Isolation and characterization of a human colon adenocarcinoma cell line resistant to doxorubicin.
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Adenocarcinoma↗
Biomedical subjects
F C Giuliani
Publications and source records attributed to F C Giuliani.
In vitro studies on anthracycline haloderivatives.
A new class of anthracycline derivatives carrying a halogen atom in the 4' position of the aminosugar moiety was tested in cytotoxicity studies on HeLa cells and on P388 cell lines sensitive and resistant (P388/DX) to doxorubicin, in comparison with the parent drugs doxorubicin (DX) and daunorubicin (DNR). 4'-Haloderivatives of DX generally appear to be more cytotoxic than DX on HeLa, P388 and P388/DX cells. Cellular kinetic studies of DX-haloderivatives on HeLa, P388 and P388/DX cell lines show that they accumulate inside the cell in higher amounts than DX, whereas DNR haloderivatives accumulate in HeLa and P388 cells at levels similar to DNR; only in P388/DX is their accumulation higher as compared with DNR. The results reported suggest that, besides drug accumulation, other factors are involved in the cytotoxic mechanism of action of this class of compounds. Therefore 4'-haloderivatives represent a class of compounds with promising activity, in particular regarding anthracycline-resistant cell lines.
Animals↗
Correlation of drug sensitivity on human colon adenocarcinoma cells grown in soft agar and in athymic mice.
A well-differentiated colorectal tumor T 219 which grows as a xenograft in athymic mice (human-tumor-nude-mouse system) and forms colonies in culture (soft agar colony-formation assay) has been used to test the correlation between the above two methods of exposure of human tumor cells to antineoplastic agents. In in vitro studies, two protocols were used: 1 h drug exposure and continuous drug exposure. In the 1 h drug exposure experiments six drugs, doxorubicin (DX), 4'-deoxydoxorubicin (deoDX), 4'epidoxorubicin(epiDX), 4'-O-methyldoxorubicin (O-DX), N-trifluoroacetyldoxorubicin-14-valerate (AD-32) and 5-fluorouracil (FUra) were studied, while in continuous drug exposure experiments four of the above drugs (DX, deoDX, epiDX, O-DX) were studied. The survival of the tumor clonogenic cells (HC219) was determined by counting the number of colonies formed during 13-14 days of incubation and dose-response curves were obtained. In in vivo studies, the mice were treated with all of the drugs used in in vitro 1 h drug exposure experiments (DX, deoDX, epiDX, O-DX, AD-32 and FUra). To quantitate the chemotherapeutic effectiveness of the drugs, T/C% (relative tumor volume of treated group as percentage of the control group) values were calculated each time the tumors were measured. The experimental data suggest that in vitro 1 h drug exposure results are in good agreement with the in vivo results, while the continuous drug exposure results do not agree with the in vivo data. The most active drug in in vivo studies, deoDX, was found to be the most active drug in the in vitro 1 h drug exposure experiments as well. However, in continuous drug exposure experiments, O-DX, not deoDX, was found to be the most active drug. Activities of the other drugs tested also differed from their respective activities in in vivo studies. Although the relative effectiveness of various drugs can be compared by determining molar concentrations of the drugs producing 50% inhibition of colonies (ID50) the expression, PEI = LD10/ID50 X 1000, which takes into consideration toxicity of the drugs, is probably a better indicator of the in vitro drug activity. The results suggest that soft agar colony-formation assay (with established cell lines from the same tumor) may be used for the prediction of in vivo activity of potential antineoplastic agents against human tumor xenografts in nude mice.
Adenocarcinoma↗
Comparison of the activity of doxorubicin analogues using colony-forming assays and human xenografts.
The potential use of nude mouse xenografts as a source of human tumor tissue for preclinical assessment of drug activity was examined by a comparison of in vitro sensitivity to four anthracycline derivatives of eight xenografts maintained in nude mice and tumor colony-forming units (CFU) from the xenografts grown in agar. Results obtained in the two systems with doxorubicin (Dx) and a new, closely related derivative (epi-doxorubicin, epi-Dx) correlated well. In vivo tumor growth delay and maximum in vitro tumor CFU kill for these two drugs showed a significant correlation (r = 0.64, P less than .01). Separation of tumors into "sensitive" and "insensitive" tumor populations on the basis of maximum in vitro CFU kill also predicted the in vivo response to these two drugs in 88% of cases. Similar analyses performed on in vitro and in vivo results with two other new anthracyclines (4'-deoxy-doxorubicin, deoxy-Dx and 4'-O-methyl-doxorubicin, O-Me-Dx) showed a significant negative correlation between in vivo and in vitro results; the in vitro system failed to predict in vivo activity of these two drugs. No significant differences in in vitro activity against normal, granulocyte/macrophage progenitors (CFU-GM) or against various tumor CFUs were detected. Thus, the selectivity (activity against normal tissue compared with that against tumor) of the four drugs appeared equal. These data suggest that in vitro screening of drugs using tumor CFUs from nude mouse xenografts may predict the in vivo activity of drugs for which pharmacologic data are available, but illustrate the difficulties in attempting to predict the in vivo activity of new drugs for which no such data are available.
Animals↗
Chemotherapy of human colorectal tumor xenografts in athymic mice with clinically active drugs: 5-fluorouracil and 1-3-bis-(-2-chloroethyl)-1-nitrosourea (BCNU). Comparison with doxorubicin derivatives: 4'deoxydoxorubicin and 4'-O-methyldoxorubicin.
The effects of single-agent therapy with two clinically useful drugs, 5-fluorouracil (5-FU) and 1-3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) against nine human colorectal tumors (rectum T 157 and T 348, lung metastasis T 84, lymph-node metastasis T 245, colon, T 183, T 219, T 347, T 362 and T 380) transplanted and passed serially in thymic (nude) mice were studied. In addition, chemosensitivity of the tumors to 5-FU and BCNU was compared with the chemosensitivity of the tumors to two new doxorubicin analogues, 4'-deoxydoxorubicin and 4'-0-methyldoxorubicin. BALB/c nude mice were treated intravenously on a weekly basis for 3-4 weeks, starting when the tumor volume became relatively large (advanced stage of tumor treatment). All the tumors showed a 90-100% take rate and stable growth. In these experiments, 77% (5/9) of the colorectal tumors were biologically sensitive to the treatment with 5-FU but the percentage of statistically significant sensitive tumors was 22%, which is in good agreement with the clinical data reported in the literature (21%). In patients, BCNU has been reported to give up to 13% response. In contrast, we have found a 33% statistically significant response rate in our panel of colorectal tumors. The difference could be related to the higher tolerance of nude mice to certain drugs, including BCNU. The results suggest that the two new doxorubicin derivatives, 4'-deoxydoxorubicin and 4'-0-methyldoxorubicin, should be more active in the patient than both of the clinically used drugs, 5-FU and BCNU. Furthermore, there is a good correlation between the results obtained in the experimental system (human tumor/nude mouse) and in human patients with the active drugs, 5-FU and BCNU.
Adenocarcinoma↗
Therapeutic response of human tumor xenografts in athymic mice to doxorubicin.
In order to establish the usefulness of the human tumor-nude mouse system as a predictive screen for anticancer agents, 17 tumors (3 breast, 3 colon, 3 lung, 3 melanoma, 2 ovary, 1 prostate, 1 sarcoma, and 1 larynx), serially transplantable in athymic mice, were used to study antitumor activity of doxorubicin (Adriamycin). BALB/c nude mice were treated i.v. on a weekly basis for 3 to 4 weeks, starting when the tumor volume became relatively large (advanced stage of tumor treatment). All the tumors except lung tumor T 293 showed a 90 to 100% take rate and stable growth. Doxorubicin, at dose levels of 6 and 10 mg/kg/injection i.v. every week for 3 weeks, showed significant activity against all of the three breast tumors studied. As was expected on the basis of clinical data, doxorubicin showed no antitumor activity against the three different colon tumors. In the case of lung tumors, statistically significant activities against oat cell carcinoma T 293 and epidermoid carcinoma T 222 were observed. In contradiction to clinical data, doxorubicin was found to have significant activity against various melanomas studied and slight but not statistically significant activity against ovarian tumor T 17. Experimental results obtained using doxorubicin against prostate, sarcoma, and larynx tumors also parallel the reported clinical data.
Animals↗
New doxorubicin analogs active against doxorubicin-resistant colon tumor xenografts in the nude mouse.
The antitumor activity of doxorubicin and three new derivatives modified on the position 4' of the amino sugar was tested against five human colon tumors and two human rectal tumors (originating from different patients) and xenografted into nude mice. The drugs tested were: 4'-epidoxorubicin; 4'-deoxydoxorubicin; and 4'-O-methyldoxorubicin. Mice were treated i.v. on a weekly basis for 3 to 4 weeks, starting when the tumors were well established (advanced stage of tumor treatment). No statistically significant effect was observed against the tumors tested with the drugs doxorubicin and 4'-epidoxorubicin. 4'-Deoxydoxorubicin was active against all the colon tumors tested (4 of 5 statistically significant), and 4'-O-methuldoxorubicin was active against 4 of 5 colon tumors tested (statistically significant). Overall, the activity of 5'-O-methyldoxorubicin was less than that of 4'-deoxydoxorubicin against the colon carcinomas tested. Neither analog was active against the two rectal carcinomas tested. The results of these studies indicate that: (a) the modifications in the chemical structure of doxorubicin can alter the biological properties and thus create new drugs varying in activity against different human tumors; (b) the two antracycline derivatives, 4'-deoxydoxorubicin and 4'-O-methyldoxorubicin, appear to be good candidates for clinical trial against colon carcinoma; and (c) the nude mice system can offer a great potential for identification of new anthracycline analogs and, in general, new anticancer agents of clinical interest.
Adenocarcinoma↗
Bbr 2778, an aza-anthracenedione endowed with preclinical anticancer activity and lack of delayed cardiotoxicity.
With the aim to provide second-generation anthracenedione analogues endowed with reduced side effects and a wider spectrum of action than mitoxantrone and doxorubicin, a large number of new molecules bearing nitrogen atoms in the chromophore was synthesized and screened in vitro and in vivo. From this screening, BBR 2778 (6,9-bis[(2-aminoethyl)amino] benzo[g]isoquinoline-5,10-dione dimaleate) emerged as the most interesting compound. BBR 2778 was tested in vitro on several murine and human tumor cell lines and showed cytotoxic potency lower than that of mitoxantrone and doxorubicin. BBR 2778 was more cytotoxic in leukemia and lymphoma cell lines than in solid tumor cell lines. Although against in vivo models BBR 2778 was less potent than mitoxantrone and doxorubicin, its antitumor activity was equal or superior (in certain tumor models) to that of the above standard compounds. In particular, BBR 2778 was curative against L1210 murine leukemia and YC-8 murine lymphoma. Moreover, it showed an antitumor activity comparable to that of mitoxantrone and doxorubicin on solid tumors. No cardiotoxic effect of BBR 2778 in animals not pretreated with anthracyclines was observed compared to standards. In light of its spectrum of activity and marked efficacy against lymphomas and leukemias over a wide dose range, together with its lack of delayed cardiotoxicity, BBR 2778 has been entered in clinical studies.
Animals↗
Absolute and relative activities of 4' -iodo-4'-deoxydoxorubicin against human colo-rectal tumors, as evaluated by a short-term in vitro assay.
A short-term antimetabolic assay based on the interference with 3H-thymidine and 3H-uridine incorporation after 3 hours of in vitro treatment was used to compare the cytotoxicity of a new halogenated anthracycline, 4'-Iodo-4'-deoxydoxorubicin (IDX), with that of its parent compound Doxorubicin (DX) against 44 human colorectal carcinomas. IDX had a marked dose-dependent effect, with frequencies of activity consistently greater than those of DX at all concentrations. The minimal dose of IDX required to induce a significant antimetabolic effect obtained by extrapolation from the dose-effect plots for each drug was 1/10 that of DX (2.3 micrograms/ml vs 23 micrograms/ml). When the relative activities of the two drugs on the same tumor specimen were determined, there was 71% to 86% overall agreement, depending on the concentration used. Lack of agreement was always attributed to sensitivity to IDX and resistance to the parent compound.
Colorectal Neoplasms↗
DNA polymerases and DNA topoisomerases as targets for the development of anticancer drugs.
Studies of a variety of compounds designed as derivatives of prototype active molecules aphidicolin and doxorubicin are reported. So far none of the aphidicolin simpler analogues is as active as the parental molecule. Ten anthracycline analogues, characterized for their cytotoxicity, antitumor activity and inhibition of the relaxing activity of purified human DNA topoisomerase II can be divided into five groups. The majority of the tested compounds shows properties very similar to those of doxorubicin. Epirubicin shows extremely high inhibitory activity toward the relaxing property of topoisomerase II but its antitumor activity and cytotoxicity are similar to those of the former group. The third group includes a compound with extremely high cytotoxicity. The fourth group is represented by a compound which shows a cytotoxicity. The fourth group is represented by a compound which shows a cytotoxicity. The fourth group is represented by a compound which shows a cytotoxicity typical of anthracyclines and good antitumor activity but which has no specific inhibitory activity on topoisomerase II. A fifth group includes a totally inactive compound. Our results suggest that the inhibition of human DNA topoisomerase II is only partially correlated with antitumor activity.
Animals↗
Effect of 4'-doxorubicin analogs on heterotransplantation of human tumors in congenitally athymic mice.
The antitumor activity of three new doxorubicin (DX) derivatives with less cardiotoxicity than the parent compound was tested against several human tumors representative of some of the major classes of human cancer. The tested DX derivatives, modified on the 4' position of the amino sugar, were 4'-epiDX, 4'-deoxyDX, and 4'-O-methylDX. Fourteen human tumors (three breast tumors, three lung tumors, three melanomas, two ovarian tumors, one prostate tumor, one sarcoma, and one larynx tumor) serially transplanted in athymic mice were used to screen the antineoplastic activity of the 4'-DX derivatives. BALB/c nude mice were treated iv with equitoxic doses of each as a single agent (less than or equal to LD10) on a weekly basis for 3-4 weeks, starting when the tumor became relatively large. 4'-EpiDX, which has a higher threshold limit of cardiac toxicity in man, was found active against breast, lung (epidermoid and oat cell carcinoma), prostate, and ovarian tumors. This drug showed particularly good activity against melanomas. 4'-DeoxyDX was active against breast and prostate tumors, while 4'-0-methylDX was active against breast and ovarian tumors and possibly sarcoma.
Animals↗