy of murine ovarian cancer with cis-diamminedichloroplatinum(II) and 10-ethyl-10-deazaaminopterin incorporating systemic leucovorin protection.

Administration i.p. of 10-ethyl-10-deazaaminopterin (10EDAM) with cis-diamminedichloroplatinum(II) (cis-Pt) had significant antitumor activity against the murine ovarian tumor. This tumor is a teratoma originating in the ovary with pathogenesis and metastatic properties similar to those of human ovarian cancer. Drug was given on a schedule of once every 3 days for 3 doses 1 or 2 days after i.p. implant of 10(7) tumor cells. Despite the 2-fold attenuation of dosage required, antitumor activity of the combination (increased life span, 161%) was approximately twice that obtained with maximum tolerated doses of either agent alone and tumor-free, long-term survivors were obtained. Incorporation of s.c. calcium leucovorin administration 16 h after each dose of 10EDAM and cis-Pt allowed a 4-fold increase in dosage of 10-EDAM without an increase in toxicity, increased median survival by an additional 120%, and quadrupled the number of tumor-free, long-term survivors to 40% of treated animals. By comparison, methotrexate was only modestly active against this tumor model either as a single agent, with cis-Pt, or with delayed s.c. calcium leucovorin administration. These results appear to suggest that 10EDAM with cis-Pt may have considerable potential for intracavitary therapy of human cancer, including ovarian carcinoma, particularly when incorporating delayed systemic calcium leucovorin administration.

Aminopterin↗
PubMed1988

Structural design, biochemical properties, and evidence for improved therapeutic activity of 5-alkyl derivatives of 5-deazaaminopterin and 5-deazamethotrexate compared to methotrexate in murine tumor models.

Studies are described examining a new class of 4-aminofolate analogues modified by an N to C conversion and alkyl substitution at the N-5 position of aminopterin and methotrexate. All of these analogues were equivalent to aminopterin and methotrexate as inhibitors of tumor cell dihydrofolate reductase (Ki = 3.49-5.16 pM). N to C conversion at the N-5 position of aminopterin reduced its influx (inferred from the change in Ki) 3-fold, but the same modification increased influx of methotrexate 2-3-fold in Sarcoma 180 cells. Alkylation (methyl or ethyl) of this position on 5-deazaaminopterin increased influx 3-fold, while a similar alteration of 5-deazamethotrexate increased influx 4-5-fold. Influx of the methotrexate analogues was increased a total of 14-fold as a result of these modifications. Similar differences among these analogues were observed for inhibition of Sarcoma 180 cell growth in culture. Inhibitory potency was in the ascending order methotrexate less than 5-deazamethotrexate less than 5-deazaaminopterin less than aminopterin less than 5-alkyl (methyl or ethyl) analogues of 5-deazaaminopterin and 5-deazamethotrexate (the ethyl analogues were 2-fold more inhibitory than the methyl analogues). All of the analogues examined were equivalent in regard to efflux from Sarcoma 180 cells. Differences in transport alone did not account for all of the increased inhibitory potency (up to 33-fold) of the 5-alkyl-5-deaza analogues compared to the parent compounds. The extent of polyglutamylation of 5-deazaaminopterin and 5-deazamethotrexate and their 5-alkyl derivatives in Sarcoma 180 cells was substantially less compared to aminopterin and equivalent to methotrexate. Transport inward of 5-deazaaminopterin in isolated crypt cell epithelium from mouse small intestine was 2-fold lower than aminopterin (influx Km = 14.2 +/- 2 microM), while influx of 5-deazamethotrexate was 2-fold greater than methotrexate (influx Km = 98.6 +/- 23). However, transport inward of all of the 5-alkyl derivatives of these 5-deaza analogues was intermediate [influx Km = 44.4 +/- 11 (SEM) to 49.8 +/- 12 microM] between values for aminopterin and methotrexate. These differences accounted, to some extent, for the reduced toxicity of the 5-alkyl-5-deazaaminopterin analogues compared to aminopterin and the increased toxicity of 5-methyl-5-deazamethotrexate compared to methotrexate. All of the 5-alkyl derivatives of aminopterin and methotrexate were more active in vivo than methotrexate against four murine tumor models.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1988

L1210 leukemia hybrids isolated after fusion of alkylating agent-resistant sublines.

The two resistant lines, L1210/CPA (cyclophosphamide) and L1210/MeCCNU (1-(2-chloroethyl)-3-(trans-4-methyl-cyclohexyl)-1-nitrosourea) were used, each of which is not cross-resistant to the drug to which the other line is resistant. Their resistance was used as markers as well as the basis for selection of the hybrids. For the production of hybrids five in-vivo or in-vitro schedules were employed. The in-vitro methods produced six successful hybrid lines, but the in-vivo schedules produced none. Resistance to both CPA and MeCCNU was expressed dominantly in the hybrids. The hybrids had chromosome modes ranging from 68 to 78. This study shows that CPA and MeCCNU can be used both as markers and as selective agents, and that CPA and MeCCNU resistance in L1210 leukemia are dominantly expressed in the hybrid.

Alkylating Agents↗
PubMed1987

10-Ethyl-10-deaza-aminopterin: structural design and biochemical, pharmacologic, and antitumor properties.

The new folate analog 10-ethyl-10-deaza-aminopterin (10EdAM) was equivalent to methotrexate (MTX) as an inhibitor of dihydrofolate reductase, but was more effectively transported and polyglutamylated in most tumor cells. Also, the transport and polyglutamylation of 10EdAM in tumor cells vis-a-vis normal proliferative tissue is substantially increased compared to MTX, favoring much greater accumulation of 10EdAM as cytotoxic polyglutamates in some of these tumor cells. 10EdAM was superior to MTX against 4 of 6 murine ascites tumors (L1210, S180, Ehrlich and Tapper) and far superior against 4 of 6 solid murine tumors (S180, Tapper, E0771 mammary AC, T241 fibrosarcoma). 10EdAM produced 10% to 30% complete regressions against S180, E0771 and T241 tumors. Both agents showed similar activity against P288 and 1498c leukemias and the Lewis lung tumor, but were inactive against B16 melanoma. Marked superiority of 10EdAM compared to MTX was also shown against the following human tumor xenografts: MX-1 (mammary carcinoma), LX-1 (small cell lung carcinoma) and CX-1 (colon carcinoma). 10EdAM produced 30% to 40% complete regressions against the MX-1 tumor.

Aminopterin↗
PubMed1986

Synthesis and biological activity of resolved C-10 diastereomers of 10-methyl- and 10-ethyl-10-deazaminopterin.

Synthesis and evaluation of the antitumor drugs 10-methyl- and 10-ethyl-10-deazaminopterin (15a,b) were previously reported for the diastereomeric mixtures, lacking resolution at the C-10 position. In order to assess biological properties of the individual diastereomers, the C-10 isomers of 4-amino-4-deoxy-10-methyl- and 10-ethyl-10-deazapteroic acids (13a,b) were prepared by total synthesis. Coupling with L-glutamate afforded the appropriate diastereomers of the title compounds. Biochemical, transport, and cell growth inhibitory properties in L1210 cells and folate-dependent bacteria were measured. Differences were generally less than 2-fold between diastereomeric pairs, but a factor of 3 was noted for d,L-15b vs. l,L-15b in inhibition of DHFR from L1210 cells and in cytotoxicity toward L1210 cells. An in vivo comparison of the isomers of 15b with racemic compound against L1210 in mice did not show a significant efficacy difference (ILS) among the compounds. However, d,L-15b showed an acute toxicity about 2.5 times that of l,L-15b.

Aminopterin↗
PubMed1986

Cytostatic and cytotoxic properties of pyronin Y: relation to mitochondrial localization of the dye and its interaction with RNA.

Pyronin Y (PY) is an intercalating cationic dye that shows specificity towards RNA. In viable cells this dye also accumulates in mitochondria. The cytostatic and cytotoxic effects of PY on L1210 and Chinese hamster ovary cells were studied in relation to its intracellular localization and compared with the affinity of PY to bind to double-stranded DNA and RNA and its propensity to condense single-stranded DNA and RNA. Antitumor properties of PY were tested on L1210 leukemia and Sarcoma 180 ascites in mice. At a concentration of 1.7 to 3.3 microM, PY was localized almost exclusively in mitochondria of cultured cells, similar to another mitochondrial probe, rhodamine 123. At that concentration PY was not toxic but suppressed cell growth, arresting cells in G1. At a concentration of 6.7 to 33.0 microM, PY was also localized in nucleoli and uniformly in cytoplasm, bound to the RNase-sensitive material therein. At that high concentration PY induced cell arrest in G2 and S and was cytotoxic. The dye exhibited a propensity to bind and condense (precipitate) single-stranded nucleic acids, and condensation could be measured by the appearance of light-scattering products. Among a variety of natural and synthetic nucleic acids the most sensitive were the RNA polymer, polyriboadenylate, and the copolymer, polyriboadenylate and polyriboguanylate, which underwent condensation at a PY concentration of 6.6 to 10.0 microM. Natural and synthetic DNA polymers were resistant to condensation. The data suggest that the cytostatic (G2 and S arrest) and cytotoxic (inability to exclude trypan blue, loss of clonogenicity) effects of PY seen at 6.7 to 33.0 microM concentration may be a consequence of the dye binding to RNA. PY may intercalate to double-stranded RNA and/or cause the specific condensation of single-stranded RNA; the polyadenylated sections of mRNA appear to be the most sensitive cellular targets to undergo condensation. PY showed antitumor properties extending survival of L1210 leukemic mice by 50% and slowing growth of Sarcoma 180 ascites tumor. The possibility that certain antitumor drugs, generally believed to act via intercalation to DNA, may exert chemotherapeutic effects via their interactions with RNA is discussed.

Animals↗
PubMed1986

Drug sensitivity of methylnitrosourea- and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea-resistant L1210 lines.

Drug sensitivity of methylnitrosourea (MNU)- and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU)-resistant L1210 lines have been compared. In the production of the MeCCNU-resistant line full resistance to MeCCNU was obtained after 15 generations with a gradual increase of the treatment dose. Treatment of L1210 with MNU (40 mg/kg i.p. on days 1, 3, and 5) produced after five or more treatment generations a MNU-resistant subline with reduced tumor growth in the untreated controls. Therapeutic responses of L1210, L1210-MeCCNU and L1210-MNU to MeCCNU, MNU, cyclophosphamide, 2,2'-dichloro-N-methyldiethylamine hydrochloride, 1-beta-D-arabinofuranosylcytosine, methotrexate, and 6-mercaptopurine were compared in both non-and X-irradiated (400 R) mice. The L1210 and L1210-MeCCNU lines reacted similarly except that L1210-MeCCNU was resistant to Me-CCNU and MNU. However, the L1210-MNU line differed greatly from the parent line. The survival times in nonirradiated mice were increased in all except the MNU- and MeCCNU-treated groups, and in irradiated mice they were less than 30 days and only cyclophosphamide and 2,2'-dichloro-N-methyldiethylamine hydrochloride caused long-term survivors. The different behavior of L1210-MNU and L1210-MeCCNU is apparently due to the fact that at maximum tolerated doses the monofunctional alkylating agent MNU is more mutagenic than the bifunctional MeCCNU. Antigenic change and loss of growth potential presumably are the reasons for the different sensitivity of L1210-MNU as indicated by tests in X-irradiated and nude mice. Apparently this host-related sensitivity is not directly related to the development of drug resistance.

Alkylating Agents↗
PubMed1985

[13N]Ammonia and L-[amide-13N]glutamine metabolism in glutaminase-sensitive and glutaminase-resistant murine tumors.

The short-term metabolic fate of labeled nitrogen derived from [13N]ammonia or from L-[amide-13N]glutamine was determined in murine tumors known to be resistant (Ridgeway Osteogenic Sarcoma (ROS] or sensitive (Sarcoma-180 (S-180)) to glutaminase therapy. At 5 min after intraperitoneal injection of [13N]ammonia or of L-[amide-13N]glutamine, only about 0.7% of the label recovered in both tumors was in protein and nucleic acid. After [13N]ammonia administration, most of the label (over 80%) was in a metabolized form; a large portion of this metabolized label (50-57%) was in the urea fraction with a smaller amount in glutamine (37-42%). The major short-term fate of label derived from L-[amide-13N]glutamine was incorporation into components of the urea cycle with smaller amounts in the acidic metabolites and in acidic amino acids. No labeled urea was found during in vitro studies in which S-180 tumor slices were incubated with [13N]ammonia, suggesting that the [13N]urea formed in the tumor in the in vivo experiments was not due to de novo synthesis through carbamyl phosphate in the tumor. Both tumors exhibited very low glutamine synthetase activity. Following glutaminase treatment, glutamine synthetase and gamma-glutamyltransferase activities, while remaining low, increased in the resistant tumor but not in the sensitive tumor; this increase may be related to the insensitivity of the ROS tumor toward glutaminase treatment.

Amino Acids↗
PubMed1985

Further evaluation of bimolane and analogs as potential antitumor agents.

Bimolane has been shown to have good antitumor activity and on an equitoxic basis its activity is usually better than the chemically related razoxane. Resistance patterns of these two piperazinediones were similar. They exhibited cross-resistance to each other but little or no cross-resistance to most other clinically used drugs tested. Partial resistance was observed, however, between the piperazinediones and vincristine, daunorubicin and doxorubicin. The antitumor activities of three new analogs were compared with bimolane, ICRF-154 and razoxane against four rodent tumors. In general, bimolane was most effective.

Animals↗
PubMed1985

Syntheses and evaluation as antifolates of MTX analogues derived from 2, omega-diaminoalkanoic acids.

Methotrexate (MTX) analogues 27a-c bearing 2, omega-diaminoalkanoic acids (ornithine and its two lower homologues) in place of glutamic acid were synthesized by routes proceeding through N2-[4-(methylamino)benzoyl]-N omega-[(1,1-dimethylethoxy)carbonyl]-2, omega-diaminoalkanoic acid ethyl esters and N2-[4-(methylamino)benzoyl]-N5-[(1,1-dimethylethoxy)carbonyl]-2, 5-diaminopentanoic acid followed by alkylation with 6-(bromomethyl)-2, 4-pteridinediamine hydrobromide. Reactions at the terminal amino group of 27-type analogues or of appropriate precursors led to other MTX derivatives whose side chains terminate in ureido, methylureido, N-methyl-N-nitrosoureido, N-(2-chloroethyl)-N-nitrosoureido, and 4-chlorobenzamido groups. Also prepared were unsymmetrically disubstituted ureido types resulting from addition of ethyl isocyanatoacetate and diethyl 2-isocyanatoglutarate to the ethyl esters of 27a,b. Of these ureido adducts (32a,b and 33a,b, respectively), only 33a was successfully hydrolyzed to the corresponding pure acid, in this instance the tricarboxylic acid 34, a pseudo-peptide analogue of the MTX metabolite MTX-gamma-Glu. Biological evaluations of the prepared compounds affirmed previous findings that the gamma-carboxyl is not required for tight binding to dihydrofolate reductase (DHFR) but is operative in the carrier-mediated transport of classical antifolates through cell membranes. High tolerance levels observed in studies against L1210 leukemia in mice suggest the reduced potency may be due not only to lower transport efficacy but also to loss of the function of intracellular gamma-polyglutamylation. The N-nitrosoureas 30 and 31 showed appreciable activity in vivo vs. L1210, but the activity did not appear to be due to antifolate action as evidenced by their poor inhibition of both L1210 DHFR and cell growth in vitro.

Animals↗
PubMed1985

Stereoselective antitumor properties in the Lewis lung carcinoma model using bis(morpholinomethyl) derivatives of tricyclic bis(dioxopiperazines).

Geometric isomers of 2,11-bis(morpholinomethyl)tetrahydrodipyrazino[1,2-a:2',1'-c]pyraz ine-1, 3,10,12-(2H,4H,9H,11H)-tetrone (3 and 4) and the parent bisimides (1 and 2) were studied for their stereoselective antimetastatic activity in the Lewis Lung carcinoma model. The morpholinomethyl cis-syn-trans isomer 4 was more effective as an inhibitor of metastasis than the other three analogues. Using a postamputation protocol, the order of decreasing activity was cis morpholinomethyl analogue 4 greater than trans morpholinomethyl analogue 3 greater than parent cis imide 2 greater than parent trans imide 1. Increased activity observed for the morpholinomethyl derivatives may reflect differences in solubility and delivery (prodrug) or an intrinsic antitumor activity of the morpholinomethyl-N functionality.

Animals↗
PubMed1985

Synthesis and antimetastatic properties of stereoisomeric tricyclic bis(dioxopiperazines) in the Lewis lung carcinoma model.

Synthesis of trans- and cis-tetrahydrodipyrazino[1,2-a:1',2'-d] pyrazine-1,3,7,9(2H,4H,8H,10H)-tetrone analogues 10 and 11 belonging to the bis(dioxopiperazine) class of antitumor agents and their bis(morpholinomethyl) derivatives 12 and 13 are described with use of 2,5-dimethylpyrazine as the starting material. Synthetic studies utilizing 3,6-disubstituted 2,5-dioxopiperazine precursors are included. Evaluation of 10-13 in the Lewis Lung carcinoma model indicated the bis(morpholinomethyl) analogue cis-13 to be antimetastatic, whereas the trans isomer 12 was toxic at a similar dose effecting a decrease in the life span of treated mice. The parent bis(dioxopiperazines) 10 and 11 were ineffective as antitumor or antimetastatic drugs.

Animals↗
PubMed1985

Mutagenic and chemotherapeutic activity in L1210 leukemia of several monofunctional alkylating agents.

The mutagenic and chemotherapeutic activities of the following monofunctional alkylating agents were compared in vivo: beta-chloroethylamine, dimethyl- and diethylaminoethyl chloride; methyl- and ethylmethanesulfonate; methyl- and ethylnitrosourea; and procarbazine. The bifunctional alkylating agent diethylamine 2,2'-dichloro-N-methyl-hydrochloride was used as reference. The alkylating activity was assessed by reacting with 4-(p-nitrobenzyl)pyridine, and antitumor activity was determined against L1210 in vitro and in vivo. The L1210 response, which is consistent with useful alkylating reactivity, was very marked with the two nitrosoureas and procarbazine. The nitrosoureas and, to some extent, procarbazine decreased the tumorigenicity of L1210 leukemia as evidenced by the increase in survival times with increasing numbers of treatment generations. After treatment for about five transfers (10(6) cells i.p.) with methylnitrosourea (40 mg/kg i.p. on Days 1, 3, and 5), the untreated control mice consistently survived free of tumor, whereas the treated mice died before Day 30. After treatment with ethylnitrosourea (80 mg/kg), the survival times also increased but more in the treated than in the corresponding control groups. Methylnitrosourea was most efficient in increasing the survival times and abolishing tumor transplantability. Antigenic change and loss of growth potential presumably were the reason for this increase in survival time, as indicated by tests in X-irradiated and nude mice. The fact that nitrosoureas and triazenes, besides reducing tumorigenicity, have similarities in their chemistry in that they decompose or are metabolically converted into diazohydroxides and then to carbonium ions is possibly of significance.

Alkylating Agents↗
PubMed1985

New folate analogs of the 10-deaza-aminopterin series: markedly increased antitumor activity of the 10-ethyl analog compared to the parent compound and methotrexate against some human tumor xenografts in nude mice.

In an extension of our prior studies in murine tumor models, we examined two new folate analogs in the 10-deaza-aminopterin series for antitumor activity against a group of human tumor xenografts in nude mice. In all three xenograft models studied, MX-1 mammary carcinoma, LX-1 lung carcinoma, and CX-1 colon carcinoma, 10-deaza-aminopterin was minimally active, while methotrexate was inactive. In contrast, against the MX-1 and LX-1 tumors, 10-ethyl, 10-deaza-aminopterin at or near the LD10 dose (2-4.5 mg/kg) given once per day X 5 produced frank regressions. Activity of this analog against the CX-1 tumor was less, but retardation of tumor growth was observed with some minor regressions.

Aminopterin↗
PubMed1983

Uptake, initial effects, and chemotherapeutic efficacy of harringtonine in murine leukemic cells sensitive and resistant to vincristine and other chemotherapeutic agents.

[3H]Harringtonine was shown to be taken up rapidly by L1210/0 cells using a fast-mixing, fast-separating technique and was retained with a slow rate of limited release to the medium. Cells resistant to vincristine (L1210/VCR) showed impaired capability to take up the drug at 20 degrees. Its initial uptake in L1210 sublines in vitro was: L1210/0 greater than L1210/cyclophosphamide, L1210/1-beta-D-arabinofuranosylcytosine, L1210/6-mercaptopurine greater than L1210/5-fluorouracil, L1210/Adriamycin greater than L1210/VCR. In [3H]harringtonine-preloaded cells, L1210/0 retained significantly more radioactivity than did L1210/VCR cells after repeated washing with fresh medium at 37 degrees. The radioactivity appeared to be predominantly bound to the microsomal fractions. [3H]Leucine incorporation into protein in L1210/0 cells was inhibited 90% within 15 min by harringtonine (0.5 micrograms/ml); incorporation of [3H]thymidine into DNA and [3H]cytidine into RNA was much less inhibited and showed an apparent lag of onset for 5 and 10 min, respectively. The relative potency of harringtonine to inhibit [3H]leucine incorporation in the above sublines in vitro follows an order similar to their rates of uptake of harringtonine by these sublines of cells. The efficacy of harringtonine, 2.4 or 3.6 mg/kg i.p., in increasing the life span of C57BL/6 X DBA/2 F1 mice bearing the sublines of leukemic cells, on the average, was: L1210/0 greater than L1210/cyclophosphamide, L1210/6-mercaptopurine greater than L1210/1-beta-D-arabinofuranosylcytosine, L1210/5-fluorouracil greater than L1210/Adriamycin, L1210/VCR. These results suggest that: (a) protein synthesis is the major initial target for the effect of harringtonine; (b) harringtonine bound more tightly to the cellular components of VCR-sensitive leukemic cells than to VCR-resistant cells; and (c) cellular uptake of harringtonine and the relative potency of inhibiting protein synthesis in sublines have a rank order similar to the chemotherapeutic efficacy of harringtonine in these cells.

Alkaloids↗
PubMed1978

Antitumor tests of amygdalin in transplantable animal tumor systems.

Except for oral administration, there was no grossly observed toxicity from carefully administered high doses of amygdalin in the experimental systems used. The compound in high doses was ineffective against the DMBA-induced rat mammary carcinoma and the following transplanted experimental tumors: Sarcoma 180, plasma cell tumor LPC-1, leukemia L1210, Mecca lymphosarcoma, Ridgway osteogenic sarcoma, sarcoma T241, mammary carcinoma E0771, Taper liver tumor, Ehrlich carcinoma (solid and ascites), and Walker carcinosarcoma 256. Amygdalin did not noticeably influence the toxicity or impair the efficacy of these chemotherapeutic agents in their respective systems: Cytosine arabinoside, methotrexate, cytoxan, or 5-fluorouracil in L1210; the latter two in LPC-1; 6-mercaptopurine in Ridgway osteogenic sarcoma; estradiol-17beta or 2alpha-methyldihydrotestosterone propionate in the DMBA-induced rat mammary carcinoma.

Amygdalin↗