Novel Combinations With Oxaliplatin

December 1, 2000

Oxaliplatin (Eloxatin) is a novel antineoplastic platinum derivative that may exert its cytotoxic effects by blocking DNA replication/transcription, thus resulting in cell death in proliferating cells, as well as apoptosis.

ABSTRACT: Oxaliplatin (Eloxatin) is a novel antineoplastic platinumderivative that may exert its cytotoxic effects by blocking DNAreplication/transcription, thus resulting in cell death in proliferating cells,as well as apoptosis. Oxaliplatin is often more potent than other platinums suchas cisplatin (Platinol) in vitro, and shows greater efficacy in preclinicalstudies against many tumor cell lines, including some that are resistant tocisplatin and carboplatin (Paraplatin). Oxaliplatin is approved for use with thefluoropyrimidines in the treatment of metastatic colorectal cancer in Asia,Latin America, and Europe. In light of the broad efficacy of oxaliplatin inseveral solid tumors and the encouraging preclinical data on combination therapywith novel agents (eg, thymidylate synthase inhibitors, epidermal growth factor-receptorantagonists, microtubule interactive agents), this article will review thepublished literature on novel combinations that have been tested in thelaboratory and/or the clinic. [ONCOLOGY14(Suppl 11):52-58, 2000]

Introduction

Oxaliplatin(cis-[(1R,2R)]-1,2-cyclohexanediamine-N,N´ oxalato (2-)-O,O´] platinum,Eloxatin) is a novel antineoplastic platinum derivative with a1,2-diaminocyclohexane (DACH) carrier ligand.[1] Although its precise mechanismof action is unknown, platinum compounds in general are thought to exert theircytotoxic effects through the formation of DNA adducts that block both DNAreplication and transcription, resulting in cell death in actively dividingcells as well as the induction of apoptosis.[2,3] Oxaliplatin is often morepotent than cisplatin (Platinol) in vitro, requiring fewer DNA adducts toachieve an equal level of cytotoxicity, and shows the same or greater efficacyagainst many tumor cell lines in preclinical studies, including some that areresistant to cisplatin and carboplatin (Paraplatin).[4-6]

Based on provocative responses seen in patients with metastaticcolorectal cancer, oxaliplatin has been approved for use with thefluoropyrimidines in the treatment of metastatic colorectal cancer in Asia,Latin America, and Europe. Studies with oxaliplatin have also demonstrated itsbroad efficacy in several solid tumors and yielded encouraging preclinical dataon combination therapy with novel agents (eg, thymidylate synthase inhibitors,epidermal growth factor-receptor antagonists, microtubule interactive agents).

Novel drug combinations with oxaliplatin that have entered theclinic may be grouped as follows:

Combinations with topoisomerase inhibitors

Combinations with novel thymidylate synthase inhibitors

Combinations with DNA interactive agents

Combinations with microtubule interactive agents

Other novel combinations

Many of the above combinations have been described in detail byother investigators in this supplement. Because oxaliplatin is a new drug,several approaches that have the potential for clinical application are beingtested; however, data supporting these applications are still predominantlypreclinical.

Preclinical Studies of Novel Combinations

In vitro and in vivo studies of oxaliplatin have shown itsadditive or synergistic cytotoxic properties with the fluoropyrimidines(fluorouracil [5-FU]), thymidylate synthase inhibitors (AG337, raltitrexed[Tomudex]), nucleoside analogs (gemcitabine [Gemzar]), topoisomerase Iinhibitors (topotecan, irinotecan [Camptosar], and SN-38), microtubule bindingagents (paclitaxel [Taxol]), and DNA modifying/alkylating agents (cisplatin andcyclophosphamide [Cytoxan, Neosar]).[7-13]

Although oxaliplatin demonstrates additive/synergistic activityin combination with many standard anticancer agents in preclinical models, somecombinations do not show increased in vivo activity and are sometimes associatedwith increased toxicity.[14] More extensive synergy studies withirinotecan/SN-38 and oxaliplatin in HT-29 colon carcinoma cell lines and GRImouse mammary and other human tumor models suggest that there is increasedstabilization of DNA adducts in cells exposed to topoisomerase I inhibitors afterexposure to platinum. There are increased DNA topoisomerase I cleavablecomplexes that result in increased inhibition of DNA elongation and S-phasearrest.[8,9]

Other combinations include increased platinum-DNA adducts withhyperthermia exposure to cultured SW 1573 cells,[15] potentiation ofplatinum-DNA adducts and cellular cytotoxicity when combined with antisenseoligonucleotides against XPA (or CSB),[16] and potentiation of oxaliplatincytotoxicity by ZD1839 (Iressa), an epidermal growth factor receptor-selectivetyrosine kinase inhibitor.[17]

Clinical Data

The efficacy of oxaliplatin monotherapy in patients withadvanced colorectal cancer has been evaluated in several studies, and objectiveresponse rates achieved with oxaliplatin as first-line therapy averaged 18%while those of oxaliplatin as second-line therapy averaged 10%.[18-21]Furthermore, this single-agent response rate is comparable to that achieved withirinotecan alone in patients with colorectal cancer.[22] Nevertheless,single-agent use of oxaliplatin is not currently recommended as standard therapyexcept in some European countries for patients with dihydropyrimidinedehydrogenase deficiency, which is associated with an increased risk for severeor lethal 5-FU toxicity, or in patients with 5-FU-related cardiotoxicity.

Combinations With 5-FU and Leucovorin

Given the relatively high response rates reported withoxaliplatin in colorectal cancer, an obvious choice was to study combinationswith 5-FU and leucovorin in a front-line setting. These trials have beenreviewed elsewhere in this supplement; however, in summary, the response ratesvaried from 25% to 67% depending on the delivery schedules of 5-FU/leucovorin.The major toxicities of oxaliplatin/5-FU/leucovorin combination therapy werediarrhea, stomatitis, peripheral sensory neuropathy, and nausea and vomiting.Multiple reviews of these trials have been published, and confirmatory data fromrandomized trials of oxaliplatin (with or without 5-FU/leucovorin) in the UnitedStates are awaited.[23]

Oxaliplatin/Fluorouracil/Irinotecan

The next obvious point of investigation is the combination ofoxaliplatin with 5-FU, with or without irinotecan. Several tumor models (eg,HT-29 colon carcinoma, GRI mouse mammary tumor) have shown that the combinationof irinotecan and oxaliplatin has synergistic activity. At the molecular level,there is increased stabilization of adducts in cells exposed to thetopoisomerase I inhibitor after exposure to platinum. There are increasedDNA topoisomerase I cleavable complexes that result in prolonged inhibition ofDNA elongation and S-phase arrest.[8,9]

Scheduling for Optimal Efficacy: The observed preclinicalsynergy and the potential for nonoverlapping toxicities in the combination hasstimulated several clinical studies. Various irinotecan combinations deliveredon a number of schedules, eg, every 3 weeks, weekly, or every 2 weeks, have beenstudied (Table 1).[24-27] Wasserman et alinvestigated the every-3-week schedule of irinotecan and oxaliplatin delivery.The maximum tolerated dose (recommended phase II dose) of irinotecan was 200mg/m2 with oxaliplatin administered at a doseof 85 mg/m2.[24] Toxicities included neuropathyand gastrointestinal events. No pharmacokinetic interactions between the twodrugs were noted, and 7 of 24 patients had partial responses.

In a subsequent study, Goldwassser and colleagues described anevery-2-week schedule of irinotecan administered with oxaliplatin. The maximumtolerated dose of the combination was irinotecan at 175 mg/m2and oxaliplatin at 85 mg/m2.[25] There was aslightly higher incidence of myelosuppressive events in this study compared withthose described in the Wasserman study; however, the regimen was well toleratedoverall, and significant responses were reported.

Rothenberg and collaborators have reported on the combination ofirinotecan and oxaliplatin using an every-2-week schedule. The maximum tolerateddose has not yet been reached at 200 mg/m2 ofirinotecan and 85 mg/m2 oxaliplatin (MaceRothenberg, personal communication).

Other studies of irinotecan in the United States include one ofa weekly schedule that is currently underway at Memorial Sloan-Kettering CancerCenter.[24] Additional phase I and II studies have reported on the tolerabilityof this combination and also on the synergistic responses.[28,29] The toxicityof the triple combination of irinotecan, oxaliplatin, and 5-FU, with or withoutleucovorin, is predominantly dictated by the dose schedule of 5-FU/leucovorin.

The bulk of published studies indicate that it is feasible andsafe to combine these three drugs [30-33]; however, there are examples ofcombinations that are very toxic and that do not significantly increase theactivity of irinotecan and oxaliplatin. Gil-Delgado et al published a study ofthe triplet combination, which incorporated a modified de Gramont schedule(leucovorin at 200 mg/m2 followed by a 400 mg/m2bolus of 5-FU plus continuous intravenous 5-FU at 600 mg/m2)in combination with irinotecan and oxaliplatin. The triplet was very toxic—morethan 50% of patients presented with grade 3/4 diarrhea, and 1 of the 10 patientsenrolled developed septic shock.[34]

Combinations With Oral Fluoropyrimidines

An obvious point of departure is the use of oralfluoropyrimidines in combination with oxaliplatin, with or withoutirinotecan.[27,35,36] In the United States, several groups are presentlyassessing combinations of the oral fluoropyrimidines, and the results of theseassessments will provide additional data that may be necessary as we begin tocontemplate irinotecan oral combination therapy.

Raltitrexed

Other novel regimens that may substitute for 5-FU (incombination with oxaliplatin) include combinations with raltitrexed.[37-46]Although raltitrexed has not been widely used in trials or in practice in theUnited States, it is popular in Europe where the drug is approved. Inpreclinical testing, raltitrexed and oxaliplatin are at best additive (and alsoshown to be antagonistic in two cell lines); however, given that theirtoxicities are nonoverlapping, it is reasonable to investigate the utility ofthis combination in the clinic.[47]

In a phase I study by Fizazi et al, 30 patients (18 males/12females) with advanced cancer and a median age of 53 years (range: 32-71years) received raltitrexed as a 15-minute infusion followed by oxaliplatin over2 hours repeated every 3 weeks. The maximum tolerated dose of raltitrexed wasestablished at 3.5 mg/m2 and oxaliplatin at 130 mg/m2 with amaurosis fugax,stomatitis, and asthenia among the dose-limiting toxicities.[41]

Two patients with cisplatin-resistant mesothelioma had a partialresponse, and although pharmacokinetic interaction studies were performed, thepharmacokinetic data were not reported in the abstract.[39]

In a subsequent phase II study, this combination wasadministered to 50 patients (37 males/13 females) with predominantlychemotherapy-naive malignant mesothelioma. The objective response rate was 28.6%(95% confidence interval: 9.2%-47.9%), and the stable disease rate was 54.2%.Of 15 (31.3%) chemotherapy-naive patients, 5 had a partial response, and 1 of 11patients with cisplatin-refractory cancer had a partial response.

The toxicities reported in this trial included grade 3 asthenia(2 patients), neutropenia (1 patient), diarrhea (1 patient), and grade 2 anemia.Neutropenia, vomiting, nausea, and paresthesia were uncommon.[40]

Raltitrexed in Advanced Cancer: Responses in patients withmesotheliomas have been reported in subsequent phase II studies.[42,43] Theregimen is tolerable for delivery on an outpatient basis with limited sideeffects, in particular hematologic effects and alopecia. Fluorouracil has beenadded to raltitrexed and oxaliplatin. This triplet combination (with leucovorinincluded) may be given at the doses recommended for the individual drugs.[42]

In a phase I study in patients with advanced cancer, oxaliplatinat 85 mg/m2 was followed by raltitrexed at 2.5 to 3mg/m2 (day 1), and by a2-hour infusion of leucovorin at 250 mg/m2, then by 5-FU at doses ranging from750 to 1,050 mg/m2 (day 2) repeated every 2 weeks. The dose-limiting toxicitiesdefining the maximum tolerated dose of oxaliplatin at 85 mg/m2, raltitrexed at 3mg/m2, and 5-FU at 900 mg/m2 included neutropenia, diarrhea, and stomatitis.

Of 18 evaluable patients (11%), two achieved a partial responsewhile 13 showed a minor response (1 patient) or stable disease (12 patients). Itwas concluded that full doses of all cytotoxic agents could be safelyadministered every 2 weeks.[42]

Gemcitabine and Oxaliplatin

Preclinical synergy has been demonstrated with the combinationof gemcitabine and oxaliplatin.[11] Once again both drugs have toxicities thatare nonoverlapping. Several reports, mostly in abstract form, have shown thefeasibility of combining these two drugs.

Phase I Trial: Mavroudis et al reported on a phase I trialof the combination of oxaliplatin and gemcitabine in which gemcitabine wasadministered on days 1 and 8 as a 30-minute infusion at doses ranging between1,000 and 1,600 mg/m2 followed by oxaliplatin as a2-hour infusion at doses ranging from 60 to 110 mg/m2 repeated every 3weeks.[48] The maximum tolerated dose has not been reached, and accrualcontinues with patients receiving gemcitabine at a dose of 1,600 mg/m2 andoxaliplatin at a dose of 110 mg/m2. Other investigators have shown lowermaximally tolerated doses of gemcitabine; however, overall the toxicities, asexpected, include myelosuppression and neuropathy.[48,49]

The combination of oxaliplatin with gemcitabine is appealingbecause it may be used for a variety of solid tumors (eg, lung, breast,ovarian), including the typically chemoresistant tumors like pancreaticcancer.[50] We have used the broad applicability of this regimen to combine itfurther with 5-FU, making this triplet useful for many solid tumors. The basisfor the combination of 5-FU and gemcitabine stems from our earlier experiencewith this combination using several schedules of infusional 5-FU in combinationwith weekly gemcitabine (either on days 1 and 8 or days 1, 8, and 15).

In our prior studies, we concluded that gemcitabine is bestdelivered in combination with infusional 5-FU on days 1 and 8 only—wefrequently had to omit day 15 dosing due to toxicity.[51] Furthermore, there areknown pharmacokinetic interactions with 5-FU and gemcitabine.[52]

Current Phase I Trial: At Albert Einstein College ofMedicine, we have embarked on a phase I trial (T99-0023) of the combination ofgemcitabine, oxaliplatin, and 5-FU sponsored by the Cancer Therapy EvaluationProgram (CTEP), National Cancer Institute (NCI). The study aims to describe thetoxicities and maximum tolerated doses of the individual drugs given incombination. The trial is using the NCI accelerated titration design format withexpansion of the recommended phase II dose to a minimum of 12 patients in orderto better study toxicities. We have also incorporated into the study assessmentsfor pharmacokinetic interactions between these drugs as well as assessments forinteractions in drug sequence.

During the phase I escalation of the trial, we studied thefollowing schedules:

In cycle 1: Oxaliplatin over 2 hours followed by gemcitabineover 30 minutes followed by infusional 5-FU

In cycle 2: Gemcitabine over 30 minutes followed byoxaliplatin over 2 hours followed by infusional 5-FU

All subsequent cycles incorporate the cycle 1 schedule of drugdelivery. Detailed pharmacokinetic studies were conducted during cycles 1 and 2for ultrafilterable and total platinum, gemcitabine (and its metabolites), and5-FU. Thus far, 12 patients have been treated with varying dose levels (Table2).

We have established the maximum tolerated dose of thecombination of oxaliplatin, 5-FU, and gemcitabine, and on preliminary review,the regimen appears to be well suited for outpatient therapy. The toxicities arepredominantly diarrhea and neutropenia; however, these data have to be viewedwith caution as the trial is ongoing.

Combinations With the Taxanes

Combination therapy with the taxanes is important, especially aswe expand the use of oxaliplatin. Several phase I trials of docetaxel (Taxotere)combinations that assessed an every-3-week docetaxel/oxaliplatin schedule havebeen reported. In one study, the recommended phase II dose of the combinationwas 75 mg/m2 of docetaxel with 80 mg/m2 of oxaliplatin.[53] In ovariancarcinoma, a dose-finding study of the paclitaxel/oxaliplatin combination usedan every-3-week schedule and yielded a 48% response rate, with a responseobserved in platinum-resistant patients.[53,54]

There was no apparent increase in the incidence ofmyelosuppression or neuropathy as compared with the taxanes given alone;however, this finding was preliminary and must be viewed with caution. There area number of other oxaliplatin combinations (eg, vinorelbine [Navelbine],cisplatin [Platinol], multitargeted folate antagonists), and among them are theoptimizing agents used for the treatment of colorectal cancer.[55-58]

Several questions, however, regarding the use and development ofoxaliplatin for solid tumors remain unanswered. There have been a proliferation ofphase I studies with a number of combinations and schedules being tested. Forexample, in colorectal cancer, several irinotecan combinations are beingclinically explored. The question is which schedule or combination will assumethe lead in the development of oxaliplatin in combination with irinotecan? Ifany particular schedule is chosen, where will the combination of irinotecan andoxaliplatin fall within the treatment schemes now available for colorectalcancer (eg, the current standard for frontline treatment of metastatic diseaseis irinotecan given with 5-FU and leucovorin)? Cooperative group studies arecurrently underway and poised to help answer some of these questions.

Conclusions

This review hopes to stimulate the reader to look for othernovel combinations with oxaliplatin based on the current knowledge of themechanism of action of oxaliplatin. Departing from existing combinations andindications for clinical use, there are data suggesting that oxaliplatin may bean effective radiation sensitizer.[59] Other combinations are currently beingdeveloped and have their roots in basic concepts of receptor-enhancedchemosensitivity and reduced nucleotide excision repair of platinum-DNAadducts.[16,60-92]

Receptor-enhanced chemosensitivity[86] has potential clinicalapplications based on the fact that (1) the dose-effect relationship ofanti-HER2/neu antibody plus cisplatin is synergistic; (2) this synergism isspecific for cells that overexpress the HER2/neu receptor; (3) the combinationof cisplatin plus anti-HER2/neu antibody results in a two-log increase in cellkilling; and (4) the combination yields pathologic complete remissions againstHER2/neu-overexpressing human breast carcinoma xenografts in athymic nudemice.[83-87]

Furthermore, given the similarity of oxaliplatin tocisplatin-induced DNA lesions, [90] we hypothesize that strategies forinhibiting DNA repair will augment the efficacy of cisplatin as well asoxaliplatin and newer generation platinum agents. In fact, we have demonstratedthe synergistic cytotoxicity of oxaliplatin and trastuzumab (Herceptin) inHER2-overexpressing SKBR-3 breast carcinoma cells (Lu Y, Mani S, Bregman DB,unpublished data). In addition, we recently reported that A2780/CP70 cellstreated with antisense oligonucleotides targeting Xeroderma pigmentosum group Acomplementing protein (XPA) showed enhanced sensitivity to cisplatin andoxaliplatin.[16]

To date, studies of nucleotide excision repair (NER) have takenadvantage of genetic mutants in humans, yeast, and rodents. Now, with theclinical development of anti-HER2 antibodies, miscellaneous agents withdemonstrated anti-NER activity such as UCN-01, and the development of antisenseoligonucleotides targeting specific NER proteins, pharmacologic reagents will beavailable to complement the genetic tools available for the study of nucleotideexcision repair. Moreover, these combinations may prove useful to furtherenhance the selective cytotoxic potential of oxaliplatin.

References:

1. Burchenal JH, Kalaher K, O’Toole T, et al: Lack ofcross-resistance between certain platinum coordination compounds in mouseleukemia. Cancer Res 37:3455-3457, 1977.

2. Gibbons GR, Page JD, Mauldin SK, et al: Role of carrierligand in platinum resistance in L1210 cells. Cancer Res 50:6497-6501, 1990.

3. Schmidt W, Chaney SG: Role of carrier ligand in platinumresistance of human carcinoma cell lines. Cancer Res 53:799-805, 1993.

4. Vaisman A, Varchenko M, Umar A, et al: The role of hMLH1,hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: Correlationwith replicative bypass of platinum-DNA adducts. Cancer Res 58:3579-3585, 1998.

5. Jennerwein MM, Eastman A, Khokhar AR: Characterization ofadducts produced in DNA by isomeric 1,2-diaminocyclohexaneplatinum(II)complexes. Chem Biol Interact 70:39-49, 1989.

6. Page JD, Husain I, Sancar A, et al: Effect of thediaminocyclohexane carrier ligand on platinum adduct formation, repair, andlethality. Biochemistry 29:1016-1024, 1990.

7. Noji M, Okamoto K, Kidani Y, et al: Relation of conformationto antitumor activity of platinum (II) complexes of 1,2-cyclohexanediamine and2-(aminomethyl) cyclohexylamine isomers against leukemia P388. J Med Chem24:508-515, 1981.

8. Zeghari-Squalli N, Misset JL, Cvitkovic E, et al: Mechanismof the in vitro synergism between SN38 and oxaliplatin (abstract). Proc Am AssocCancer Res 38:A20, 1997.

9. Zeghari-Squalli N, Raymond E, Cvitkovic E, et al: Cellularpharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 andthe diaminocyclohexane platinum derivative oxaliplatin. Clin Cancer Res5:1189-1196, 1999.

10. Goldwasser F, Bozec L, Zeghari-Squalli N, et al: Cellularpharmacology of the combination of oxaliplatin with topotecan in the IGROV-1human ovarian cancer cell line. Anticancer Drugs 10:195-201, 1999.

11. Faivre S, Raymond E, Woynarowski JM, et al: Supra-additiveeffect of 2',2'-difluorodeoxycytidine (gemcitabine) in combination withoxaliplatin in human cancer cell lines. Cancer Chemother Pharmacol 44:117-123,1999.

12. Misset JL, Goldwasser F, Riofrio M, et al:Topotecan-oxaliplatin every 3 weeks: A phase I and pharmacologic study (abstract845). Proc Am Soc Clin Oncol 18:220a, 1999.

13. Szelenyi H, Huetter G, Staab HJ, et al: Oxaliplatin incombination with continuous infusion of topotecan in patients with 5-FUrefractory metastatic colorectal carcinoma: A phase IB study (abstract 895).Proc Am Soc Clin Oncol 19:229a, 2000.

14. Raymond E, Buquet-Fagot F, Djelloul C, et al: Antitumoractivity of oxaliplatin in combination with 5-fluorouracil and the thymidylatesynthase inhibitor AG337 in human colon, breast, and ovarian cancers. AnticancerDrugs 8:876-885, 1997.

15. Rietbroek RC, van de Vaart PJ, Haveman J, et al:Hyperthermia enhances the cytotoxicity and platinum-DNA adduct formation oflorbaplatin and oxaliplatin in cultured SW 1573 cells. J Cancer Res Clin Oncol123:6-12, 1997.

16. Lu Y, Mani S, Agarwal S, et al: Mixed backboneoligonucleotides targeting the nucleotide excision repair protein XPA potentiatecisplatin cytotoxicity (abstract 4085). Proc Am Assoc Cancer Res, 2000.

17. Ciardello F, Caputo R, Bianco R, et al: Antitumor effect andpotentiation of cytotoxic drug activity in human cancer cells by ZD-1839(Iressa), an epidermal growth factor receptor-selective tyrosine kinaseinhibitor. Clin Cancer Res 6:2053-2063, 2000.

18. Becouarn Y, Rougier P: Clinical efficacy of oxaliplatinmonotherapy: Phase II trials in advanced colorectal cancer. Semin Oncol 25(suppl5):23-31, 1998.

19. Diaz-Rubio E, Sastre J, Zaniboni A: Oxaliplatin as singleagent in previously untreated colorectal carcinoma patients: A phase IImulticentric study. Ann Oncol 9:105-108, 1998.

20. Machover D, Diaz-Rubio E, de Gramont A, et al: Twoconsecutive phase II studies of oxaliplatin (L-OHP) for treatment of patientswith advanced colorectal carcinoma who were resistant to previous treatment withfluoropyrimidines. Ann Oncol 7:95-98, 1996.

21. Lévi F, Perpoint B, Garufi C, et al: Oxaliplatin activityagainst metastatic colorectal cancer. A phase II study of 5-day continuousvenous infusion at circadian rhythm modulated rate. Eur J Cancer 29a:1280-1284,1993.

22. Rothenberg ML: Efficacy and toxicity of irinotecan inpatients with colorectal cancer. Semin Oncol 25:36-46, 1998.

23. De Gramont A, Figer A, Seymour M, et al: Leucovorin andfluorouracil with or without oxaliplatin as first-line treatment in advancedcolorectal cancer. J Clin Oncol 18:2938-2947, 2000.

24. Wasserman E, Cuvier C, Lokiec F, et al: Combination ofoxaliplatin plus irinotecan in patients with gastrointestinal tumors: Results oftwo independent phase I studies with pharmacokinetics. J Clin Oncol17:1751-1759, 1999.

25. Goldwasser F, Chouaki N, Buthaud X, et al:CPT-11/oxaliplatin every two weeks: A phase I study in patients with advanceddigestive tumors (abstract 927). Proc Am Soc Clin Oncol 17:242a, 1998.

26. Kemeny N, Tong W, Stockman J, et al: Phase I trial of weeklyoxaliplatin and irinotecan in previously treated patients with metastaticcolorectal cancer (abstract 948). Proc Am Soc Clin Oncol 19:245a, 2000.

27. Hoff PM, Pazdur R: Oxaliplatin and UFT/oral calcium folinatefor advanced colorectal carcinoma. Oncology 13(supp 3):48-50, 1999.

28. Scheithauer W, Kornek GV, Raderer M, et al: Combinedirinotecan and oxaliplatin plus granulocyte colony-stimulating factor inpatients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer.J Clin Oncol 17:902-906, 1999.

29. Ivy SP, Blatner G, Cheson BD: Clinical trials referralresource. Clinical trials of combination regimens containing oxaliplatin.Oncology 13:1116-1118, 1999.

30. Calvo E, Gonzalez-Cao M, Cortes J, et al: Combinedirinotecan, oxaliplatin, 5-FU in patients with metastatic colorectal cancer(abstract 1008). Proc Am Soc Clin Oncol 19:259a, 2000.

31. Falcone A, Masi G, Pfanner E, et al: Phase I-II study ofirinotecan, oxaliplatin, leucovorin, and 5-fluorouracil 48 hours continuousinfusion (abstract 1161). Proc Am Soc Clin Oncol 19:297a, 2000.

32. Conroy T, Seitz J, Capodano G, et al: Phase I study oftriple combination of oxaliplatin + irinotecan + LV5FU2 in patients withmetastatic solid tumors (abstract 921G). Proc Am Soc Clin Oncol 19:236a, 1999.

33. Lerebours F, Cottu P, Hocini H, et al: Oxaliplatin (OXA),irinotecan (CPT-11), and 4-day continuous infusion 5-fluorouracil (CIVFU) every3 weeks: A phase I study in advanced gastrointestinal tumors (abstract 1237).Proc Am Soc Clin Oncol 19:313a, 2000.

34. Gil-Delgado MA, Bastian G, Guinet F, et al: Phase I-II trialand pharmacokinetic analysis of oxaliplatin plus 5-FU/leucovorin plus irinotecancombination in advanced colorectal carcinoma (abstract 1093). Proc Am Soc ClinOncol 18:254a, 1999.

35. Diaz-Rubio E, Evans J, Tabernero J, et al: Phase I study ofcapecitabine in combination with oxaliplatin in patients with advancedmetastatic solid tumors (abstract 772). Proc Am Soc Clin Oncol 19:198a, 2000.

36. Garcia-Giron C, Feliu J, Vincent JM, et al: Phase II trialof oxaliplatin-UFT-Leucovorin combination in first-line treatment of advancedcolorectal cancer (abstract 1148). Proc Am Soc Clin Oncol 19:293a, 2000.

37. Armand JP, Seymour L, Evans TR: Raltitrexed (tomudex) incombination with platinum-based agents and/or anthracyclines: Preliminaryresults of phase I clinical trials. Eur J Cancer 35(suppl 1):S14-S18, 1999.

38. Fizazi K, Soria JC, Bonnay M, et al: Phase I/II dose-findingand pharmacokinetic study of Tomudex in combination with oxaliplatin in advancedsolid tumors (abstract 773). Proc Am Soc Clin Oncol 17:638a, 1998.

39. Fizazi K, Viala J, Daniel C, et al: Raltitrexed (tomudex)and oxaliplatin: An active outpatient regimen in malignant mesothelioma. Eur JCancer 35(suppl 4):252, 1999.

40. Fizazi K, Caliandro R, Soulie P, et al: Combinationraltitrexed (Tomudex)- oxaliplatin: A step forward in the struggle againstmesothelioma? The Institut Gustave Roussy experience with chemotherapy andchemo-immunotherapy in mesothelioma. Eur J Cancer 36:1514-1521, 2000.

41. Fizazi K, Ducreux M, Ruffie P, et al: Phase I, dose-finding,and pharmacokinetic study of raltitrexed combined with oxaliplatin in patientswith advanced cancer. J Clin Oncol 18:2293-2300, 2000.

42. Casaretti R, DeLucia L, DeVita F, et al: Oxalipaltin +Tomudex and levo-folinic acid + fluorouracil every 2 weeks. A dose finding studyin advanced colorectal carcinoma. Eur J Cancer 35(suppl 4):289S, 1999.

43. Bennouna J, Seitz JF, Paillot B, et al: Tomudex plusoxaliplatin in previously untreated metastatic colorectal cancer patients: Anactive combination. Eur J Cancer 35(suppl 4):75S, 1999.

44. Catalano G, Casaretti R, De Lucia L, et al: Oxaliplatin(L-OHP) and tomudex (TOM) followed by levo-leucovorin (LLV)-modulated5-fluorouracil (5FU) IV bolus every 2 weeks. A dose finding study in advancedcolorectal carcinoma (ACC) (abstract 1062). Proc Am Soc Clin Oncol 19:272a,2000.

45. Scheithauer W, Kornek GV, Ulrich-Pur H, et al: Promisingtherapeutic potential of oxaliplatin + raltitrexed in patients with advancedcolorectal cancer (ACC): Results of a phase I/II trial (abstract 997). Proc AmSoc Clin Oncol 19:257a, 2000.

46. Douillard JY, Michel P, Gamelin E, et al: Raltitrexed(Tomudex) plus oxaliplatin: An active combination for first-line chemotherapy inpatients with metastatic colorectal cancer (abstract 971). Proc Am Soc ClinOncol 19:250a, 2000.

47. Jackman AL, Kimbell R, Ford HE: Combination of raltitrexedwith other cytotoxic agents: Rationale and preclinical observations. Eur JCancer 35(suppl 1):S3-S8, 1999.

48. Mavroudis D, Agelaki S, Kalbakis K, et al: A dose findingand toxicity study of the gemcitabine-oxaliplatin combination in patients withadvanced solid tumors. Eur J Cancer 35(suppl 4):S289, 1999.

49. Klapdor R, Svendsen J, Seutter R, et al: Combination therapywith oxaliplatin + gemcitabine in advanced pancreatic cancer. Eur J Cancer35(suppl 4):S146, 1999.

50. Buchele T, Grothey A, Voigt W, et al: Biweekly docetaxel,gemcitabine, oxaliplatin in heavily pretreated patients with solidtumors-preliminary results of a phase I study. Eur J Cancer 35(suppl 4):S288,1999.

51. Mani S, Gordon G, Vogelzang NJ, et al: A phase I trial ofcontinuous infusion 5-FU and weekly gemcitabine: Updated results of an activecombination for renal cell, hepatocellular, and colon cancer. Ann Oncol 2:632,1998.

52. Correale P, Cerretani D, Petroli R, et al: Gemcitabine(dFdC) affects 5-fluorouracil (5-FU) pharmacokinetics in cancer patients(abstract 2546). Proc Am Assoc Cancer Res 40:384a, 1999.

53. Kouroussis CH, Androuliakis N, Kalbakis K, et al: A phase Istudy of docetaxel and oxaliplatin as frontline treatment in metastatic breastcancer and non-small-cell lung cancer: Preliminary results. Eur J Cancer35(suppl 4):S293, 1999.

54. Faivre S, Kalla S, Cvitkovic E, et al: Oxaliplatin andpaclitaxel combination in patients with platinum-pretreated ovarian carcinoma:An investigator-originated compassionate-use experience. Ann Oncol 10:1125-1128,1999.

55. Fumuleau P, Gamelin E, Misset JL, et al: A phase I study ofthe multitargeted antifolate (MTA) (LY 231514) in combination with oxaliplatinin metastatic solid tumors. Eur J Cancer 35(suppl 4):S292, 1999.

56. DeCremoux H, Bekradda M, Monnet I, et al: Preliminary reporton oxaliplatin/navelbine phase I/II multicentric trial in patients with advancednon-small-cell lung cancer (NSCLC): An active combination (abstract 1852).Proc Am Soc Clin Oncol 17:481a, 1998.

57. Bokemeyer C, Kollmannsberger C, Harstrick A, et al:Treatment of patients with cisplatin-refractory testicular germ-cell cancer.German Testicular Cancer Study Group (GTCSG). Int J Cancer 83:848-851, 1999.

58. Soulie P, Garrino C, Bensmaine MA, et al: Antitumoralactivity of oxaliplatin/cisplatin-based combination therapy incisplatin-refractory germ cell cancer patients. J Cancer Res Clin Oncol125:707-711, 1999.

59. Hess S, Blackstock W: Oxaliplatin: In vitro and in vivoevidence of its radiation sensitizing activity-preclinical observations relevantto ongoing clinical trials (abstract 335). Proc Am Assoc Cancer Res 41:53a,2000.

60. Lawley, PD, Phillips DH: DNA adducts from chemotherapeuticagents. Mutat Res 355:13-40, 1996.

61. Reed E: Platinum-DNA adduct, nucleotide excision repair, andplatinum based anti-cancer chemotherapy. Cancer Treat Rev 24:331-344, 1998.

62. De Laat WL, Jaspers NG, Hoeijmakers JH: Molecular mechanismof nucleotide excision repair. Genes Dev 13:768-785, 1999.

63. Wood, RD: Nucleotide excision repair in mammalian cells. JBiol Chem 272:23465-23468, 1997.

64. Roy R, Adamczewski JP, Seroz T, et al: The MO15 cell cyclekinase is associated with the TFIIH transcription-DNA repair factor. Cell79:1093-1101, 1994.

65. Zhen W, Evans M K, Haggerty CM, et al: Deficient genespecific repair of cisplatin-induced lesions in Xeroderma pigmentosum andFanconi’s anemia cell lines. Carcinogenesis 14:919-924, 1993.

66. Jones JC, Zhen WP, Reed E: Gene-specific formation andrepair of cisplatin intrastrand adducts and interstrand cross-links in Chinesehamster ovary cells. J Biol Chem 266:7101-7107, 1991.

67. States JC, Reed E: Enhanced XPA mRNA levels incisplatin-resistant human ovarian cancer are not associated with XPA mutationsor gene amplification. Cancer Lett 108:233-237, 1996.

68. Zeng-Rong N, Paterson J, Alpert L, et al: Elevated DNArepair capacity is associated with intrinsic resistance of lung cancer tochemotherapy. Cancer Res 55:4760-4764,1995.

69. Chao CC: Cross-resistance tocis-diamminedichloroplatinum(II) of a multidrug-resistant lymphoma cell lineassociated with decreased drug accumulation and enhanced DNA repair. Eur JPharmacol 305:213-222, 1996.

70. Chao, CC: Enhanced excision repair of DNA damage due to cis-diamminedichloroplatinum(II) in resistant cervix carcinoma HeLa cells. Eur JPharmacol 268:347-355, 1994.

71. Eastman A, Schulte N: Enhanced DNA repair as a mechanism ofresistance to cis-diamminedichloroplatinum(II). Biochemistry 27:4730-4734, 1988.

72. Lee KB, Parker RJ, Bohr V, et al: Cisplatinsensitivity/resistance in UV repair-deficient Chinese hamster ovary cells ofcomplementation groups 1 and 3. Carcinogenesis 14:2177-2180, 1993.

73. Li Q, Bostick-Bruton F, Reed E: Effect of interleukin-1alpha and tumour necrosis factor-alpha on cisplatin-induced ERCC-1 mRNAexpression in a human ovarian carcinoma cell line. Anticancer Res 18:2283-2287,1998.

74. Li Q, Gardner K, Zhang L, et al: Cisplatin induction ofERCC-1 mRNA expression in A2780/CP70 human ovarian cancer cells. J Biol Chem273:23419-23425, 1998.

75. Damia G, Guidi G, D’Incalci M: Expression of genesinvolved in nucleotide excision repair and sensitivity to cisplatin andmelphalan in human cancer cell lines. Eur J Cancer 34:1783-1788, 1998.

76. Cleaver JE, States JC: The DNA damage-recognition problem inhuman and other eukaryotic cells: The XPA damage binding protein. Biochem J328:1-12, 1997.

77. De Vries A, van Oostrom CT, Hofhuis FM, et al: Increasedsusceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excisionrepair gene XPA. Nature 377:169-173, 1995.

78. Reese DM, Slamon DJ: HER-2/neu signal transduction in humanbreast and ovarian cancer. Stem Cells 15:1-8, 1997.

79. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer:Correlation of relapse and survival with amplification of the HER-2/neuoncogene. Science 235:177-182, 1987.

80. Hung MC, Lau YK: Basic science of HER-2/neu: A review. SeminOncol 26:51-59, 1999.

81. Hynes NE, Stern DF: The biology of erbB-2/neu/HER-2 and itsrole in cancer. Biochem Biophys Acta 1198:165-184, 1994.

82. Sliwkowski MX, Lofgren JA, Lewis GD, et al: Nonclinicalstudies addressing the mechanism of action of trastuzumab (Herceptin). SeminOncol 26:60-70, 1999.

83. Pietras RJ, Fendly BM, Chazin VR, et al: Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovariancancer cells. Oncogene 9:1829-1838, 1994.

84. Pietras RJ, Pegram MD, Finn RS, et al: Remission of humanbreast cancer xenografts on therapy with humanized monoclonal antibody to HER-2receptor and DNA-reactive drugs. Oncogene 17:2235-2249, 1998.

85. Pegram M, Hsu S, Lewis G, et al: Inhibitory effects ofcombinations of HER-2/neu antibody and chemotherapeutic agents used fortreatment of human breast cancers. Oncogene 18:2241-2251, 1999.

86. Pegram MD, Lipton A, Hayes, DF, et al: Phase II study ofreceptor-enhanced chemosensitivity using recombinant humanized anti-p185 HER2/neu monoclonal antibody plus cisplatin in patients withHER2/neu-overexpressing metastatic breast cancer refractory to chemotherapytreatment. J Clin Oncol 16:2659-2671, 1998.

87. Pegram MD, Slamon DJ: Combination therapy with trastuzumab(Herceptin) and cisplatin for chemoresistant metastatic breast cancer: Evidencefor receptor-enhanced chemosensitivity. Semin Oncol 26:89-95, 1999.

88. Tsai CM, Chang KT, Perng RP, et al: Correlation of intrinsicchemoresistance of non-small-cell lung cancer cell lines with HER-2/neu geneexpression but not with ras gene mutations. J Natl Cancer Inst 85:897-901, 1993.

89. Tsai CM, Yu D, Chang KT, et al: Enhanced chemoresistance byelevation of p185neu levels in HER-2/neu- transfected human lung cancer cells. JNatl Cancer Inst 87:682-684, 1995.

90. Reardon JT, Vaisman A, Chaney SG, et al: Efficientnucleotide excision repair of cisplatin, oxaliplatin, andbis-aceto-amine-dichloro-cyclohexylamine-platinum (IV) (JM216) platinumintrastrand DNA diadducts. Cancer Res 59: 3968-3971, 1999.

91. Dixit M, Yang JL, Poirier MC, et al: Abrogation ofcisplatin-induced programmed cell death in human breast cancer cells byepidermal growth factor antisense RNA (see comments). J Natl Cancer Inst89:365-373, 1997.

92. Zhang L, Hung MC: Sensitization of HER-2/neu-overexpressingnon-small-cell lung cancer cells to chemotherapeutic drugs by tyrosine kinaseinhibitor emodin. Oncogene 12:571-576, 1996.