e-7010 and Leukemia-P388

Described herein is the discovery of a novel series of antitumor sulfonamides targeting G1 phase of the cell cycle. Cell cycle control in G1 phase has attracted considerable attention in recent cancer research, because many of the important proteins involved in G1 progression or G1/S transition have been found to play a crucial role in proliferation, differentiation, transformation, and programmed cell death (apoptosis). We previously reported our first antitumor sulfonamide E7010 as a novel tubulin polymerization inhibitor. Interestingly enough, continuous research on structurally related compounds led us to the finding of another class of antitumor sulfonamides that block cell cycle progression of P388 murine leukemia cells in G1 phase, but not in M phase. Of the compounds examined, N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070) showed significant antitumor activity against HCT116 human colon carcinoma both in vitro (IC(50) 0.11 microg/mL in cell proliferation assay) and in vivo (not only growth suppression but also a marked reduction of tumor size in nude mice). Because of its promising efficacy against human tumor xenografts and its unique mode of action, E7070 is currently undergoing phase I clinical trials in European countries.

Topics: Animals; Antineoplastic Agents; Drug Design; Flow Cytometry; G1 Phase; Humans; Leukemia P388; Mice; Models, Chemical; Sulfonamides; Tumor Cells, Cultured

N-[2-[(4-Hydroxyphenyl)amino]-3-pyridyl]-4-methoxybenzenesulfonamide+ ++ (E7010) is a novel sulfonamide antimitotic agent, which is active against mouse and human tumors. E7010 binds to beta-tubulin and inhibits polymerization of microtubules. In order to clarify the mechanisms of E7010-resistance, two murine leukemic P388 subclones resistant to E7010, 0.5r-D and 4.0r-M, were characterized. The two clones showed approximately 10- and 100-fold resistance to E7010-induced growth-inhibitory effects, respectively, compared with the parental cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. These cell lines showed no cross-resistance to other anticancer agents such as taxanes, vinca alkaloids, mitomycin C, cisplatin and irinotecan hydrochloride (CPT-11). Increased alpha- and beta-tubulin protein and mRNA levels were observed in 0.5r-D and 4.0r-M cells as compared with the parental cells. We examined the isotype-specific expression of beta-tubulin in these E7010-resistant cells by a competitive reverse transcription-polymerase chain reaction method. Although a 50% increase in beta 5 isotype mRNA levels was observed in 4.0r-M cells, the levels of beta 3 isotype message in the two resistant clones were approximately 50% less than the parental cells. To elucidate the binding properties of E7010 with beta-tubulin isotypes, we prepared isotype-specific fusion proteins of beta-tubulins. Direct photoaffinity labeling of the isotype-specific fusion proteins with [14C]E7010 revealed that E7010 preferentially binds to the beta 3 isotype rather than beta 2, beta 4, and beta 5 isotype proteins. Therefore, altered expression of beta-tubulin isotypes, especially beta 3 isotype, to which E7010 binds with high affinity, may account for the decreased sensitivity of these resistant clones to E7010.

Topics: Aminophenols; Animals; Antineoplastic Agents; Drug Resistance, Neoplasm; Gene Expression; Humans; Immunosorbent Techniques; Leukemia P388; Mice; Photoaffinity Labels; Recombinant Fusion Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfonamides; Tubulin

The search for compounds active against solid tumors has led us to the discovery of a novel sulfonamide, E7010 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4- methoxybenzenesulfonamide), which inhibits tubulin polymerization. When administered orally, E7010 showed good antitumor activity against various rodent tumors and human tumor xenografts. In tests on mouse tumor, E7010, administered in doses of 25-100 mg/kg daily for 8 days, inhibited the growth of colon 38 carcinoma inoculated s.c. in mice by 60-99%. E7010 was active against s.c. inoculated M5076 fibrosarcoma (75% tumor growth inhibition), s.c. inoculated Lewis lung carcinoma (84% increase in life span), and i.p. inoculated P388 leukemia (118% increase in life span). In a test on rat tumor, E7010 inhibited the growth of SST-2 mammary carcinoma inoculated s.c. in rats by 84%. In tests on s.c. inoculated human tumor xenografts, E7010, when administered orally, showed a broad spectrum of activity. E7010 inhibited the growth of: four kinds of gastric cancer, H-81, H-111, SC-2, and SC-6 by 60-78%; three kinds of colon cancer, H-143, COLO320DM, and WiDr by 58-83%; three kinds of lung cancer, LC-376, LC-6, and LX-1 by 63-82%; and two kinds of breast cancer, H-31 and MX-1 by 79-87%. In studies on drug-resistant P388 leukemia, E7010 was effective against vincristine-resistant P388, cisplatin-resistant P388, and 5-fluorouracil-resistant P388 sublines in mice. Because of its good activity against rodent tumors and human tumor xenografts, E7010 is currently undergoing Phase I clinical trials.

Topics: Aminophenols; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Division; Cell Line; Colorectal Neoplasms; Female; Kidney Neoplasms; Leukemia P388; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Mice, Nude; Mouth Neoplasms; Neoplasms; Neoplasms, Experimental; Rats; Rats, Inbred SHR; Stomach Neoplasms; Sulfonamides; Transplantation, Heterologous; Tumor Cells, Cultured

Topics: Animals; Antineoplastic Agents; Cell Division; Colonic Neoplasms; Humans; Leukemia L1210; Leukemia P388; Nasopharyngeal Neoplasms; Sulfonamides; Tropanes; Tumor Cells, Cultured