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PubMed1988

Camptothecin-resistant mutants of Chinese hamster ovary cells containing a resistant form of topoisomerase I.

In Chinese hamster ovary cells, stable mutants that exhibit 250- to 350-fold resistance to camptothecin (CptR mutants) have been isolated from mutagen-treated cultures. The CptR mutants exhibited no cross-resistance towards drugs such as colchicine, vinblastine, taxol, or puromycin but showed slightly (2- to 3-fold) enhanced sensitivity towards various drugs that inhibit DNA topoisomerase II (namely teniposide, etoposide, doxorubicin, mitoxantrone, amsacrine, ellipticine), suggesting that the genetic lesion in these mutants was highly specific. In contrast to the wild-type cells, the CptR line was resistant to camptothecin-induced DNA strand breaks as measured by alkaline elution. Biochemical studies revealed that in CptR mutants the cellular activity as well as protein content of DNA topoisomerase I were reduced to about 40-50% of the level in wild-type cells. Normal levels of activity and content were observed for the related enzyme DNA topoisomerase II. Studies with DNA topoisomerase I purified from the wild-type and the mutant cells showed that the enzyme from the CptR cells was markedly resistant to camptothecin as assayed by the drug's effects either on relaxation of supercoiled DNA or on stabilization of the covalent enzyme-DNA intermediate. The presence of a camptothecin-resistant form of DNA topoisomerase I in the mutant cells provides further evidence that this enzyme is the cellular target of camptothecin. Cell hybridization studies between the CptR and CptS cells showed that the hybrids formed between these two cell lines were sensitive to camptothecin. The recessive behavior of the CptR mutation provides a plausible explanation for the reduced topoisomerase I content (about one-half of wild-type cells) of the mutant cells and also for their enhanced sensitivity towards inhibitors of topoisomerase II.

Animals↗

PubMed1985

Cross-resistance of vinblastine- and taxol-resistant mutants of Chinese hamster ovary cells to other anticancer drugs.

Stable mutants resistant to the anticancer drug vinblastine (VinR mutants) have been isolated after a single selection step from Chinese hamster ovary cells. Of the two types of VinR mutants which are obtained, one class exhibits specific cross-resistance to only some of the microtubule inhibitors. However, the second type of mutants, which is affected in membrane permeability, exhibits cross-resistance to a wide variety of unrelated compounds. Both classes of VinR mutants showed codominant expression in cell hybrids formed between resistant and sensitive cells. The cross-resistance patterns of the VinR mutants and a single-step mutant resistant to the anticancer drug taxol (TaxR mutant) toward various anticancer drugs have been determined. The mutants resistant to both of these drugs showed significantly increased resistance toward aclarubicin, dactinomycin, doxorubicin, bisantrene, bruceantin, chromomycin A3, demecolcine, colchicine, daunorubicin, ellipticine, emetine, ethidium bromide, maytansine, mithramycin, mitoxantrone, nitidine chloride, olivomycin, podophyllotoxin, puromycin, taxol, vinblastine, vincristine, vindesine, teniposide, and etoposide. Interestingly, either one or both of the above mutants exhibited somewhat enhanced sensitivity toward vidarabine, acivicin, bleomycin, cisplatin, cytarabine, alpha-difluoromethyl-ornithine, 5-FU, tegafur, and tiazofurin. For a number of other anticancer drugs which were examined (chlorambucil, mitolactol, IMPY, hexamethylmelamine, hydroxyurea, diglycoaldehyde, methotrexate, mitoguazone, mitomycin, nocodazole, and 6-thioguanine), the level of resistance of these mutants was found to be unaltered. The information regarding cross-resistance and collateral sensitivity patterns of VinR and TaxR mutants should prove to be very useful in the design of drug combinations which could prove more effective in cancer chemotherapy.

Alkaloids↗

PubMed1986

Reduced formation of protein-associated DNA strand breaks in Chinese hamster cells resistant to topoisomerase II inhibitors.

DNA intercalating drugs and the epipodophyllotoxins etoposide and teniposide interfere with the action of mammalian DNA topoisomerase II by trapping an intermediate complex of the enzyme covalently linked to the 5'-termini of DNA breaks. This effect can be observed in intact cells by alkaline elution measurement of protein-associated DNA strand breaks. To assess the cytotoxic role of this effect, we have studied a subline of DC3F Chinese hamster lung cells selected for resistance to the intercalating agent 9-hydroxyellipticine. This subline (DC3F/9-OHE) was cross-resistant to other intercalators as well as to etoposide. Resistance to Adriamycin was associated with reduced uptake. However, resistance to 4'-(9-acridinylamino)methanesulfon-m-aniside and 2-methyl-9-hydroxyellipticinium was observed in the absence of changes in drug uptake, suggesting a second mode of resistance. DC3F/9-OHE cells formed fewer protein-associated DNA strand breaks in response to 4'-(9-acridinylamino)methanesulfon-m-aniside, 2-methyl-9-hydroxyellipticinium, or etoposide than did the sensitive parental cells. The same was true for isolated nuclei from these cells, which is consistent with a mode of resistance unrelated to drug uptake through the plasma membrane. These data suggest that resistance to DNA topoisomerase II inhibitors exhibited by DC3F/9-OHE cells is due in part to a modification of topoisomerase II activity.

Alkaloids↗

PubMed1987

Structure-activity relationships of podophyllin congeners that inhibit topoisomerase II.

Various analogs of etoposide have been studied and compared in different tests in order to identify which tests best correlate with antitumor activity. These tests included DNA breakage assays using standard alkaline elution procedures as a means of studying topoisomerase II inhibition in intact cells, cytotoxicity studies in naturally sensitive and resistant human carcinoma cell lines, in vitro assays of the effect of the different congeners on topoisomerase II activity, and a preliminary evaluation of the ability of etoposide and teniposide to induce resistance. As in previous studies, a direct correlation was seen between double strand DNA breakage and cytotoxicity but not between single strand DNA breakage and cytotoxicity. Analogs with blocked 4'-hydroxyl groups were poor antitumor agents but were still capable of inhibiting topoisomerase II as evidenced by the production of DNA breaks. However, this DNA breakage was qualitatively different from that produced by VP16. None of the analogs were able to overcome either naive or acquired drug resistance. The dihydroxy analog of VP16, a possible bioactivated analog, was much less potent and possibly less stable than VP16. A model is proposed for the inhibition of topoisomerase II by demethylepipodophyllotoxins that may explain the relationship between double strand DNA breakage and cytotoxicity.

Cell Line↗

PubMed1988

Physical-chemical properties shared by compounds that modulate multidrug resistance in human leukemic cells.

Multidrug resistance (MDR), typified by resistance to Vinca alkaloids and anthracyclines, is a well characterized experimental phenomenon that may have some clinical correlates. Verapamil, chloroquine, and related drugs have been shown previously to be capable of enhancing anticancer drug cytotoxicity in multi-drug-resistant cells, but the mechanism(s) by which these agents do this is(are) unclear. Since these agents did not seem to have common features, we studied these and other compounds for their ability to "modulate" Vinca alkaloid resistance in order to determine whether they possessed any common chemical or physical features. In addition to verapamil, 24 compounds, consisting of indole alkaloids, lysosomotropic agents, and amines, were tested for their ability to enhance the cytotoxicity of vinblastine and/or vincristine in our human leukemic multidrug-resistant cell line, CEM/VLB100. Seventeen compounds that enhance the cytotoxicity of the Vinca alkaloids by more than 5-fold have been identified. These include quinolines (chloroquine, quinine, chinchonidine, and primaquine), acridines (acridine, acridine orange, and quinacrine), and indole alkaloids (yohimbine, corynanthine, reserpine, physostigmine, and the vindoline and catharanthine moieties of the Vinca alkaloids), as well as other alkaloids and amines (chlorpromazine, propranolol, atropine, and tryptamine). Vindoline, catharanthine, and quinacrine also enhanced the cytotoxicity of doxorubicin and teniposide in these cells, indicating that this "modulation" was not limited to Vinca alkaloids. We examined some well known lysosomotropic compounds (methylamine, epinephrine, suramin, and trypan blue) and found that they were not able to enhance the cytotoxicity of vincristine in the CEM/VLB100 cells, indicating that lysosomotropic activity per se is not required for modulator activity. Three-dimensional computer modeling permitted molecular comparisons of conformationally related congeners of vinblastine, vindoline, and verapamil and revealed three regions of structural homology. We measured the hydrophobicity (by oil/water partitioning) and calculated the molar refractivity (by the additive substituent constant method) of active and inactive compounds. We found that those cationic agents--verapamil, quinacrine, indole alkaloids, and quinolines--that were lipid soluble at physiologic pH and had similar molar refractivities were best able to enhance the cytotoxicity of the Vinca alkaloids in our multidrug-resistant cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibiotics, Antineoplastic↗

PubMed1988

Reinduction therapy in 297 children with acute lymphoblastic leukemia in first bone marrow relapse: a Pediatric Oncology Group Study.

Many children with acute lymphoblastic leukemia (ALL) develop a marrow relapse during or shortly following initial continuation chemotherapy. Achievement of a second complete remission is the initial step in a successful retreatment effort. Reinduction results using two or three drugs have been unsatisfactory, and previous reports of four-drug reinduction programs have included relatively small numbers of patients. Pediatric Oncology Group protocol 8303 was designed for patients with ALL in first marrow relapse during or within 6 months after cessation of chemotherapy. The results of reinduction therapy in 297 study patients are described here. Four-drug reinduction therapy consisted of daily oral prednisone, weekly vincristine and daunorubicin, and asparaginase three times weekly for 4 weeks (PVDA). CNS retreatment consisted of two doses of triple intrathecal chemotherapy. Of the 297 patients receiving reinduction, 245, or 82%, entered second complete remission, six died of infection or progressive disease, and 46 others still had M2 or M3 bone marrow status. Forty of these latter patients received four doses (during a 2-week period) of teniposide and cytarabine, after which 13 (32%) achieved complete remission status. Thus, the overall second complete remission rate with PVDA with or without teniposide/cytarabine was 258 of 297, or 87%. The treatment program was generally well tolerated. Among the numerous factors analyzed by using logistic regression, only female sex (P = .035), the presence of blasts on the blood smear at the time of relapse (P = .0002), and a length of initial complete remission less than 12 months (P = .021) were independent predictors of failure to enter second remission. We conclude that the intensive reinduction program described here is a highly effective first step in the delivery of salvage therapy to patients with ALL in first marrow relapse. The current challenge is to develop improved continuation treatment for these children.

Adult↗

PubMed1988

[Anti-cancer drug sensitivity test against human testicular cancer xenograft--comparison with clinical results of chemotherapy].

The antitumor effect of vinblastine (VBL), vincristine (VCR), etoposide (VP-16), teniposide (VM-26), cisplatin (CDDP), CBDCA (JM-8, Carboplatin), CHIP (JM-9), DWA2114R and recombinant human tumor necrosis factor (TNF) on four human testicular cancers heterotransplanted in nude mice were studied. The treatments with CDDP, CBDCA or CHIP significantly reduced the transplanted tumors. Combination chemotherapy with CDDP, bleomycin and VBL or VCR or VP-16 or VM-26 also revealed significant tumor regression. The antitumor effect of TNF on human testicular xenografts was much more evident when it was given intratumorally than when given intravenously. Teratoma was resistant to TNF even when it was administered intratumorally. Those results are briefly discussed and compared with the clinical results of chemotherapy. Several problems in anticancer drug sensitivity test against human tumor xenografts are also discussed.

Animals↗

PubMed1988

Twelve-year experience with chemotherapy in adult metastatic renal cell carcinoma at the Institut Gustave-Roussy.

One hundred fifty-three adult patients with metastatic renal carcinoma were treated over a 12-year period. Five successive chemotherapeutic protocols were used: vincristine or teniposide plus CCNU, elliptinium weekly or monthly, ifosfamide, and lastly, a multidrug regimen with adriamycin, vindesine, cyclophosphamide, cisplatinum, and dacarbazine. Results obtained with these different consecutive protocols were very disappointing with only ten (7%) objective responses encountered.

Adult↗

PubMed1987

[Assessment of the establishing individual protocol for effective chemotherapy of ovarian cancer--fundamental research using human tumor-nude mouse system].

Experimental chemotherapy was performed using the human tumor-nude mouse system. The tumors were mucinous cystadenocarcinoma (OVA-1), undifferentiated carcinoma (OVA-2), endometrioid adenocarcinoma (OVA-3), serous cystadenocarcinoma (OVA-4) and three yolk sac tumors (YST-1, -2, -3). The drugs tested were adriamycin, bleomycin, cisplatin, cyclophosphamide, 5-fluorouracil, ifosfamide, mitomycin C, vinblastine, etoposide and teniposide. The dosages employed here were about one-third and one-ninth of the LD50 used for conventional mice. The results obtained were as follows: 1 A clear correlation between the antitumor activity of the drug and the histological type of the tumor was observed. The results indicated the importance of making a chemotherapeutic protocol according to the histological type of the individual tumor. 2 The antitumor activity depended on the dosage of the drug. The results suggested that it was necessary to increase the dosage of the anticancer drugs to obtain further clinical effects on patients with ovarian cancer. 3 The administration of a single drug in a sufficient dosage produced more effective antitumor activity rather than multidrug treatment. The results suggested that combination chemotherapy might not necessarily be the best way to effectively treat patients with ovarian cancer.

Adenocarcinoma↗

PubMed1987

Improved assay for etoposide in plasma by radial-compression liquid chromatography with electrochemical detection.

We describe a rapid, sensitive, and expedient radial-compression liquid-chromatographic method for routine quantification of etoposide (VP-16-213) in plasma of cancer patients undergoing chemotherapy with this agent. Teniposide was used as the internal standard. The mobile phase was a mixture of 10 mmol/L phosphate solution and methanol (50.7/49.3, by vol), adjusted to pH 3 with phosphoric acid. The flow rate was 2 mL/min. We used a 5-micron particle size C18 cartridge with a radial-compression separation system. The effluent was monitored with an electrochemical detector. Plasma samples are extracted with chloroform and the chloroform is evaporated. The residue, reconstituted in mobile phase, is injected onto the cartridge. Assay results were linearly related to concentration (r greater than 0.9944) over the range examined, 0.010-28.0 mg/L. The intra-run CV was less than 4.4%, and we encountered no interference from anticancer drugs or other compounds. We present data for plasma sampled at different intervals from two cancer patients being infused with etoposide.

Adolescent↗

PubMed1986

Data on the clinical aspects and therapy of primary gastrointestinal lymphomas.

Fifteen cases of primary gastrointestinal lymphoma diagnosed over 8 years are reviewed. In the period 1980 to 1982 there was a cumulative appearance of GI lymphomas, nine out of 15 cases were diagnosed in that period. According to its localization, lymphoma occurred in 12 cases in the stomach, and in 3 in the small intestines and the colon. One case of gastric lymphoma was Hodgkin type, the others were non-Hodgkin types. The clinical symptoms were not characteristic of lymphoma. The age of the patients was, on the average, ten years lower than the mean age of carcinoma patients. Preoperative diagnosis by gastric biopsy was successful in four cases. In patients with lymphoma of the colon not subjects to surgery, colonoscopy verified the origin of lymphoma. Exact clinical classification in the majority of cases was made intraoperatively. In the non-operated cases, sonography and lymphography were performed. In general, operation was attempted, but patients in stage II, in very poor condition, were possibly not operated. The possibility and indications of the "second look" operation are discussed. Histological typing was made according to the Kiel classification. In the literature, in the most controversial question of therapy, individual consideration of the cases is recommended. Based on our experience, in devising therapy or therapeutic strategy as well as concerning prognosis, the degree of malignancy according to histological type, clinical stage and anatomical localization seem to be the most decisive factors. In exceptionally malignant cases a protocol with doxorubicine + bleomycin + teniposide and prednisolone was applied.

Adolescent↗

PubMed1985

Treatment of Burkitt's lymphoma: the African experience.

Although Burkitt's lymphoma (BL) can be treated by surgery, radiotherapy and immunotherapy, chemotherapy is the mainstay of treatment. This paper summarizes the various clinical trials undertaken in Africa over the past decade. The single most effective drug for BL is cyclophosphamide (CPM). Given alone for remission induction, CPM is as effective as combinations consisting of either CPM, vincristine (VCR) and methotrexate (MTX) or CPM, VCR and cytosine arabinoside (Ara-C). Survival data indicate that single-dose CPM is comparable to multiple doses. Thus, maintenance therapy may not be necessary, and may in fact worsen the final outcome. Intrathecal (IT) MTX given together with systemic therapy significantly delays central nervous system (CNS) relapse, which is not prevented by cerebrospinal irradiation. For established CNS disease, IT-Ara-C for three days followed by MTX on the fourth day is effective. Bacillus Calmette-Guérin scarification, while provoking measurable responses in vivo and in vitro, had no measurable, specific anti-tumour reaction, since no effect was observed on relapse rate, duration of remission or survival. High-dose CPM produces objective responses in patients previously resistant to conventional doses. Teniposide (VM 26) is currently undergoing phase 2 trial, and definite short-lived responses have been recorded.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Differentiated treatment of myeloma. A non-randomised phase two study.

Seventeen consecutive, well stratified stage II and III myeloma patients were given differentiated, combination chemotherapy (cyclophosphamide, vincristine, daunorubicin, etoposide, teniposide, lomustine (CCNU), procarbazine, cytosine arabinoside, and prednisolone), which was more intensive in advanced stages and changed as soon as the patients became refractory. A comparison was made to a previous series of 17 consecutive patients treated with a simple regime of melphalan-prednisolone. Within the first 15 months only one patient in the study group given differentiated treatment died in contrast to 6 patients in the melphalan control group. The median survival times after diagnosis were 45 and 29 months, the 3-year survival 58 and 43%, respectively, and the survival for the first 15 months significantly (p less than 0,05) better in the group given differentiated treatment. The significant difference remained, when comparable patient groups were selected.

Adult↗

PubMed1984

Acquisition of multiple drug resistance by CCRF-CEM cells selected for different degrees of resistance to vincristine.

We studied the acquisition of multiple drug resistance to several "natural product" drugs by cultured human leukemic lymphoblasts selected for increasing resistance to vincristine (VCR). Three apparent types of cross-resistance patterns could be distinguished: specific, pleiotropic, and mixed. Cross-resistance to vindesine developed in parallel with VCR resistance, appearing at the lowest levels of VCR resistance (approximately fivefold). Vinblastine resistance did not become noticeable until VCR resistance was higher (approximately equal to 50-100-fold). Cross-resistance resistance to three other tubulin-binding agents developed in a different pattern, however. While cross-resistance to maytansine was seen in cells of intermediate (approximately equal to 50-fold) resistance to VCR, colchicine cross-resistance occurred only in cells that were highly resistant to VCR (approximately equal to 500-fold). Even at the highest level of VCR resistance (approximately equal to 600-fold), complete sensitivity to podophyllotoxin was retained. Conversely, cross-resistance to the epipodophyllotoxins , teniposide and etoposide, semisynthetic derivatives of podophyllotoxin, was seen in cells that were greater than 50-fold resistant to VCR. The same pattern obtained for the anthracyclines, doxorubicin and daunorubicin. We conclude that resistance to low concentrations of VCR does not uniformly confer cross-resistance to other classes of natural product drugs.

Animals↗

PubMed1983

Preclinical screening for drugs effective against 5-fluorouracil-resistant cells with a murine L5178Y cell line in vitro.

A subline of L5178Y cells has been established in vitro that exhibits a fiftyfold order of resistance to 5-fluorouracil (FUra) as compared to that of the parent line. The cytotoxic effects of 24-hour exposures to 23 antitumor drugs and to radiation were compared in the two cell lines. Four patterns of response were identified: 1) Only two drugs, mitomycin C and adriamycin, proved significantly more cytotoxic to FUra-resistant cells. 2) Four other drugs--anguidine, 4'-(9-acridinylamino)-methanesulfon-m-anisidide, melphalan, and quelamycin--showed marginal superiority against resistant cells. 3) X-radiation and the majority of drugs tested--including 5-azacytidine, 1,3-bis(2-chloroethyl)-1-nitrosourea, cisplatin, bleomycin, dibromodulcitol, razoxane, hydroxyurea, methotrexate, teniposide, etoposide, and three experimental agents, metoprine, spirogermanium HCl, and ellipticinum--proved equally cytotoxic to both cell lines. 4) Cross-resistance with FUra was exhibited with vincristine, vindesine, pyrazofurin, and indicine-N-oxide. This experimental system provides a simple method of testing agents for activity against FUra-resistant cells before phase 1 clinical studies.

Animals↗

PubMed1995

[Cytotoxic chemotherapy in elderly patients: present and future].

Cancer in elderly people accounts for more than 50% of the malignant tumors treated per year in France and this population of patients has a rather high-life expectancy. Chemotherapy is active in these elderly patients but clearly more toxic than for young ones. The general tendency among the physicians to empirically reduce the doses is due to the known increased risk of unexpected toxicities. That is why there is such a large variety of conflicting opinions in the literature concerning the benefit and toxic effects of cytostatic drugs in the elderly. Therefore, it appears consistent to adjust chemotherapy regimen according to physiological criteria. Among them is biological age which is a better parameter than chronological age to describe the biological heterogeneity of this population of patients. Nakamura et al have published an interesting model for the calculation of biological age by principal component analysis using 11 easily measurable biological and clinical variables in a series of healthy elderly people. This kind of approach is not at present available for cancer patients but it allows to demonstrate that the chronological age is only one among many other age-related variables and is not sufficient to fully describe it. The variations in pharmacokinetic data are more frequent in the elderly than in younger people and this reflects age-related physiological heterogeneity. This factor is well taken into account in recently described population pharmacokinetic models, bayesian fittings and adaptative control which may represent promising approaches of cytostatics dose adjustments. Such models have been successfully developed in young patients receiving doxorubicin, methotrexate, melphalan and teniposide. They require a low number of blood samples to determine individual parameters and further adjust the doses, and are therefore of potential interest in old patients. Prospective studies are warranted in the future in order to recommend their use in the elderly.

Aged↗

PubMed1995

L-asparaginase may potentiate the leukemogenic effect of the epipodophyllotoxins.

The risk for induction of epipodophyllotoxin-related acute myeloid leukemia (AML) depends largely on the schedule of drug administration and, to a lesser degree, the cumulative dose. Concomitant use of other genotoxic drugs, such as alkylating agents and cisplatin, can increase the hazard further. We have treated 154 consecutive higher-risk cases of acute lymphoblastic leukemia in our recent Total Therapy Study XIII with an intensive post-remission regimen of chemotherapy that included etoposide given every other week or less often-a schedule associated with a relatively low cumulative incidence of secondary AML in our Study XI. Unexpectedly, four patients have developed secondary AML at 12 to 23 months from the start of treatment (median, 16 months). The 2-year cumulative risk estimate significantly exceeds that for 185 historical controls in Study XI whose continuation regimen included epipodophyllotoxins every other week: 5.4% (95% confidence interval, 0-11%) compared with 1.1% (0-2.6%), P = 0.046. Compared to patients treated in Study XI, those enrolled in Study XIII receive fewer scheduled doses of epipodophyllotoxin (48 (all etoposide) vs 63 (30 etoposide, 33 teniposide)) but 16 to 19 additional doses of L-asparaginase and eight additional doses of high-dose methotrexate, all within the week preceding etoposide treatment. We attribute the apparently increased rate of secondary AML in Study XIII to the use of L-asparaginase immediately before etoposide administration. On this schedule, the enzyme could increase systemic exposure to etoposide or its catechol metabolites and reduce the ability of cells to repair DNA damage.

Acute Disease↗

PubMed1993

Stroma-supported immunocytometric assay (SIA): a novel method for testing the sensitivity of acute lymphoblastic leukemia cells to cytotoxic drugs.

The accuracy of drug-sensitivity assays for neoplastic cells depends on the ability to sustain cell survival in vitro, but cells in most cases of acute lymphoblastic leukemia (ALL) rapidly die by apoptosis in culture. We recently reported that allogeneic bone marrow stromal layers support long-term culture of ALL cells. We now describe the standardization of a novel drug-sensitivity assay for ALL lymphoblasts maintained on stromal layers, in which the viability of treated and untreated cells is compared using flow cytometry. Cultures were performed in U-bottomed 96-well plates: 2 x 10(4) stromal cells per well produced rapidly confluent layers which supported the survival of ALL blasts. In four ALL cases studied, 68.8-106% (median 94.8%) of the lymphoblasts originally seeded were recovered after 7 days of culture, in contrast to < 5% recovered in the absence of stroma. Sensitivity to five antileukemic drugs was tested at the indicated concentrations: vincristine (0.001-1 microgram/ml); dexamethasone (0.001-100 microM); 6-thioguanine (0.078-20 micrograms/ml); teniposide (0.001-10 microM); cytosine arabinoside (0.039-10 microM). After 4 days of culture, cells were labeled with CD19 monoclonal antibody and analyzed by flow cytometry. The concentration of each antileukemic agent producing 50% cytotoxicity (LC50) was determined for each patient by fitting a sigmoid model to the drug concentrations versus percentage viability data. Clinically relevant drug concentrations produced cytotoxic effects, and ALL blast sensitivity varied considerably among patients. We conclude that this is an informative method of systematically evaluating drug sensitivity in ALL patients.

Adolescent↗