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PubMed2006

Differential induction of Leishmania donovani bi-subunit topoisomerase I-DNA cleavage complex by selected flavones and camptothecin: activity of flavones against camptothecin-resistant topoisomerase I.

Emergence of the bi-subunit topoisomerase I in the kinetoplastid family (Trypanosoma and Leishmania) has brought a new twist in topoisomerase research related to evolution, functional conservation and preferential sensitivities to the specific inhibitors of type IB topoisomerase family. In the present study, we describe that naturally occurring flavones baicalein, luteolin and quercetin are potent inhibitors of the recombinant Leishmania donovani topoisomerase I. These compounds bind to the free enzyme and also intercalate into the DNA at a very high concentration (300 microM) without binding to the minor grove. Here, we show that inhibition of topoisomerase I by these flavones is due to stabilization of topoisomerase I-DNA cleavage complexes, which subsequently inhibit the religation step. Their ability to stabilize the covalent topoisomerase I-DNA complex in vitro and in living cells is similar to that of the known topoisomerase I inhibitor camptothecin (CPT). However, in contrast to CPT, baicalein and luteolin failed to inhibit the religation step when the drugs were added to pre-formed enzyme substrate binary complex. This differential mechanism to induce the stabilization of cleavable complex with topoisomerase I and DNA by these selected flavones and CPT led us to investigate the effect of baicalein and luteolin on CPT-resistant mutant enzyme LdTOP1Delta39LS lacking 1-39 amino acids of the large subunit [B. B. Das, N. Sen, S. B. Dasgupta, A. Ganguly and H. K. Majumder (2005) J. Biol. Chem. 280, 16335-16344]. Baicalein and luteolin stabilize duplex oligonucleotide cleavage with LdTOP1Delta39LS. This observation was further supported by the stabilization of in vivo cleavable complex by baicalein and luteolin with highly CPT-resistant L.donovani strain. Taken together, our data suggest that the interacting amino acid residues of topoisomerase I may be partially overlapping or different for flavones and CPT. This study illuminates new properties of the flavones and provide additional insights into the ligand binding properties of L.donovani topoisomerase I.

Animals↗
PubMed2000

Growth inhibitory effect of a new camptothecin analog, DX-8951f, on various drug-resistant sublines including BCRP-mediated camptothecin derivative-resistant variants derived from the human lung cancer cell line PC-6.

DX-8951f, a new water-soluble camptothecin (CPT) derivative, has been reported to show potent antitumor effects against various tumors in vitro and in vivo. We further evaluated the cytotoxic effect of DX-8951f against eight drug-resistant sublines derived by stepwise exposure of human oat cell carcinoma PC-6 to various drugs. In paclitaxel-, adriamycin-, vincristine- and etoposide-resistant cells, overexpression of P-glycoprotein (P-gp) and a correlative reduction in drug accumulation and typical drug-sensitivity pattern were confirmed. The etoposide-resistant line with the highest P-gp level was cross-resistant also to SN-38, CPT-11 and topotecan (TPT), but not to 9-aminocamptothecin (9-AC), CPT and DX-8951f. SN-38- and CPT-11-resistant cells, of which topoisomerase I activities and levels were similar to those of the parent cells, showed cross-resistance clearly to TPT, 9-AC and mitoxantrone, but hardly to DX-8951f. In these two resistant sublines, the intracellular topotecan level was significantly lower than that in parental PC-6 and the reduced accumulation was found to be mediated by breast cancer resistant protein (BCRP). The cisplatin-resistant variant, which had a 2-fold increase in glutathione content, showed no cross-resistance and the 5-fluorouracil-resistant variant, which had a 50% decrease in glutathione content, exhibited collateral sensitivity to most of the other anticancer agents including DX-8951f. We concluded that DX-8951f showed a potent cytotoxic effect on various types of drug-resistant cells.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

A comparative study of protein profiling by proteomic analysis in camptothecin-resistant PC3 and camptothecin-sensitive LNCaP human prostate cancer cells.

INTRODUCTION: Drug resistance is a major obstacle for the therapy of prostate cancer, but its underlying mechanisms are not clarified. To detect some candidate marker proteins which may confer resistance to the anticancer drug camptothecin (CPT; DNA topoisomerase 1 inhibitor), the current study deals with the comparative proteomic profiling of CPT-resistant PC3 and CPT-sensitive LNCaP human prostate cancer cell lines which have been widely employed as a useful model to investigate prostate cancer cells. MATERIALS AND METHODS: The global profiling of the protein expression was investigated in CPT-resistant PC3 and CPT-sensitive LNCaP prostate cancer cells using 2-dimensional polyacrylamide gel electrophoresis/matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS: 144 proteins were identified and their expression levels were compared between the two cell lines. Four proteins - annexin A1, glutathione-S-transferase (GST) pi, galectin (Gal) 3 and glucose-regulated protein 78/Bip - that are suggested to contribute to the development of drug resistance were found to be preferentially or highly expressed in PC3 cells, whereas LNCaP cells did not show detectable expression of annexin A1, GST-pi and Gal-3. CONCLUSION: The expression level of these proteins and/or mRNAs could be a useful parameter to evaluate the chemotherapy resistance in clinical specimens of prostate cancer.

Antineoplastic Agents, Phytogenic↗
PubMed1991

Chemical modification of an antitumor alkaloid camptothecin: synthesis and antitumor activity of 7-C-substituted camptothecins.

A radical substitution reaction of 20(S)-camptothecin (1) with methanol furnished 7-hydroxymethylcamptothecin (2). Reaction of 1 with primary alcohols higher than methanol gave 7-alkylcamptothecins (4), of which alkyl groups were one carbon less than the alcohols used and also 7-hydroxyalkylcamptothecins (5). For the preparation of 7-alkylcamptothecin (4), aldehydes were used as a radical source and several alkylated derivatives were synthesized. 7-Acyloxymethyl derivatives (6), 7-carbaldehyde (7), iminomethyl derivatives (10), acid (11), esters (12) and amides (13) were synthesized starting from 2. 7-Ethyl- (4b) and 7-propylcamptothecin (4c), acyloxymethyl compounds 6a, 6c and ethyl ester (12b) exhibited higher antitumor activity than 1 against L1210 in mice.

Animals↗
PubMed2004

Rubitecan: 9-NC, 9-Nitro-20(S)-camptothecin, 9-nitro-camptothecin, 9-nitrocamptothecin, RFS 2000, RFS2000.

Rubitecan [Orathecin, 9-nitrocamptothecin, 9NC, RFS 2000] is a topoisomerase I inhibitor extracted from the bark and leaves of the Camptotheca acuminata tree, which is native to China. Rubitecan is an oral compound being developed for the treatment of pancreatic cancer and other solid tumours by SuperGen. One of the major benefits of rubitecan is that it can be administered in an outpatient setting, so patients can be treated in their homes. Rubitecan was isolated by the Stehlin Foundation in the US. SuperGen is currently awaiting regulatory approval in the US and the EU for rubitecan in the treatment of pancreatic cancer. At the BIO-2004 conference, SuperGen announced it is seeking a partner for rubitecan for territories outside the US. SuperGen acquired exclusive worldwide rights to rubitecan from the Stehlin Foundation in 1997 except in Mexico, Canada, Spain, Japan, the UK, France, Italy and Germany. SuperGen has also received approval from the US FDA to use its own manufactured rubitecan in clinical trials. SuperGen and the Stehlin Foundation have an 8-year research agreement that secures global rights to other camptothecins and additional anticancer compounds for the former. In December 1999, SuperGen and Abbott signed a worldwide sales and marketing agreement for rubitecan. Under the terms of the agreement, Abbott had exclusive distribution and promotion rights for rubitecan outside the US, and co-promotion rights with SuperGen within the US. In return, Abbott made an initial equity investment in SuperGen. SuperGen and Abbott Laboratories ended their collaboration agreement in February 2002 by mutual consent with SuperGen stating that the dissolution of the agreement was based on commercial motivation rather than anything to do with rubitecan's safety or efficacy. Abbott no longer has rights or obligations to purchase shares of SuperGen stock or an option to purchase up to 49% of the company. For its part, SuperGen will no longer receive milestone payments worth up to $US57 million. SuperGen has formed a clinical and business alliance with US Oncology (created by the merger between American Oncology Resources and Physician Reliance Network in the US), and will collaborate on clinical trials of rubitecan. SuperGen believes that this relationship will increase the patient population available for trials and enable it to market the drug directly to Oncologists. SuperGen and Capital Research and Management Company have completed a $US16.6 million private placement transaction that will enable future funding for the rubitecan programme as well as other oncology programmes. In July 2004, SuperGen's European subsidiary, EuroGen Pharmaceuticals, submitted a Marketing Authorisation Application for rubitecan in the treatment of pancreatic cancer. The application will be reviewed under the EMEA Centralised Procedure. In June 2003, the EMEA granted SuperGen orphan drug status for rubitecan for the treatment of pancreatic cancer. The US FDA has also granted orphan drug status for rubitecan in the treatment of pancreatic cancer and fast-track status for rubitecan for the treatment of locally advanced or metastatic pancreatic cancer that is resistant or refractory to chemotherapy. SuperGen has conducted three phase III pivotal trials in patients with pancreatic cancer. A phase III randomised trial in chemotherapy-naive patients was conducted at 132 centres throughout the US. The trial enrolled approximately 994 patients who were randomised to receive rubitecan or gemcitabine. Enrollment was completed in October 2001. Another phase III trial has compared rubitecan with the most appropriate chemotherapy in chemotherapy-resistant patients. Enrollment of over 400 patients at 200 medical centres across the US was completed in June 2001. Results from the trial were presented at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003) [Chicago, US; 31 May - 3 June 2003], after they had been compiled, analysed and submitted to the FDA. The results of the study showed that rubitecan could not help all chemotherapy-resistant patients, but could increase survival in those that do respond. The other phase III pivotal trial was conducted in patients with pancreatic cancer who had failed treatment with gemcitabine. This trial completed enrollment in October 2001, and had enrolled approximately 448 patients. SuperGen is conducting phase II trials of rubitecan in patients with solid tumours in the UK, Italy, France, Germany, the Netherlands and Denmark. Each trial will enroll 100-150 patients with various tumour types, including colorectal, lung, breast, gastric, prostate, cervical and head and neck cancers. Phase I/II trials are underway to investigate rubitecan as a radiosensitiser in patients with lung cancer, and phase II trials in patients with breast cancer are also being conducted. A phase II study in ovarian cancer patients is also being conducted. Results from an ongoing phase II study in cancer patients have shown that rubitecan was effective against chordomas, a rare type of bone cancer. Phase II studies are also underway in haematological malignancies including myelodysplastic syndrome (preleukaemia) and chronic myelomonocytic leukaemia. In February 2000, SuperGen announced that its IND submission for rubitecan had been approved by the Therapeutics Products Programme of Canada. The company stated that it intended to begin clinical trials in Canada in the near future. In February 2004, SuperGen announced an offering of shares of its common stock to finance the commercialisation of rubitecan capsules. In July 2003, SuperGen was granted a US patent covering combination therapies with chemotherapeutic anthracycline agents and structural modifications that may one day lead to next-generation rubitecan compounds. In December 2002, SuperGen was granted US patent No. 6,482,830, covering its polymorphic formulations of rubitecan. The patent also covers a class of polymorphs that are similar to the one at the centre of rubitecan. In addition, SuperGen was also issued US patent No. 6,485,514 in December 2002, covering the local delivery of rubitecan via stents and/or catheters to sites of proliferating cells. Stent- or catheter-delivered rubitecan may be beneficial in certain types of cardiac procedures, such as ablation or angioplasty, as well as for direct injection into a certain number of solid tumours. SuperGen is also developing an inhaled, liposomal formulation of rubitecan. It acquired the worldwide rights to this formulation from the Clayton Foundation in December 1999. Inhaled rubitecan is in clinical trials in the US for the treatment of lung cancer and pulmonary metastatic cancer.

Animals↗
PubMed2000

Activity of a novel camptothecin analogue, homocamptothecin, in camptothecin-resistant cell lines with topoisomerase I alterations.

Homocamptothecin (hCPT), which differs from camptothecin (CPT) by the presence of an additional methylene group in the E-ring, was evaluated in CPT-resistant cell lines. Topoisomerase I (top1)-deficient leukemia P388/CPT45 cells were highly resistant to hCPT, which demonstrates that top1 is the primary target of hCPT. Three CPT-resistant cell lines with top1 point mutations (Chinese hamster lung fibroblast DC3F/C10, human prostate carcinoma DU-145/RC1, and human leukemia CEM/C2) and their top1 enzymes were cross-resistant to hCPT. The antiproliferative activity of hCPT was greater than that of CPT in both parental and CPT-resistant cell lines, particularly in the prostate cell lines. The top1 cleavage complexes formed in the presence of hCPT appear to be more stable than those induced by CPT. Together, these data indicate that hCPT is a specific top1 inhibitor, which shares a common binding site with CPT in the topl-DNA cleavage complexes. Because of its potency, hCPT might overcome resistance to CPT in some cancer cells.

Animals↗
PubMed1995

Camptothecin induction of a time- and concentration-dependent decrease of topoisomerase I and its implication in camptothecin activity.

Camptothecin (CPT) has been shown to induce protein-linked DNA breaks (PLDB), which are stabilized intermediates of topoisomerase I (TOP1) activity. Due to the reversible nature of PLDB and the need for replication fork movement for CPT toxicity, both the time of CPT exposure and TOP1 levels are determinants of CPT toxicity. Therefore, the effects of CPT exposure on TOP1 over time were examined in an established human cell line, KB. Using an in vivo KCl-SDS co-precipitation assay, it was determined that 1 hr of CPT exposure resulted in a concentration-dependent increase in PLDB that reached a maximum at 5 microM CPT. However, prolonged incubations with CPT revealed a concentration- and time-dependent decrease in CPT-induced PLDB formation. The most rapid loss of PLDB was within 6 hr. Neither aphidicolin nor cycloheximide cotreatments altered the PLDB decrease induced by CPT. Immunoblot analysis revealed a reduction in TOP1 protein upon CPT exposure, whereas RNA analysis revealed no changes, which suggested a post-transciptional mechanism of TOP1 down-regulation. The CPT-induced reduction was specific for TOP1, because actin and tubulin levels were unaltered by CPT exposure. Finally, clonogenic assays revealed a small but statistically significant decrease in CPT toxicity throughout the CPT exposure period. Because PLDB formation based on TOP1 levels is an important step in the toxicity of CPT, the CPT-induced TOP1 reduction could be a transient mechanism of resistance for cells to avoid toxic levels of PLDB.

Aphidicolin↗
PubMed1996

Camptothecin resistance involving steps subsequent to the formation of protein-linked DNA breaks in human camptothecin-resistant KB cell lines.

To identify mechanisms of camptothecin (CPT) resistance/toxicity, sublines from a human KB cell line were made resistant to CPT by continuous selection in increasing concentrations of CPT. Two CPT-resistant lines, 100 and 300, were 32- and 54-fold resistant to the growth-inhibitory properties of CPT compared to the KB line. After CPT-free culturing, partial revertant lines were established from each resistant line. These partial revertant lines, 100rev and 300rev, were 2.5- and 3.2-fold resistant to CPT compared to KB. When growth inhibition and toxicity were compared, the resistant lines alone displayed an enhanced cytostatic response to CPT. The resistant and partial revertant lines displayed no cross-resistance to etoposide or cisplatin. Comparisons of topoisomerase I (TOPI) activity, content, and protein-linked DNA break production by CPT revealed that resistant and partial revertant lines had one-half the levels as KB, with TOP1 activity that was equally sensitive to CPT in all cell lines tested. However, double-stranded DNA break induction by CPT was significantly reduced only in the resistant lines. Coincubation with 3-aminobenzamide, an inhibitor of poly(ADP-ribosyl) polymerase, potentiated CPT toxicity in the resistant lines alone, without affecting CPT: TOP1 interactions. Therefore, CPT resistance in the 100 and 300 lines was characterized by factors independent of TOP1, specific for CPT, and attenuated by poly(ADP-ribosyl) polymerase inhibition. This resistant phenotype produced fewer double-stranded DNA breaks and enhanced a cytostatic response to CPT.

Benzamides↗
PubMed1998

[The other camptothecins: recent advances with camptothecin analogues other than irinotecan and topotecan].

The first part of this review summarizes the clinical developments concerning camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, GG-211 and DX-8951f. The second part covers the recent developments of research on CPT analogs: CPTs with solubilizing substituents, CPTs with activating substituents, CPTs with dual activity, CPT prodrugs and CPTs with stabilized lactones.

Animals↗
PubMed1991

Camptothecin overcomes MDR1-mediated resistance in human KB carcinoma cells.

In order to understand the high efficacy of camptothecin derivatives against human colon tumor xenografts in nude mice, we have studied the transport properties of camptothecin derivatives across cellular membranes of MDR1-overexpressing cells. MDR1 overexpression was shown to have little effect on camptothecin cytotoxicity; camptothecin was equally cytotoxic to both the drug-sensitive parental cell line, KB 3-1, and its multidrug-resistant derivative, KB V1. The ability of camptothecin to overcome MDR1-mediated resistance is most likely due to unimpaired accumulation of camptothecin in MDR1 cells as suggested from the following experiments: (a) cytotoxicity of camptothecin against KB V1 cells was not altered by the known MDR1-reversing agent, verapamil; (b) camptothecin was ineffective as compared with vinblastine in competing with [3H]azidopine for photoaffinity labeling of MDR1; (c) camptothecin was equally efficient in trapping cellular topoisomerase I molecules on chromosomal DNA in the form of cleavable complexes in both KB 3-1 and KB V1 cells. The mechanism by which camptothecin overcomes MDR1-mediated resistance has been further studied using a number of uncharged and charged camptothecin derivatives. In contrast to the uncharged camptothecin derivatives, such as 9-amino-camptothecin and 10,11-methylenedioxy-camptothecin, the charged camptothecin derivative, topotecan, showed reduced cytotoxicity against MDR1-overexpressing KB V1 cells. The reduced cytotoxicity of topotecan in KB V1 cells was due to the overexpression of MDR1 in KB V1 cells since verapamil restored both topotecan accumulation and cytotoxicity. These results suggest that the charge on camptothecin can affect the drug's sensitivity to MDR1. The possible effect of membrane permeability in determining drug selectivity of MDR1 is discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Complete inhibition of growth followed by death of human malignant melanoma cells in vitro and regression of human melanoma xenografts in immunodeficient mice induced by camptothecins.

The plant alkaloid camptothecin and three camptothecin derivatives were used to study responses of human malignant melanoma (BRO) cells xenografted in immunodeficient (nude) mice. Camptothecin and its derivatives 9-nitro-20(S)-camptothecin and 9-amino-20(S)-camptothecin inhibited growth of tumors and caused regression in all tumor-bearing mice. Tumor regression was accompanied by degenerative changes in the tumor cells, as assessed by microscopic observations of histological sections prepared from the tumors. No toxic effects were observed in the drug-treated mice, with or without xenografts. In parallel experiments, camptothecin, 9-nitro-20(S)-camptothecin, and 9-amino-20(S)-camptothecin inhibited proliferation of BRO cells in vitro and resulted in dramatic morphological cellular changes comparable to those observed in the sections of solid tumors. The derivative 12-nitro-20(S)-camptothecin had no effect on BRO tumors or cell cultures. The difference between 9-nitro-20(S)-camptothecin and 12-nitro-20(S)-camptothecin is the position at which the NO2 group is attached to the camptothecin molecule. In contrast to BRO melanoma cells, none of the camptothecin derivatives had any effect on cultured human melanocytes, the normal counterparts of melanoma cells. Taken together, the findings indicate that camptothecin and derivatives exert different effects on the growth and morphology of normal and malignant (BRO) melanocytes.

Animals↗
PubMed1997

pH-dependent regulation of camptothecin-induced cytotoxicity and cleavable complex formation by the antimalarial agent chloroquine.

Two classes of drugs interact with DNA topoisomerase (topo) I, namely topoI poisons such as the camptothecins, which create DNA single-strand breaks and the catalytic inhibitors, which do not. Here, we demonstrate that the antimalarial agent chloroquine is a catalytic inhibitor of eukaryote topoI, as the drug inhibited topoI-mediated DNA relaxation. Chloroquine is known to be a topoII catalytic inhibitor and as such is able to inhibit the activity of a topoII poison, i.e. etoposide. We now show that chloroquine also inhibits the topol poison camptothecin as camptothecin-stimulated nicking of plasmid DNA was inhibited by chloroquine. These observations also apply to endogenous topoI in whole cells. Accordingly, camptothecin-induced single-strand breaks as well as cytotoxicity were antagonised by chloroquine. Further, in a band depletion assay in whole cells, chloroquine prevented camptothecin-mediated topoI trapping, indicating that chloroquine inhibits topoI by interfering with the DNA binding step of the enzyme. In contrast to camptothecin, chloroquine is a weak base and therefore does not enter the cell if the extracellular fluid is acidic, as is the case in most solid tumors. This leads to the possibility of directing cytotoxicity to solid tumors with low extracellular pH by combining a neutral anticancer agent, i.e. camptothecin with a weak base antagonist, i.e. chloroquine. To test the feasibility of this principle, we investigated the drug combination at varying extracellular pH. We found that the antagonising effect of chloroquine on camptothecin-mediated trapping of topoI and DNA single-strand break formation was abolished at acidic extracellular pH. In a clonogenic assay, camptothecin in combination with chloroquine selectively killed cells at low pH (6.2), while camptothecin cytotoxicity was antagonised by chloroquine at normal pH (7.2). In conclusion, we show that the topoI catalytic inhibitor chloroquine inhibits camptothecin and that chloroquine can target the cytotoxic effect of camptothecin to tumor cells in acidic environments.

Antimalarials↗
PubMed2001

Dual role of glutathione in modulating camptothecin activity: depletion potentiates activity, but conjugation enhances the stability of the topoisomerase I-DNA cleavage complex.

Depletion of glutathione (GSH) in MCF-7 and MDA-MB-231 cell lines by pretreatment with the GSH synthesis inhibitor buthionine sulfoximine potentiated the activity of 10,11-methylenedioxy-20(S)-camptothecin, SN-38 [7-ethyl-10-hydroxy-20(S)-camptothecin], topotecan, and 7-chloromethyl-10,11-methylenedioxy-20(S)-camptothecin (CMMDC). The greatest potentiation was observed with the alkylating camptothecin CMMDC. Buthionine sulfoximine pretreatment also increased the number of camptothecin-induced DNA-protein crosslinks, indicating that GSH affects the mechanism of action of camptothecin. We also report that GSH interacts with CMMDC to form a stable conjugate, 7-(glutathionylmethyl)-10,11-methylenedioxy-20(S)-camptothecin (GSMMDC), which is formed spontaneously in buffered solutions and in MCF-7 cells treated with CMMDC. GSMMDC was synthesized and found to be nearly as active as 10,11-methylenedioxy-20(S)-camptothecin in a topoisomerase (topo) I-mediated DNA nicking assay. The resulting topo I cleavage complexes were remarkably stable. In cell culture, GSMMDC displayed potent growth-inhibitory activity against U937 and P388 leukemia cell lines. GSMMDC was not active against a topo I-deficient P388 cell line, indicating that topo I is its cellular target. Peptide-truncated analogues of GSMMDC were prepared and evaluated. All three derivatives [7-(gamma-glutamylcysteinylmethyl)-10,11-methylenedioxy-20(S)-camptothecin, 7-(cysteinylglycylmethyl)-10,11-methylenedioxy-20(S)-camptothecin, and 7-(cysteinylmethyl)-10,11-methylenedioxy-20(S)-camptothecin] displayed topo I and cell growth-inhibitory activity. These results suggest that 7-peptidyl derivatives represent a new class of camptothecin analogues.

Antineoplastic Agents, Phytogenic↗
PubMed2002

Polymer delivery of camptothecin against 9L gliosarcoma: release, distribution, and efficacy.

Camptothecin is a potent antineoplastic agent that has shown efficacy against multiple tumor lines in vitro; unfortunately, systemic toxicity has limited its in vivo efficacy. This is the first study to investigate the release, biodistribution, and efficacy of camptothecin from a biodegradable polyanhydride polymer. Tritiated camptothecin was incorporated into biodegradable polymers that were implanted intracranially in 16 male Fischer 344 rats and the animals were followed up to 21 days post-implant. A concentration of 11-45 microg of camptothecin-sodium/mg brain tissue was within a 3 mm radius of the polymer disc, with levels of 0.1 microg at the outermost margin of the rat brain, 7 mm from the site of implantation. These tissue concentrations are within the therapeutic ranges for human and rat glioma lines tested against camptothecin-sodium in vitro. The in vivo efficacy of camptothecin-sodium was evaluated with male Fischer 344 rats implanted intracranially with 9L gliosarcoma and compared with the efficacy of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The animals were divided into four groups. Group 1 (control) had a median survival of 17 days. Group 2 (3.8% BCNU polymer) had a median survival of 23 days (P = 0.006). Group 3 (20% camptothecin polymer) had a median survival of 25 days (P = 0.023). Group 4 (50% camptothecin polymer) had a median survival of 69 days (P < 0.001). Drug loadings of 20% and 50% camptothecin released intact camptothecin for up to 1000 h in vitro. We conclude that the biodegradable polymer p(CPP: SA) releases camptothecin-sodium, produces tumoricidal tissue levels, results in little or no systemic toxicity, and prolongs survival in a rat glioma model.

Animals↗