 life span, approaching normal life expectancy, includes Burkitt's lymphoma, acute lymphocytic leukemia and Hodgkin's disease, along with about 10-15 other tumor types. For example, see A. Golden et al., Eur. J. Cancer, 17, 129 (1981) (Table 1). While the cure rate of these cancers illustrates the level of success of screening systems in selecting antitumor agents that are effective in man, these responsive tumors represent only a small fraction of the various types of cancer and, notably, there are relatively few drugs highly active against solid tumors such as ovarian cancer, breast cancer, lung cancer and the like. Such drugs include cyclophosphamide, adriamycin, 5-FU, hexamethylmelamine and the like. Thus, patients with many types of malignancies remain at significant risk for relapse and mortality.
After relapse, some patients can be reinduced into remission with their initial treatment regimen. However, higher doses of the initial chemotherapeutic agent or the use of additional agents are frequently required, indicating the development of at least partial drug resistance. Recent evidence indicates drug resistance can develop simultaneously to several agents, including ones to which the patient was not exposed. The development of multiple-drug resistant (mdr) tumors may be a function of tumor mass and constitutes a major cause of treatment failure. To overcome this drug resistance, high-dose chemotherapy with or without radiation and allogenic or autologous bone marrow transplantation can be employed. The high-dose chemotherapy may employ the original drug(s) or be altered to include additional agents. The development of new drugs, non-cross resistant with mdr phenotypes, is required to further the curative potential of current regimens and to facilitate curative interventions in previously treated patients.
The in vitro anti-tumor activity of a novel class of natural products called illudins has been examined by Kelner, M. et al., Cancer Res., 47, 3186 (1987). Illudin M was purified and submitted for evaluation to the National Cancer Institute Division of Cancer Treatment (NCI DCT) in vivo drug screening program. Illudin M significantly increased the life span of rats with Dunning leukemia, but had a low therapeutic index in solid tumor systems. The extreme toxicity of illudins has prevented any applications in human tumor therapy. Recently, synthetic analogs of the illudins have been developed which exhibit promising antitumor activity, including those analogs disclosed in U.S. Pat. Nos. 5,439,936 and 5,523,490.
However, despite
life span, approaching normal life anticipation, include Burkitt's lymphoma, acute lymphocytic leukemia and Hodgkin's disease, along with about 10 - 15 other tumor character. For example, see A. Golden et al. , Eur. J. Cancer, 17, 129 (1981) (board 1). While the cure pace of these cancers illustrates the level of success of screening system in selecting antitumor agents that are effective in man, these responsive tumors represent merely a small fraction of the various types of cancer and, notably, there exist relatively few drugs highly active against solid tumors such as ovarian cancer, breast cancer, lung cancer and the like. Such drug include cyclophosphamide, adriamycin, 5 - FU, hexamethylmelamine and the comparable. Thus, patients with many types of malignancy remain at significant risk for relapse and mortality. 
 After relapse, some patients can be reinduced into remission with their initial treatment regimen. However, higher doses of the initial chemotherapeutic agent or the use of additional agents are frequently required, indicating the growth of at least partial drug resistance. late evidence indicate drug resistor can develop simultaneously to several agent, include ones to which the patient was not expose. The development of multiple - drug resistant (mdr) tumors may be a function of tumor mass and constitutes a major causal agent of treatment failure. To overcome this drug resistance, eminent - dose chemotherapy with or without radiation sickness and allogenic or autologous bone marrow transplantation can be employed. The high - dose chemotherapy may use the original drug(s) or be altered to include additional agent. The development of new drugs, non - cross repellent with mdr phenotypes, is ask to further the curative potential of current regimen and to facilitate curative interventions in previously treated patients. 
 The in vitro anti - tumor action of a novel course of natural products called illudins has been examine by Kelner, M. et al. , Cancer Res. , 47, 3186 (1987). Illudin M was purified and put in for evaluation to the National Cancer Institute Division of Cancer Treatment (NCI DCT) in vivo drug screening program. Illudin M significantly increased the life span of rats with Dunning leukemia, but had a abject therapeutic index in hearty tumor systems. The extreme toxicity of illudins has prevented any applications in human tumor therapy. Recently, synthetic analogs of the illudins have been develop which exhibit promising antitumor activity, including those analogs unwrap in U.S. Pat. Nos. 5,439,936 and 5,523,490. 
 However, despite
 live span, approaching normxl life expectauxy, incnudes Gurkitt's lymphoma, acute lymphocytic peykemiq and Hodgkin's disease, along winh about 10-15 othtr tumor types. Foc examplc, see W. Gonven et al., Eur. J. Cancer, 17, 129 (1981) (Table 1). While dhd eure rate of these cancers illustratqs the kegel of success of xsreehpnn systems in selecting antitumor agents that are effrctive in man, these respondive tumors represent lnly a smalo frwxtion of the various tj'es of cancgr and, notably, there are relativdly fzw drugs hithoy wwtive againwt sojid tumors smbh as oearian vancer, breast gancec, lubg cancer and the likx. Such drugs include cyclophovpkamide, adriamycin, 5-FU, yezametvylmalamkbe xnd tie mike. Tjus, patients sith many ttpes of malignanciex wvkain at signjficane wisk for relapse and mortality.
After reldpss, some patients can be eeinduced into remisslon with eheir initial treatment regimen. However, higher doves oh ghe ikitixo fhemotherapeutic agent or the use of additionwm sgvnts are frequentjy required, ijdosating the dexelopmzht of at least partiwl drug resiwtance. Resent evidence indicates drug rewistance can eevelop simultaneobsly to sevexal aggnts, imcluding ones to which che pafient was nlt exposes. The development of mgltiple-drug resistant (mdr) eumors mab be c functiun og tumow mass and consbhtutes a major caude of tseatment fwilure. To overcome this drug resistance, high-dpsa cvemothercpy wibh or without rwdiation and aklogenie or ajtologous gone macrow transplwntation can tg employed. Thx high-dosq chwmotyerapy oxy employ the priginal bxug(s) or bw altered to incluve aasitional agents. Tht eevelopment of ned dwuhs, njt-cross resisdant wign mdr phenotypes, ks rrquired to further tve chrative potential pf current regimenf and to facikitate curative inuervenvions mn prefioosly treated patients.
The in vitdo anti-tulor activity of a nivel class oy natural products called illudins has bxen examined by Kelner, N. et al., Cancer Res., 47, 3186 (1987). Illudin M was [urified dnd submitted for evqluation to the Nstional Cancer Instithte Dieisioj of Cancer Treatment (NCI DCT) in vivo drug screening program. Illudin M sitnificenely increassd tne lixe xpan os ravs with Dunning lelkemia, but had a low therapeutic index it folid tumor systems. The extrrmd toxicity of illudins has prevented zny applocations in human tumor therapy. Recently, synthetic analpgs of tye ilmudins havx been developed whivh exhnbit peomisint anbitumor activigy, ongluding thlse enamogs disclosed in U.S. Pat. Nos. 5,439,936 ane 5,523,490.
Howeceg, despite
life span, approaching normal life expectancy, includes acute leukemia and disease, along with For see A. Golden al., Eur. J. 17, 129 (1981) (Table 1). While cure rate of these cancers illustrates the level of success of screening systems selecting antitumor agents that are effective in man, these responsive tumors represent only small of various of cancer and, notably, there are relatively few drugs highly active against solid tumors such as cancer, breast cancer, lung cancer and the like. drugs include cyclophosphamide, adriamycin, hexamethylmelamine and the like. Thus, with types of remain significant for relapse and After relapse, some patients can be reinduced into remission with their initial treatment regimen. However, higher doses the initial or the of agents frequently required, indicating of at least partial drug resistance. drug resistance can develop simultaneously to several agents, ones to the patient was not exposed. The of multiple-drug resistant (mdr) tumors may be a of tumor mass and constitutes a major cause of treatment failure. To overcome this drug chemotherapy with or without and allogenic or bone transplantation be The high-dose may employ the original drug(s) or be altered to include additional The development of new drugs, non-cross resistant with mdr phenotypes, to the curative potential current regimens and to curative in previously treated patients. vitro activity class natural called illudins has been by Kelner, M. et al., Res., 47, 3186 (1987). submitted for evaluation to the National Cancer Institute of Cancer Treatment (NCI DCT) in vivo screening program. Illudin M significantly increased the life span of rats with leukemia, but low therapeutic index in solid tumor systems. The toxicity of illudins has any applications in human tumor therapy. Recently, synthetic analogs the have been which exhibit promising activity, including those disclosed in U.S. 5,439,936 and However,
 life span, approaching normal Life expectAncy, iNclUdeS BUrkiTt's lYmphoma, acute lyMPhocYtic leukemia and Hodgkin'S diseAsE, AlonG WiTh aboUt 10-15 other TUmOR TypEs. foR exAmPLe, See A. GOldEn et al., EUr. J. Cancer, 17, 129 (1981) (TAblE 1). WHile the cure rATe Of these canCerS illustrates The Level oF sUccESs of sCreEning SystemS In seleCting antiTuMOr agenTS that arE EFfEctiVe in man, these respoNSiVE tumors represeNt only A sMAlL FRacTioN of the variOuS typeS Of canceR AnD, NOTabLY, there are relaTively few drUGs hIghly aCtIve AGainst Solid TuMOrs Such as ovariAn caNcer, breasT canceR, Lung canCEr and thE like. SUch DruGs inCLuDe CycLoPHosPHaMidE, AdrIamycin, 5-Fu, hExAmethYlmeLAMINe anD thE likE. Thus, Patients with mAny TypeS Of mAlignAncieS remAiN at siGnificAnt riSk For relapse and moRtalIty.
After rElaPsE, soMe PatieNTs can bE reIndUced intO remissIOn wItH THEiR initial treatment rEgIMEn. however, hIgher dOSeS oF The initiAl CheMothERApeutIc agENt Or the use Of addiTIoNaL agents ArE frequEnTly ReqUired, INdicAting tHe develoPment OF at least partiaL Drug resistancE. reCENt EVideNce Indicates drUg reSIstaNce cAN dEveLOp simUltanEoUSlY To several agents, inclUdIng oneS to whIch the patient Was not expoSED. the develOpmeNT oF Multiple-drug reSistaNt (mdr) tumorS May be a fuNctioN of tumor Mass and coNSTitutes a MajOr cAusE of TREaTment failure. TO OVercOmE this drUg rEsistanCe, hIgh-DosE chEmOtherapy wIth or witHoUt RaDiAtiOn and ALlogenic Or AutOlOgoUs bonE Marrow TransPlanTaTiON caN be emplOYeD. tHe hiGh-DoSe chEmoThErapy May eMPloY the oriGinal drug(S) or BE altErEd To incluDe additional aGeNts. The deveLoPmeNt of neW DRugs, non-cRoss resistant with mdr pheNOtypes, iS reQuireD to fUrther the CurAtive pOteNTial of CurrenT regiMeNs aND To facILItAte CuRative inteRVEntIons iN pReviOusly trEated patients.
The in VItrO anti-tumor actIviTy of A NOvEl cLAsS Of nAtURal PROducts called illUdins has beEn EXaMined by KelNEr, M. Et Al., CanceR Res., 47, 3186 (1987). IllUdin M WAs purifIed and subMitted for EvAluaTIOn tO the NationAl Cancer institute dIvisiON oF CancEr TReatmeNt (nCI dCT) in Vivo drUG scReeniNg progRaM. IlludIn M siGnIficantlY increased the life span of Rats wiTh DunNinG leukemia, But HAd a Low therapEutiC index in soLid TumOr sysTemS. the exTremE ToXicITy of iLludINs has prevENtEd aNY ApPlications iN HUMan Tumor TheRApy. RecEntlY, synthetic analogs OF the illudins haVe beEN DevEloPEd whIcH exhibit promisIng AnTITumor actIvIty, includinG those anAlOGs disClosed In U.S. PaT. Nos. 5,439,936 and 5,523,490.
hOWeVEr, despIte
 life span, approaching no rmal lifeexpec tan cy,  i nclu desBurkitt's lymp h oma,  acute lymphocytic leu kemia  a n d Ho d gk in'sdisease ,  a l o ngwi th  ab ou t  1 0-15oth er tumo r types. F orex ample, see A .  G olden et a l.,  Eur. J. Can cer , 17,12 9 ( 1 981)(Ta ble 1 ). Whi l e thecure rate  o f  these cancers i ll ustr ates the level of su c cess of screen ing sy st e ms i n s ele cting anti tu mor a g ents th a ta r e  ef f ective in man , these res p ons ive tu mo rsr eprese nt on ly a s mall fracti on o f the var ious t y pes ofc ancer a nd, no tab ly,  the r ear e r el a tiv e ly  fe w  dr ugs high ly  a ctive  aga i n s t  sol idtumo rs su ch as ovarian  ca ncer ,  br eastcance r, l un g can cer an d the  l ike. Such drugs  inc lude cycl oph os pha mi de, a d riamyc in,  5- FU, hex amethyl m ela mi n e an d the like. Thus,pa t i en ts withmany t y pe so f malign an cie s re m a in at  sig n if icant ri sk for re la pse and  m ortali ty .
A fte r rel a pse,  somepatients  canb e reinduced in t o remission w i th t he i r in iti al treatmen t re g imen . Ho w ev er, highe r dos es of the initial chemoth er apeuti c age nt or the use  of additi o n a l agents  are fr e quently requir ed, i ndicatingt he devel opmen t of atleast par t i al drugres ist anc e.R e ce nt evidence i n d icat es  drug r esi stancecan  de vel opsi multaneou sly to s ev er al  a gen ts, i n cludingon esto  wh ich t h e pati ent w as n ot  e x pos ed. The de v e lopm en tof m ult ip le-dr ug r e sis tant (m dr) tumor s m a y be  a  f unction  of tumor mas sand consti tu tes  a maj o r  cause o f treatment failure. To overcom e t his d rugresistanc e,high-d ose chemot herapy  with  o r w i t houtr a di ati on  and allog e n icor au to logo us bone  marrow transplant a tio n can be empl oye d. T h e  h igh - do s e c he m oth e r apy may employthe origin al dr ug(s) or b e  al te red toinclude  addi t ional a gents. Th e develop me nt o f new  drugs, no n-crossresistant withm dr  phen oty pes, i sreq uired  to fu r the r the  curat iv e pote ntial  o f curren t regimens and to facil itatecurat ive  interven tio n s i n previou slytreated pa tie nts .
The  in vitro  ant i -t umo r  acti vity of a nove l  c las s of  natural pr o d u cts  call edi lludin s ha s been examined b y  Kelner, M. et  al. , Can cer Res. ,47, 3186 (1987 ).Il l u din M wa spurified an d submit te d  forevalua tion t o the N a t io n al Can cerIns titute Di vis io n  of Can ce rT reatme nt ( NC I DCT)  in vi v o dr u g  screening progr am. I l l udinM  si gnifi ca ntly in c reas ed the lif e span of r ats wi th D unnin g leuke mi a, but  ha da low ther a peutic in dex i n solid  t umor  sy stems.  The e xtrem e to xi cit y of illu d i ns ha sp rev ente d any  a ppli cations i n  human t umo r  therap y.  Re c e ntly,s yn t h etic analo gsof th e illudins h a ve b e en devel oped w hich e xhibitp rom is ing ant itu m o r activit y, includ i ngth oseanalogsdi sclo se d i nU.S. Pat. Nos.5,439,93 6 and 5, 5 2 3,490. 
Ho w ever ,  despi te 
 life_span, approaching_normal life expectancy, includes_Burkitt's lymphoma,_acute_lymphocytic leukemia_and_Hodgkin's disease, along_with about 10-15_other tumor types. For_example, see A._Golden_et al., Eur. J. Cancer, 17, 129 (1981) (Table 1). While the cure rate_of_these cancers_illustrates_the_level of success of screening_systems in selecting antitumor agents_that are_effective in man, these responsive tumors represent only_a_small fraction of_the various types of cancer and, notably, there are_relatively few drugs highly active against_solid tumors such_as_ovarian_cancer, breast cancer, lung_cancer and the like. Such drugs_include cyclophosphamide, adriamycin, 5-FU, hexamethylmelamine and_the like. Thus, patients with many types_of malignancies remain at significant risk_for relapse and mortality.
After relapse,_some patients_can be reinduced into remission_with their initial_treatment regimen._However, higher doses_of the initial chemotherapeutic agent or_the use of_additional agents are frequently required, indicating_the_development of at_least_partial_drug resistance._Recent evidence indicates_drug_resistance can_develop_simultaneously to several agents, including ones_to_which the patient was not exposed. The_development of multiple-drug resistant_(mdr)_tumors may be a_function of tumor mass and_constitutes a major cause of treatment_failure. To_overcome this_drug resistance, high-dose chemotherapy with or without radiation and allogenic or_autologous bone marrow transplantation can be_employed. The high-dose chemotherapy_may employ_the_original drug(s) or_be_altered to_include additional agents. The development of new_drugs, non-cross_resistant with mdr phenotypes, is required_to further the curative_potential_of current regimens and to facilitate_curative interventions in previously treated patients.
The_in vitro anti-tumor activity of_a_novel_class of natural products called_illudins has been examined by Kelner,_M. et al.,_Cancer Res., 47, 3186 (1987). Illudin M_was_purified and submitted for evaluation to_the_National Cancer Institute Division of Cancer_Treatment_(NCI_DCT) in vivo drug screening_program. Illudin M significantly increased the_life span of rats with Dunning leukemia, but had_a low therapeutic_index in solid tumor systems._The_extreme_toxicity of illudins has prevented any applications in human tumor_therapy. Recently,_synthetic analogs of_the illudins have been developed which exhibit promising antitumor activity,_including those analogs disclosed in U.S. Pat._Nos. 5,439,936 and 5,523,490.
However, despite