Combined treatment with radioestradiol-lucanthone in mouse C3HBA mammary adenocarcinoma and with estradiol-lucanthone in an estrogen bioassay.
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Adenocarcinoma↗
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Accelerated regression of brain metastases in patients receiving whole brain radiation and the topoisomerase II inhibitor, lucanthone.
PURPOSE: To determine if lucanthone crossed the blood-brain barrier in experimental animals; and to determine accelerated tumor regression of human brain metastases treated jointly with lucanthone and whole brain radiation. METHODS AND MATERIALS: The organ distribution of 3H lucanthone in mice and 125I lucanthone in rats was determined to learn if lucanthone crossed the blood-brain barrier. Size determinations were made of patients' brain metastases from magnetic resonance images or by computed tomography before and after treatment with 30 Gy whole brain radiation alone or with lucanthone. RESULTS: The time course of lucanthone's distribution in brain was identical to that in muscle and heart after intraperitoneal or intravenous administration in experimental animals. Lucanthone, therefore, readily crossed the blood-brain barrier in experimental animals. CONCLUSION: Compared with radiation alone, the tumor regression in patients with brain metastases treated with lucanthone and radiation was accelerated, approaching significance using a permutation test at p = 0.0536.
Animals↗
Inhibition of the human apurinic/apyrimidinic endonuclease (APE1) repair activity and sensitization of breast cancer cells to DNA alkylating agents with lucanthone.
Cells repair DNA damage via four main mechanisms, however, damage induced by alkylators and oxidative damage is predominantly repaired by the DNA base excision repair (BER) pathway. The AP endonuclease, APE1, is one of the main enzymes in the BER pathway. It is abundant in human cells and accounts for nearly all of the abasic site cleavage activity observed in cellular extracts. APE1 expression is elevated in a variety of cancers and a high APE1 expression has been associated with poor outcome to chemoradiotherapy. The small molecule lucanthone has been shown to enhance the killing ability of ionizing radiation in cells and preliminary evidence suggests that lucanthone may inhibit AP endonuclease. Given the role APE1 plays in repairing oxidative and ionizing radiation DNA damage, the reports of lucanthone as an ionizing radiation enhancer and the potential use of lucanthone as an AP endonuclease inhibitor, we examined whether lucanthone could inhibit APE1 endonuclease activity. We report that lucanthone inhibits the repair activity of APE1, but not its redox function or exonuclease activity on mismatched nucleotides. Lucanthone also appears to inhibit exonuclease III family members (APE1 and ExoIII), but not endonuclease IV AP endonucleases, nor bifunctional glycosylase/lyases such as endonuclease VIII or formamidopyrimidine-DNA glycosylase (Fpg). Furthermore, the addition of lucanthone inhibits APE1 repair activity from cellular extracts and enhances the cell killing effect of the laboratory alkylating agent methyl methanesulfonate (MMS) and the clinically relevant agent temozolomide (TMZ). Given these initial findings, it would be of interest to further develop lucanthone as an APE1 inhibitor through the use of structure-function studies as a means of enhancing the sensitization of tumors to chemotherapeutic agents.
Antineoplastic Agents, Alkylating↗
Lucanthone modification of cyclophosphamide toxicity in the Chinese hamster.
The interaction of lucanthone and cyclophosphamide (CYC) was investigated in the Chinese hamster in terms of the LD50/7 and LD50/30. These values may be indicative of gastrointestinal stem cell depletion and bone marrow stem cell depletion, respectively. When a nonlethal dose of 100 mg/kg lucanthone preceded CYC injection, the LD50/7 for CYC reached its minimum value of 470 mg/kg at a treatment interval of 10 hours. Lucanthone administered simultaneously with CYC had no effect on the control LD50/7 of 750 mg/kg, and by 48 hours after lucanthone administration the LD50/7 had returned to the control value. When CYC administration preceded that of lucanthone, the LD50/7 reached a minimum of value of 610 mg/kg at an interval of 5 hours; however, for the entire sequence it was approximately 640 mg/kg over all intervals up to 48 hours. The LD50/30 for CYC was only slightly reduced by the presence of lucanthone, indicating that bone marrow sensitivity to CYC was only marginally affected by lucanthone. These data indicate that lucanthone may interact with CYC damage in much the same way as it interacts with radiation damage, viz, by reducing cellular capacity to accumulate and repair sublethal damage.
Animals↗
Abasic sites in DNA of HeLa cells induced by lucanthone.
Abasic sites in HeLa cell DNA were increased in frequency by exposing the cells to lucanthone. Cell growth in the presence of lucanthone caused progressive accumulation of abasic sites and loss of cellular DNA. After 2 hr in 8 microM lucanthone, the abundance of abasic sites was 2.4 fold greater than the background of 9.9 +/- 2.0 SE abasic sites/10(6) nucleotides; 80 microM lucanthone in the growth medium increased the level 12.6 +/- 2.5 SE fold and decreased the DNA content in HeLa cells to one-half of the value obtained in untreated cells. The frequency of abasic sites in cellular DNA was determined by the aldehyde reactive probe method, with reference to abasic sites created in plasmid pBR322. The ability of lucanthone to inhibit the normal repair of abasic sites might reflect inhibition of apurinic/apyrimidinic endonuclease (HAP1) by the drug, thereby preventing an early step in the base excision repair pathway. Unrepaired abasic sites prevalent after ionizing radiation are cytotoxic lesions that promote DNA strand breaks. These results suggest a rationale for the joint lethal effects of lucanthone and ionizing radiation in cells and the accelerated tumor regression observed in cancer patients who received the combined therapy.
Binding Sites↗
Effect of lucanthone hydrochloride on the radiation response of intestine and bone marrow of the Chinese hamster.
A sublethal dose of 100 mg lucanthone hydrochioride/kg (Miracil D, Nilodin; NSC-14574) administered ip into Chinese hamsters [median lethal dose for 30-day survival (LD50/30) of 315 mg/kg] reduced the radiation tolerance of the small intestine and had little or no effect on the radiation tolerance of the bone marrow. Lucanthone hydrochloride was administered at various times before and after whole-body 60Co gamma-irradiation. The median lethal dose for 7-day survival (LD50/7), indicative of death from gastrointestinal epithelial denudation, was reduced from 1,235 rads to minimum values of 995 rads or 985 rads by lucanthone hydrochloride inoculation 10 hours before irradiation or 7.5 hours post irradiation, respectively. The LD50/30, indicative of death from bone marrow stem cell depletion, remained unaltered at approximately 990 rads over the entire treatment scheme, which indicated that the radioresponsiveness of bone marrow stem cells was unaffected by lucanthone hydrochloride. The lucanthone hydrochloride effect was reversible in that control values of LD50/7 were attained by 40 hours post inoculation. Serum concentration of lucanthone hydrochloride in the Chinese hamster, determined spectrophotometrically, reached a peak of 8 microgram/ml by 1.5 hours post inoculation and then decreased exponentially with a half-life of approximately 6 hours, so that by 30 hours post inoculation it was unmeasurable.
Animals↗
A comparative study of the effects of lucanthone (miracil D) and actinomycin D on the Chinese hamster cells grown in cultures.
Chinese hamster cells of an established clone line grown in monolayers were incubated for up to two hours with either lucanthone (0.3-30 mug/ml) or actinomycin D (0.06-0.10 MUG/ML) AND SUbjected to radioautographic investigations with 3H-uridine during the period of treatment. At concentration of 9 mug/ml lucanthone selectively inhibited the synthesis of nucleolar (ribosomal) RNA while the extranucleolar RNA synthesis proceeded at a high level. Similar results were obtained with 0.08 mug/ml actinomycin D. Protein synthesis and mitotic activity were also affected by lucanthone but the drug did not markedly interfere with DNA synthesis. Lucanthone appeared to be much less effective in cell killing than actinomycin D and its inhibitory effects on the nucleolar RNA synthesis and other cellular processes proved readily reversible. The results allow to conclude that lucanthone may be useful as a tool for studying RNA synthesis in animal cells.
Cell Line↗
Stimulation of topoisomerase II-mediated DNA cleavage by an indazole analogue of lucanthone.
Lucanthone is an antitumour drug used as an adjuvant in radiation therapy. The drug intercalates into DNA and inhibits topoisomerase II. An indazole analogue of lucanthone (IA-5) was examined for its ability to modulate topoisomerase II-DNA cleavable complex formation in vitro. The drug contains a methylbenzothiopyranoindazole chromophore instead of the methyl-thioxanthenone nucleus of lucanthone. Using a radiolabelled linear plasmid DNA as a substrate, both lucanthone and the indazole analogue were shown to promote the cleavage of DNA by human topoisomerase II. Sequencing experiments with different restriction fragments indicated that the indazole drug promoted DNA cleavage primarily at sites having a C on the 3' side of the cleaved bond (-1 position). By contrast, in the same sequencing methodology lucanthone exerted a much weaker effect on topoisomerase II. The sequence selectivity of IA-5 is reminiscent of that of the anticancer drug mitoxantrone and its anthrapyrazole analogue losoxantrone, which is structurally close to IA-5. Binding to DNA and topoisomerase II inhibition are two distinct processes contributing separately to the cytotoxic activity of the indazole drug.
DNA↗
Topoisomerase inhibition by lucanthone, an adjuvant in radiation therapy.
PURPOSE: To determine whether lucanthone can inhibit human topoisomerases in vitro. METHODS AND MATERIALS: Lucanthone was incubated with human topoisomerases II and I together with their plasmid substrates, to determine if lucanthone interfered with the catalytic activities of topoisomerases and if it enhanced the formation of DNA strand breaks, as determined by agarose gel electrophoresis of the resultant plasmid forms. RESULTS: Incubation of the enzymes with lucanthone inhibited the catalytic activity of topoisomerases II and I. With topoisomerase II, it increased the abundance of DNA double strand breaks (cleavable complexes). CONCLUSION: Lucanthone, like actinomycin D, inhibited topoisomerases II and I. It may act to enhance the yield of DNA double strand breaks in cells through a mechanism of topoisomerase II inhibition.
Antineoplastic Agents, Phytogenic↗
Effect of lucanthone (miracil D) on transcription of ribosomal RNA genes from Tetrahymena in vivo and in vitro.
Addition of lucanthone (1-5 mug/ml) to cultures of Tetrahymena results in a preferential inhibition of the synthesis of ribosomal RNA. Transcriptional studies with isolated nucleoli from Tetrahymena demonstrate that the endogenous RNA polymerases of the r-chromatin (chromatin form of rDNA) do not recognize the normal termination and move into the spacer region distal to the terminator in the presence of lucanthone. This is shown by hybridization of the transcript synthesized in the presence of the drug to restriction fragments of rDNA. Lucanthone seems specific in its action on termination as it does not inhibit the elongation process on the chromatin. Among various DNA-binding drugs tested only lucanthone and proflavine are found to cause repression of the termination. The data obtained suggest that the reduced synthesis of rRNA in lucanthone-treated eukaryotic cells is due to lack of reinitiating RNA polymerases possibly caused by improper termination.
Animals↗
Effects of lucanthone on the sedimentation properties of DNA from HeLa cells.
Exposure of HeLa cells to lucanthone (3 microgram/ml) caused dissociation of a fast-sedimenting duplex DNA complex, as judged by lysis and sedimentation in alkaline sucrose gradients. The effect of lucanthone on the DNA complex resembled that of actinomycin D and ionizing radiation. Protein synthesis inhibitors such as cycloheximide or inhibitors of DNA synthesis such as hydroxyurea did not lead to dissociation of the complex. Lucanthone was more active than were hycanthone and five other closely related thiaxanthenones tested. Lucanthone promoted X-ray-induced denaturation of DNA in intact cells, as judged by their nuclear immunoreactivity to antinucleoside antibodies. Lucanthone did not inhibit repair of X-ray-induced DNA single-strand breaks.
Centrifugation, Density Gradient↗
Radiosensitization and radioprotection studies on Ehrlich ascites tumor. II. Experimental trial of lucanthone to enhance the radiosensitivity of the tumor.
Lucanthone (miracil D) is reported to be carcinostatic and a radiosensitizer. But in our study lucanthone alone (70 mg/kg body weight) had no lasting effect on the Ehrlich carcinoma in mice. Based on mitotic studies, 4-day old ascites tumor was not sensitized to X-rays when pretreated with lucanthone. Tumor growth, evaluated as the average weight of solid tumors or the number of tumor cells in ascites bearing mice, was not significantly different between the group treated with X-rays only and the one treated with lucanthone plus X-rays. Thus lucanthone seems to enhance the radiosensitivity of certain cell types but not of the tumor tested. The orobable mechanism of action of the drug leading in some cases to enhanced radiosensitivity is presented.
Animals↗
Preferential intercalation at AT sequences in DNA by lucanthone, hycanthone, and indazole analogs. A footprinting study.
DNAase I footprinting has been used to probe the DNA sequence selectivity of the antitumor intercalating agents lucanthone (1), hycanthone (2), 6-chlorolucanthone (7), and four indazole analogs (IA-3-IA-6). The latter have a benzothiopyranoindazole chromophore substituted with a diethylaminoethyl side chain identical to that attached to the thioxanthenone chromophore of compounds 1, 2, and 7. IA-3 and IA-5 are lucanthone analogs bearing a methyl group at position 4, whereas IA-4 and IA-6 are hycanthone analogs bearing a hydroxymethyl group. IA-3 and IA-4 have an additional chloro group at position 6. Studies employing the 160-bp tyrT DNA fragment as substrate to assay inhibition of DNAase I-mediated cleavage show that both lucanthone and hycanthone bind preferentially to AT sites. They discriminate against GC-rich sequences as well as short runs of a single base, which are often cut more readily in the presence of the drugs compared to the control. The indazole analogs exhibit more pronounced selectivity of binding to AT sequences and promote enhanced DNAase I cleavage both at GC-rich sequences and at homooligomeric runs of adenines or thymines. The results of further DNAase I cleavage inhibition assays, performed with three more restriction fragments having different base pair arrangements, are fully consistent with those obtained with the tyrT fragment. They reveal that the preferred binding sequences for lucanthone, hycanthone, and the indazole analogs are predominantly composed of alternating A and T residues.(ABSTRACT TRUNCATED AT 250 WORDS)
Base Sequence↗
Microbial transformation of lucanthone by growing cultures, washed mycelia and non-germinating spores of fungi from the Aspergillus group.
Whole broth cultures, washed mycelia and non-germinating spores of 13 aspergilli scored from among 91 moulds isolated from soil and air transformed lucanthone (I) into three to five products with increased polarity. Biotransformations brought about by actively growing cultures were also performed by washed mycelia and non-germinating spores of the same strains. Lucanthone (I) was oxidized by growing cultures, washed mycelia and spore suspensions of an Aspergillus species (no. 2) into: hycanthone (II) as the main product, its aldehyde analogue (III) and its carboxylic acid derivative (IV). The pathway of lucanthone (I) oxidation by this strain involved hydroxylation of the 4-methyl group (to give hycanthone, II) followed by dehydrogenation of the resulting primary alcohol (to give the aldehyde, III). The aldehyde III was finally slowly oxidized to the corresponding carboxylic acid analogue IV. Evidence is presented to show that mycelial and spore enzymes effecting these oxidative reactions are intracellular and non-inducible in nature. Spore-mediated transformations were found not to require a source of energy and could be conducted in distilled water over a wide range of incubation temperature (from 4 to 37 degrees C). Use of the spores in successive transformations did not affect lucanthone (I) hydroxylation into hycanthone (II) or the dehydrogenation of the latter into the aldehyde analogue (III) but the ability of the spores to oxidize the aldehyde (III) to the carboxylic acid (IV) was lost.
Aspergillus↗
The effect of lucanthone on the radiation response of intestinal stem cells in Chinese hamsters.
Crypt microcolony assay was used to determine the effect of lucanthone on the radiation response of intestinal stem cells in Chinese hamsters . The Dq of the crypt microcolony radiation--survival curve was maximally reduced by 205 rads when lucanthone injection preceded irradiation by 10 hours and was reduced by 140 rads when injection followed irradiation by 5 hours. On simultaneous injection and irradiation, Dq was reduced by only 20 rads; when injection and irradiation were separated by approximately 30 hours, Dq returned to the control value. Lucanthone never affected Do. Thus at non-toxic concentrations, lucanthone reversibly modifies cellular ability to accumulate and repair sublethal radiation damage without affecting radiation sensitivity.
Animals↗
The effect of lucanthone on sublethal radiation damage, in vivo.
The capacity of the Chinese hamster jejunal crypt cell to accumulate and repair sublethal radiation damage was determined by analyzing the return of the shoulder of the radiation dose-crypt microcolony survival curve (Dr) after a priming dose of 1250 rad. The control split dose crypt cell survival curve exhibited a D0, Dr and "n" of 179 +/- 3 rad, 261 +/- 3 rad and 4.3 respectively; repair of sublethal radiation damage was completed by two hours post-irradiation. The effect of lucanthone (an antischistosomal DNA intercalating agent) on the crypt cell's capacity to accumulate and repair sublethal radiation damage was determined by injecting the drug (100 mg/kg, i.p.) at intervals before irradiation with a priming dose of 1250 rad, followed two hours later by graded doses. Injection coincident with the priming dose of radiation resulted in a 22 rad reduction of the Dr (compared to control Dr). Injection eight hours before the priming dose almost completely inhibited the accumulation and repair of sublethal radiation damage so that the resultant Dr two hours later was only 29 rad (a 232 rad reduction). At no time was the D0 of the crypt cell survival curve affected by lucanthone. These data confirm previous results from whole crypt analysis and LD50/7 analysis that non-toxic concentrations of lucanthone reversibly inhibit the accumulation and repair of sublethal radiation damage in a time-dependent manner with complete inhibition approximately eight hours post-injection. This drug is useful for the study of sublethal radiation damage in vivo and may be beneficial in radiation therapy of cancer when it is desirable to inhibit the repair of sublethal radiation damage.
Animals↗
The adjuvant effect of lucanthone (miracil D) in clinical radiation therapy.
Clinical trials were undertaken to determine whether lucanthone (miracil D) affects radiation-induced regression in measurable pulmonary metastases and advanced squamous-cell oral and pharyngeal tumors. The time required for 50% tumor regression was decreased by approximately 50% in those patients who received lucanthone in addition to irradiation. These results indicate that lucanthone has a definite adjuvant effect when used together with irradiation.
Carcinoma, Squamous Cell↗
Overadditive synergism between the intercalators mitoxantrone and lucanthone in advanced L 12010 and P 388 leukemia.
The combination of mitoxantrone with lucanthone, a schistosomicidal and nonmyelotoxic agent, yielded a therapeutic synergism in L 1210 and P 388 leukemia with no increase in toxicity. In that combination the nonmyelotoxic lucanthone enabled the use of the optimal dose of mitoxantrone. The recent hypothesis that planar polycyclic aromatic compounds, mostly comprised by the term intercalators, intercalate with DNA or bind to DNA may need receiving with respect to membrane target sites.
Animals↗