A newly discovered gene product, with potential for treating cancersand non-malignant hyperproliferation, is on the verge of its first invivo trial _ to reverse drug-induced hair loss.At Baylor College of Medicine in Houston, a husband-and-wife teamof molecular biologists, James and Olivia Smith, discovered andcloned the gene that inhibits cell growth, and named its protein"senescence-derived inhibitor-1, SDI-1 for short.Their research paper, out today in the October issue of MolecularCarcinogenesis, reports evidence that SDI-1 can arrest cell growth bymechanisms other than those of the well-known tumor suppressorprotein, p53.That paper's title, "Evidence for a p53-independent pathway forupregulation of SDI-1/CIP-1/WAF-1/p21 RNA in human cells," liststhe SDI-1 under four synonymous acronyms.In fact, at least three other laboratories have within the past year orso published their discovery of the same SDI-1 molecule under theirown serial numbers, to wit:* WAF-1 ("wild-type p53-activated fragment") by Bert Vogelstein,et al., Johns Hopkins University In Baltimore.* As p21, (molecular weight 21 kiloDaltons) by David Beach at ColdSpring Harbor Laboratory;* CIP-1 ("cyclin-dependent, kinase interacting protein") found byHarper & Elledge at Baylor College of Medicine's biochemistrydepartment, (quite independent of the Smiths' division of molecularvirology).By whatever name, the SDI-1 cDNA measures 2.1 kilobases, andresides on the short arm of human chromosome 6. It encodes a 164-amino-acid protein, which blocks cell-cycle progression, byinhibiting cyclin-dependent kinase activity.This same process slows down human cells after they complete theirprime-of-life doubling, and settle down to the senescence of old age.For most cells, this "Hayflick number" usually adds up to 80doublings in fibroblasts. In his lab at Baylor, James Smith has keptsuch past-their-prime, no-longer-dividing human cells alive andhealthy for years.He originally cloned SDI-1's gene product in E. coli from suchsenescent cells. Smith and the three other investigators showed thatSDI-1 is the chosen molecular instrument by which p53 exerts itstumor-suppressing activity, inhibiting the growth of DNA-damagedcells.His paper goes a step further, finding in vitro that SDI-1 can regulatecell growth by inhibiting DNA synthesis beyond the control of p53.As his demonstrator-model cell line, Smith isolated humanfibroblasts from neonatal foreskins.For clinical models of immortalized cells, he obtained cultures offamilial breast cancer (Li-Fraumeni syndrome), osteosarcoma,bladder cancer, glioblastoma and transformed skin and liverfibroblasts.When he treated the young, actively proliferating normal human skincells with a variety of agents that inhibit DNA synthesis, RNA levelsof SDI-1 always rose in correlation with the degree of cell-growtharrest.Move Over, p53"Of particular interest," the paper reported, was that hydroxyurea,(an anti-tumor drug used, notably, to treat melanoma and ovariancancer), "caused an increase in SDI-1 levels, despite the fact thatsuch treatment does not affect p53 activity." Other experimentssupported this freedom of SDI-1 from p53 control. For example thebladder and liver carcinoma cultures "did not express wild-type p53but did express high levels of SDI-1 RNA."The Smiths' studies of senescent cell biology led them two years agoto found SENNES Drug Innovations, Inc., a privately held companyin Houston, to put their findings into clinical practice. "SENNES,"explains the firm's director of business development, BethanyPimentel, "is derived from the word `senesce.'"Under a technology transfer agreement, Pimentel told BioWorldToday, Baylor College of Medicine has all rights to technologies andpatents developed by the Smiths, in exchange for equity in thecompany, where they also act as consultants.James Smith is sole inventor on U.S. patent, No. 5,302,706, issuedApril 12, 1994, titled "Senescent cell derived inhibitors of DNAsynthesis." It claims DNA and RNA molecules "having the sequenceof senescent cell derived inhibitor-1, SDI-1," and "antisense nucleicacids that reduce the inhibition of DNA synthesis."SENNES holds the exclusive license to practice this patent, Pimentelsaid, as well as a second one covering the encoded protein, for whichthe patent office has just notified the inventor of an allowance.Alopecia Comes FirstAlthough SDI-1's greatest potential lies in controlling malignanciesand non-cancer hyperproliferating cells, its first clinical applicationwill be in treating alopecia medicamentosa _ the hair loss incidentto cancer chemotherapy."It is a unique area where we are getting some very good preliminaryresults," said molecular biologist Deborah Wilson, director ofresearch at SENNES.She told BioWorld Today that "In the next couple of weeks, we willselect a suitable animal model, probably a rat or mouse susceptible todrug-induced alopecia. These subjects," Wilson continued, "willhave their falling fur treated with liposome microcarriers payloadedwith the SDI-1 protein, targeted to their hair follicles."Pimentel added that "we could conceivably file an investigationalnew drug application with the FDA in 1995," for preliminary humantrials.Also, "within the next month," the company will commence "verygeneral proof-of-concept animal studies in treating melanoma celllines with SDI-1, at both the gene and liposome-delivery levels.High in the SENNES clinical program is treatment for psoriasis,Wilson said, "where there's a hyperproliferative component, butsome normal growth constraints that are still available to the cell."Regarding "all this literature that's been coming out the last coupleof days on the p53 gene therapy approaches," Wilson observed, "weare now becoming aware of various tumor lines where SDI-1 appearsto be more effective at reducing tumor size than p53."Pimentel added, "There may be instances where p53 is effective, butothers in which SDI-1 is more so." n


-- David N. Leff Science Editor

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