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Clinical Cancer Research Vol. 6, 1574-1578, April 2000
© 2000 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

The New Dioxolane, (-)-2'-Deoxy-3'-oxacytidine (BCH-4556, Troxacitabine), Has Activity against Pancreatic Human Tumor Xenografts1

Steve Weitman2, Jennifer Marty, Jacques Jolivet, Celine Locas and Daniel D. Von Hoff

The Institute for Drug Development, Cancer Therapy & Research Center, San Antonio, Texas 78245 [S. W., J. M., D. D. V. H.]; The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229 [S. W., D. D. V. H.]; and BioChem Pharma, Inc., Laval, Quebec, Canada H7V 4A7 [J. J., C. L.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
There is a great need for new therapeutic agents for patients with advanced pancreatic cancer. The new dioxolane analogue troxacitabine was evaluated in two human pancreatic cancer xenograft models. The models used included the Panc-01 and MiaPaCa pancreatic cancer cell lines. Whereas there is certainly no absolute evidence that either of the in vivo models is predictive for clinical activity, there is at least some evidence that they may be helpful in selecting agents for clinical trials in patients with pancreatic cancer. Troxacitabine was administered i.v. to the animals at doses of 10 and 25 mg/kg on a daily x 5 regimen. Gemcitabine was used as a positive control. The end points for the study included tumor growth inhibition (TGI), final weight, and the number of partial and complete tumor responses in the animals. Troxacitabine was highly active against the Panc-01 model (n = 8), with TGI levels of 88.5% and 84.3% at the 10 and 25 mg/kg doses, respectively. The mean final tumor weights for animals given troxacitabine were also significantly smaller (P < 0.001) compared with vehicle controls. At the 10 mg/kg dose, there were three partial tumor shrinkages and one complete tumor shrinkage, whereas at the 25 mg/kg dose, there were three partial tumor shrinkages. Troxacitabine had less activity against the MiaPaCa model (n = 10) and, by traditional response criteria, would be considered inactive, with TGIs of 4% and 22.7% at the 10 and 25 mg/kg dose level, respectively. Of note is that in comparison with gemcitabine, troxacitabine was more efficacious against Panc-01 and was equally active against MiaPaCa. These in vivo results are encouraging and support the prospect of performing Phase II and perhaps Phase III trials with troxacitabine in patients with advanced pancreatic cancer.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
There is a great need for new therapeutics for patients with advanced pancreatic cancer, which is still an almost uniformly fatal disease (1) . One way of developing new therapeutic agents against pancreatic cancer is to evaluate newly discovered agents (particularly agents with a novel mechanism of action) against human pancreatic cancer cell lines growing as xenografts in nude mice. A question in the past has been just what pancreatic cancer models are predictive for subsequent clinical activity. Based on recent findings, there may now be some in vivo models that can help predict for the clinical usefulness of some agents against the disease. Schultz et al. (2) have evaluated a number of compounds against pancreatic cancer xenografts growing in nude mice. Two pancreatic cancer models, including the Panc-01 and the MiaPaCa human xenografts, indicated that the agent gemcitabine had more activity against this tumor type than Adriamycin, cisplatin, or 5-FU.3

Whereas the activity of gemcitabine against the models was modest, at best, in vivo activity (plus the in vitro activity against human tumor colony-forming units; Ref. 3 ) was one of the reasons gemcitabine was tested in Phase II clinical trials in patients with advanced pancreatic cancer. In Phase II trials, gemcitabine demonstrated response rates in the range of 7–13% (4, 5, 6, 7) . This very minor response rate for gemcitabine was followed up with a randomized trial comparing gemcitabine with 5-FU. In that study in patients with advanced pancreatic cancer, gemcitabine was found to confer a slight but significant improvement in median survival [5.65 versus 4.41 months (P = 0.0025)], time to tumor progression [3.2 months for gemcitabine versus 1.0 month for 5-FU (P = 0.002)], and an improvement in the 1-year survival rate (18% for gemcitabine versus 2% for the 5-FU control group). The conventional response rates were 5.4% for patients receiving gemcitabine versus 0% for patients receiving 5-FU (8) . Therefore, although the efficacy of gemcitabine against pancreatic cancer is modest, the compound did have clinical activity. That modest activity was also noted in the Panc-01 and in the MiaPaCa xenograft models (2) . Therefore, if a new compound was tested in those two in vivo systems and had significant activity in either of those in vivo models, that compound should probably proceed on to Phase II or Phase III clinical trials. Whereas there is certainly no absolute evidence that either of the in vivo models is predictive for clinical activity, there is at least some evidence that they may be helpful in selecting agents for clinical trials in patients with pancreatic cancer.

Troxacitabine [(-)-2'-deoxy-3'-oxacytidine] is a dioxolane (see Fig. 1Citation ). All naturally occurring nucleosides and the majority of nucleoside analogues, which have been synthesized as antiviral or as anticancer agents, are in the ß-D stereochemical configuration. Recently, however, a number of L-enantiomers of nucleosides, particularly the dideoxycytidine analogues, have been found to have significant clinical activity against the HIV and the hepatitis B virus (9 , 10) . Recently, Grove et al. (11) described the anticancer activity of the dioxolane analogue troxacitabine. Troxacitabine undergoes phosphorylation intracellularly to its mono-, di-, and triphosphates. The triphosphate is subsequently incorporated into DNA, but not into RNA (11 , 12) . Although it has an unnatural stereochemistry, the triphosphate of troxacitabine is a good substrate for DNA polymerases (13) . Sufficient intracellular levels of the triphosphate are achievable and are retained in tumor cells for inhibition of the DNA polymerases (11 , 12) .



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  		Fig. 1. Structure of troxacitabine.

 
Troxacitabine is similar to 1-ß-D-arabinofuranosylcytosine and 2',2'-difluorodeoxycytidine (gemcitabine) in that the monophosphorylation of troxacitabine is catalyzed by deoxycytidine kinase (11 , 14) . However, unlike 1-ß-D-arabinofuranosylcytosine and gemcitabine, the L configuration confers on troxacitabine a resistance to degradation to its inactive form by deoxycytidine deaminase. Troxacitabine is also different from gemcitabine in that it does not inhibit ribonucleotide reductase.

Grove et al. (11) found that troxacitabine had activity against multiple types of human tumor cell lines including the DU-145 and PC-3 prostate cancer cell lines, hepatocellular carcinomas HepG2 and 2.2.15, and the KB nasopharyngeal carcinoma cell line. Of note, based on activity against a P-glycoprotein-positive HL-60 promyelocytic leukemia cell line, it does not appear that troxacitabine is a substrate for P-glycoprotein (15) . Recently, Siu et al. (16) published information on the activity of troxacitabine against human tumor colony-forming units taken directly from patients and growing in a human tumor cloning assay. They noted in vitro activity of troxacitabine against ovarian, renal, and melanoma colony-forming units. In addition, in paired specimen experiments, continuous exposure to the agent appeared to be more active than a 1-h exposure to the agent.

Several investigators have explored the in vivo activity of troxacitabine. Activity has been documented against murine P388 leukemia and against murine colon 38 adenocarcinoma. In addition, the agent has activity against the DU-145 prostate cancer cell line and HepG2 hepatocellular carcinoma human tumor xenografts growing in nude mice and has remarkably good activity against the CAKI-1, A498, RXF-393, and SN12C renal cell xenografts (11 , 17 , 18) . In some of these models, troxacitabine caused complete regressions of the tumors. In addition to the above-mentioned models, Rabbani et al. (19) noted marked activity of troxacitabine in the syngeneic Mat-LyLu rat prostate cancer model. It is noteworthy that in the models in which it was studied, regimens of frequent low doses produced antitumor activity that was superior to the antitumor activity noted with single high-dose bolus injections (18 , 20) . It is of importance that careful pharmacokinetic studies in a murine system (14) have indicated that the plasma concentrations achieved in the animal model are those that have activity in the various in vitro systems (11 , 16) .

The significant antitumor activity of troxacitabine against so many refractory tumor types is of great interest and caused us to examine the activity of the agent against the very refractory human pancreatic cancer cell lines Panc-01 and MiaPaCa.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Troxacitabine was provided by BioChem Pharma, Inc. (Laval, Quebec, Canada). It was dissolved in 0.9% saline to make the i.v. solutions for administration. Gemcitabine was obtained from Eli Lilly Co. (Indianapolis, IN). It was dissolved in 0.9% saline to make the i.v. solutions for administration.

Nude mice (Nu/Nu) were obtained from Harlan Sprague Dawley (Indianapolis, IN).

The Panc-01 and the MiaPaCa human pancreatic cancer cell lines were obtained from the American Type Culture Collection (Manassas, VA).

All of these studies were performed with the prior approval of the Institutional Animal Care Program of The University of Texas Health Science Center at San Antonio. For the Panc-01 studies, female nude mice were implanted s.c. by trocar with fragments of Panc-01 harvested from s.c. growing tumors in nude mice hosts. When tumors were 5 x 5 mm in size (21 days after inoculation), the animals were pair-matched into treatment and control groups. Each group contained eight tumor-bearing mice, each of which was ear-tagged and followed individually throughout the experiment. The administration of vehicle and drugs began on the day the animals were pair-matched (designated day 1).

For the MiaPaCa studies, female nude mice were implanted s.c. by trocar with fragments of MiaPaCa harvested from s.c. growing tumors in nude mice hosts. When tumors were 5 x 5 mm in size (17 days after inoculation), the animals were pair-matched into treatment and control groups. Each group contained 10 tumor-bearing mice, each of which was ear-tagged and followed individually throughout the experiment. The administration of vehicle and drugs began on the day the animals were pair-matched (designated day 1).

In both models, troxacitabine was administered i.v. at 10 and 25 mg/kg on a daily x 5 schedule. These doses were selected based on prior in vivo experience with the agent (18 , 20) . The positive control, gemcitabine, was administered i.p. at 40 and 80 mg/kg on an every third day x 4 schedule. The doses and schedule for gemcitabine were selected as the optimal doses and most effective schedule based on prior experience with gemcitabine in these in vivo models. Therefore, no formal determination of the maximum tolerated dose for either gemcitabine or troxacitabine was conducted as part of this study.

Mice were weighed twice weekly, and tumor measurements were taken by calipers twice weekly, starting on day 1. These tumor measurements were converted to milligrams of tumor weight by a well-known formula (21 , 22) , 1/2 W2 x L, and the termination date was determined when control tumors had a calculated weight of 1 g. On termination, all mice were weighed and sacrificed, and their tumors were excised. Tumors were weighed, and the mean tumor weight/group was calculated. In these models, the mean treated tumor weight/mean control tumor weight x 100% is subtracted from 100% to give the TGI for each group. Animals experiencing partial tumor shrinkage were excluded from the determination of TGI.

Tumor shrinkage is calculated for individual animals as the initial tumor weight (day 1) minus the final tumor weight (21 , 22) . The difference divided by the initial tumor weight is the percentage of shrinkage. A partial shrinkage was defined as any reduction in the actual final tumor weight compared to the calculated day 1 tumor weight (0% < percentage of tumor reduction < 100%), whereas a complete shrinkage required disappearance of the tumor (percentage of tumor reduction = 100%). For those animals experiencing partial shrinkage, the mean percentage of partial tumor shrinkage was calculated.

The significance of differences in mean tumor weights was evaluated using primarily the log-rank P test.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
MiaPaCa Xenograft Results.
Table 1Citation and Fig. 2Citation detail the specific MiaPaCa results. Troxacitabine was weakly active against the MiaPaCa tumor model with a TGI of 4% and 22.7% at 10 and 25 mg/kg, respectively. Administration of troxacitabine did not significantly decrease the final mean tumor weights compared to vehicle. In addition, there were no partial or complete tumor shrinkages at either dose of troxacitabine. Troxacitabine was well tolerated with no toxic deaths or substantial weight loss. It is noteworthy that gemcitabine was also weakly active against the MiaPaCa tumor model with TGIs of 21% and 12.9% at 40 and 80 mg/kg, respectively.


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  		Table 1 Troxacitabine versus MiaPaCa human pancreatic cancer tumor xenograft

 


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  		Fig. 2. Activity of troxacitabine and gemcitabine against the MiaPaCa human pancreatic tumor xenograft. {blacksquare}, control; gray diamond, troxacitabine, 10 mg/kg, qd x 5; gray circle, troxacitabine, 25 mg/kg; qd x 5; gray triangle, gemcitabine, 40 mg/kg, q3d x 4; , gemcitabine, 80 mg/kg, q3d x 4.

 
Panc-01 Xenograft Results.
Table 2Citation and Fig. 3Citation detail the specific Panc-01 results. Troxacitabine was highly active against the Panc-01 tumor model with a TGI of 88.5% and 84.3% at 10 and 25 mg/kg, respectively. The mean tumor weights for animals given troxacitabine were significantly smaller (P < 0.001; 102.5 mg at the 10 mg/kg dose level and 131.4 mg at the 25 mg/kg dose level versus 935.0 mg for the vehicle control) compared with vehicle controls. At the 10 mg/kg dose level, there were three partial shrinkages (mean shrinkage = 47.9%) and one complete shrinkage, whereas at the 25 mg/kg dose level, there were three partial shrinkages (mean shrinkage = 70.5%). Importantly, troxacitabine was well tolerated, with no toxic deaths or substantial weight loss (see Table 2Citation ). In comparison, the antitumor activity of gemcitabine was borderline, with a TGI of 24.0% at a dose of 80 mg/kg (see Table 2Citation ).


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  		Table 2 Troxacitabine versus Panc-01 human pancreatic cancer tumor xenograft

 


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  		Fig. 3. Activity of troxacitabine and gemcitabine against the Panc-01 human pancreatic tumor xenograft. {blacksquare}, control; gray diamond, troxacitabine, 10 mg/kg, qd x 5; gray circle, troxacitabine, 25 mg/kg, qd x 5; gray triangle, gemcitabine, 40 mg/kg, q3d x 4; , gemcitabine, 80 mg/kg, q3d x 4.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
These studies have shown that troxacitabine has very high antitumor activity against the Panc-01 xenograft, which was superior to the activity of gemcitabine studied at the same time in the same model. Tumor shrinkage in that model was particularly encouraging. The activity of troxacitabine was not as good against the MiaPaCa cell line, but it did parallel the effect noted with gemcitabine studied simultaneously in the same model. However, it should be noted that in at least one prior report, gemcitabine appeared more efficacious against these tumor models than what was observed in this study (23) . In this regard, the dose of gemcitabine administered in this study against the Panc-01 model was lower than that used in the earlier report.

As noted above, there is not enough prospective evaluation of compounds in the Panc-01 and MiaPaCa pancreatic xenograft models to indicate that they are indeed predictive for agents that will or will not work in patients with pancreatic cancer. However, the clinical information that gemcitabine can induce remissions and improve the median and 1-year survival rates for patients with pancreatic cancer (as compared with 5-FU), combined with the fact that gemcitabine has some activity in these models (albeit modest, as are the clinical results with gemcitabine), gives some hope that troxacitabine, which has activity that is superior to gemcitabine in one model and equal to it in another model, will also have some activity in the clinic.

There have not been any other in vitro or in vivo data published on the activity of troxacitabine against human pancreatic cancer cell lines. In the only primary human pancreatic cancer tested in the human tumor cloning assay, no in vitro activity was noted against the one specimen with concentrations of troxacitabine of 0.1, 1.0, and 10.0 µg/ml as a continuous exposure (16) .

Troxacitabine has completed Phase I trials in patients with solid tumors using three different schedules including a single 30-min i.v. infusion once every 3 weeks by the National Cancer Institute of Canada Clinical Trials Group (24) , a 30-min infusion daily for 5 days repeated every 4 weeks in San Antonio (25 , 26) , and a 30-min i.v. infusion on a weekly schedule for 3 consecutive weeks followed by 1 week of rest performed by the Yale Group (27) . In addition, Giles et al. (28) are performing a Phase I trial of troxacitabine in patients with advanced acute leukemia. The once-every-3-weeks schedule has now been taken into eight Phase II pilot trials, including one in patients with advanced pancreatic cancer.


   ACKNOWLEDGMENTS
 
We thank Dr. Sue Hilsenbeck for statistical analyses of the results and Laida Garcia for preparation of the manuscript. This article is dedicated to the memory of Aunt Jane Wilcox, who passed away from pancreatic cancer as the manuscript was being prepared.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by BioChem Pharma, Inc. Back

2 To whom requests for reprints should be addressed, at Institute for Drug Development, 14960 Omicron Drive, San Antonio, TX 78245. Phone: (210) 677-3800; Fax: (210) 677-3853; E-mail: sweitman{at}saci.org Back

3 The abbreviations used are: 5-FU, 5-fluorouracil; TGI, tumor growth inhibition; qd x 5, daily for 5 days; q3d x 4, every third day for four doses. Back

Received 9/ 2/99; revised 1/12/00; accepted 1/13/00.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Landis S. H., Murray T., Bolden S., Wingo P. A. Cancer statistics, 1999. CA Cancer J. Clin., 49: 8-31, 1999.[Abstract/Free Full Text]
  2. Schultz R. M., Merriman R. L., Toth J. E., Zimmermann J. E., Hertel L. W., Andis S. L., Dudley D. E., Rutherford P. G., Tanzer L. R., Grindey G. B. Evaluation of new anticancer agents against MIA PaCa-2 and PANC-1 human pancreatic carcinoma xenografts. Oncol. Res., 5: 223-228, 1993.[Medline]
  3. Hanauske A. R., Degen D., Marshall M. H., Hilsenbeck S. G., Grindey G. B., Von Hoff D. D. Activity of 2',2'-difluorodeoxycytidine (gemcitabine) against human tumor colony forming units. Anticancer Drugs, 3: 143-146, 1992.[Medline]
  4. Casper E. S., Green M. R., Kelsen D. P., Heelan R. T., Brown T. D., Flombaum C. D., Trochanowski B., Tarossoff R. G. Phase II trial of gemcitabine (2, 2'-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Investig. New Drugs, 12: 29-34, 1994.[CrossRef][Medline]
  5. Rothenberg M. L., Moore M. J., Cripps M. C., Andersen J. S., Portenoy R. K., Burris H. A., III, Green M. R., Tarassoff P. G., Brown T. D., Casper E. S., Storniolo A-M., Von Hoff D. D. A Phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann. Oncol., 7: 347-353, 1996.[Abstract/Free Full Text]
  6. Carmichael J., Fink N., Russell R. C., Spittle M. F., Harris A., Spiessel G., Blotter J. Phase II study of gemcitabine in patients with advanced pancreatic cancer. Proc. Am. Soc. Clin. Oncol., 12: A698 1993.
  7. Tempero M., Capadano M., Tarassoff P. Dose escalation of gemcitabine in previously untreated patients with pancreatic adenocarcinoma. Proc. Am. Soc. Clin. Oncol., 13: 218 1994.
  8. Burris H. A., III, Moore M. J., Andersen J., Green M. R., Rothenberg M. L., Modiano M. R., Cripps M. C., Portenoy R. K., Storniolo A. M., Tarrassoff P., Nelson R., Von Hoff D. D. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol., 15: 2403-2413, 1997.[Abstract/Free Full Text]
  9. Coates J. A., Cammack N., Jenkinson H. J., Multon I. M., Pearson B. A., Slorer R., Cameron J. M., Penn C. R. The separated enantiomers of 2'-deoxy-3'-thiacytidine (BCH-189) both inhibit human immunodeficiency virus replication in vitro. Antimicrob. Agents Chemother., 36: 202-205, 1992.[Abstract/Free Full Text]
  10. Lin T. S., Luo M. J., Liu M. C., Pai G., Cutschman G. E., Cheng Y. C. Antiviral activity of 2',3' dideoxy-ß-L-5 fluorocytidine (ß-L-FddC) against hepatitis ß virus and human immunodeficiency virus type I in vitro. Biochem. Pharmacol., 47: 171-174, 1994.[CrossRef][Medline]
  11. Grove K. L., Guo X., Liu S-H., Gao Z., Chu C. K., Chen Y-C. Anticancer activity of ß-L-dioxolane-cytidine, a novel nucleoside analogue with the unnatural L configuration. Cancer Res., 55: 3008-3018, 1995.[Abstract/Free Full Text]
  12. Grove K. L., Cheng Y-C. Uptake and metabolism of the new anticancer compound ß-L-(-)-dioxolane-cytidine in human prostate carcinoma DU-145 cells. Cancer Res., 56: 4187-4191, 1996.[Abstract/Free Full Text]
  13. Kukhanova M., Liu S-H., Mozzherin D., Lin T. S., Chu C. K., Cheng Y. C. L- and D-enantiomers of 2',3'-dideoxycytidine 5'-triphosphate analogs as substitutes from human DNA polymerase. J. Biol. Chem., 270: 23055-23059, 1995.[Abstract/Free Full Text]
  14. Moore L. E., Boudinot F. D., Chu C. K. Preclinical pharmacokinetics of ß-L-dioxolane-cytidine, a novel anticancer agents in rats. Cancer Chemother. Pharmacol., 39: 532-536, 1997.[CrossRef][Medline]
  15. Bowlin T., Genne P., Kadhim S., Gourdeau H., Attardo G. A novel cytidine nucleoside analogue, BCH 4556, with potent activity against human anthracycline-resistant leukemia. Proc. Am. Assoc. Cancer Res., 38: 100 1997.
  16. Siu L. L., Attardo G., Izbicka E., Lawrence R., Cerna C., Gomez L., Davidson K., Finkle C., Marsolais C., Rowinsky E. K., Von Hoff D. D. Activity of (-)-2'deoxy-3'-oxacytidine (BCH-4556) against human tumor colony-forming units. Ann. Oncol., 9: 885-891, 1998.[Abstract/Free Full Text]
  17. Grove K. L., Kukhanova M., Liu S. H., Guo X., Qu F., Chu C. K., Chen Y-C. Antitumor activity and biochemical pharmacology of L-(-)-dioxolane-C. Proc. Am. Assoc. Cancer Res., 36: 396 1995.
  18. Kadhim S. A., Bowlin T., Waud W. R., Angers E. G., Bibeau L., DeMuys J. M., Bednarski K., Cimpoia A., Attardo G. Potent antitumor activity of a novel nucleoside analogue, BCH-4556 (ß-L-dioxolane-cytidine), in human renal cell carcinoma xenograft tumor models. Cancer Res., 57: 4803-4810, 1997.[Abstract/Free Full Text]
  19. Rabbani S. A., Harakidas P., Bowlin T., Attardo G. Prevention of prostate cancer progression and metastasis by a novel nucleoside analogue. Proc. Am. Assoc. Cancer Res., 38: 100 1997.
  20. Attardo G., Kadhim S., Angers E., Bibeau L., Bowlin L. Dose scheduling effects on the antitumor activity of BCH-4556 against human tumor xenografts in nude mice. Proc. Am. Assoc. Cancer Res., 38: 100 1997.
  21. MacDonald J. R., Muscoplat C. C., Dexter D. L., Mangold G. L., Chen S., Kelner M. J., McMorris T. C., Von Hoff D. D. Preclinical antitumor activity of 6-hydroxymethyacylfulvene, a semisynthetic derivative of the mushroom toxin illudin S. Cancer Res., 57: 279-283, 1997.[Abstract/Free Full Text]
  22. Britten C. D., Hilsenbeck S. G., Eckhardt S. G., Marty J., Mangold G., MacDonald J. R., Rowinsky E. K., Von Hoff D. D., Weitman S. Enhanced antitumor activity of 6-hydroxymethylacylfulvene in combination with irinotecan and 5-fluorouracil in the HT29 human colon tumor xenograft model. Cancer Res., 59: 1049-1053, 1999.[Abstract/Free Full Text]
  23. Merriman R. L., Hertel L. W., Schultz R. M., Houghton P. J., Houghton J. A., Rutherford P. G., Tanzer L. R., Boder G. B., Grindey G. B. Comparison of the antitumor activity of gemcitabine and ara-C in a panel of human breast, colon, lung and pancreatic xenograft models. Investig. New Drugs, 14: 243-247, 1996.[CrossRef][Medline]
  24. Bélanger K., Moore M., Siu L., Dionne J., McLean M., Hunt W., Jolivet J., Wainman N., Seymour L. A Phase I study of the L-nucleoside analogue ß-L-dioxolane-cytidine (BCH-4556) given as a 30 minute infusion every 21 days. Proc. Am. Soc. Clin. Oncol., 18: 197a 1999.
  25. Stephenson J., Jr., Baker S. D., Johnson T., Simmons C., Smith L., Hunt W., Deforges C., Proulx L., Jolivet J., Hidalgo M., Eckhardt S. G., Hammond L., Diab S., Smith L., Von Hoff D., Rowinsky E. A Phase I and pharmacokinetic (PK) study of ß-L-dioxolan-cytidine (BCH-4556), an L-nucleoside antimetabolite on a daily x 5-day every 3-week schedule. Proc. Am. Soc. Clin. Oncol., 18: 198a 1999.
  26. Baker S. D., Stephenson J., Goetz A., Bélanger K., Moore M., Seymour L., Yee L., Chu E., Hunt W., Jolivet J., Rowinsky E. Determinants affecting ß-L-dioxolane-cytidine (BCH-4556) exposure and relationship with toxicity in Phase I trials. Proc. Am. Soc. Clin. Oncol., 18: 197a 1999.
  27. Canova A., Yee L., Baker S., Sarid R., Desforges C., Jolivet J., Hunt W., Tiedemann D., Lillo R., Gaskins A., Chu E. A Phase I and pharmacokinetic (PK) study of ß-L-dioxolo-cytidine (BCH-4556) administered weekly for three weeks every 28 days. Proc. Am. Soc. Clin. Oncol., 18: 197a 1999.
  28. Giles F. J., Cortes J. F., Beran M., Estey E., Proulx L., Jolivet J., Bivins C., Rios M. B., Kantarjian H. Phase I study of BCH4556 in patients with advanced leukemia. Proc. Am. Soc. Clin. Oncol., 18: 28a 1999.



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Mol. Pharmacol., August 1, 2004; 66(2): 285 - 292.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
C.A. Townsley, K. Chi, D.S. Ernst, K. Belanger, I. Tannock, G.A. Bjarnason, D. Stewart, R. Goel, J.D. Ruether, L.L. Siu, et al.
Phase II Study of Troxacitabine (BCH-4556) in Patients With Advanced and/or Metastatic Renal Cell Carcinoma: A Trial of the National Cancer Institute of Canada-Clinical Trials Group
J. Clin. Oncol., April 15, 2003; 21(8): 1524 - 1529.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
S. McKenna and M. Eatock
The Medical Management of Pancreatic Cancer: A Review
Oncologist, April 1, 2003; 8(2): 149 - 160.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
F. J. Giles, S. Faderl, D. A. Thomas, J. E. Cortes, G. Garcia-Manero, D. Douer, A. M. Levine, C. A. Koller, S. S. Jeha, S. M. O'Brien, et al.
Randomized Phase I/II Study of Troxacitabine Combined With Cytarabine, Idarubicin, or Topotecan in Patients With Refractory Myeloid Leukemias
J. Clin. Oncol., March 15, 2003; 21(6): 1050 - 1056.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J.-Y. Liou, G. E. Dutschman, W. Lam, Z. Jiang, and Y.-C. Cheng
Characterization of Human UMP/CMP Kinase and Its Phosphorylation of D- and L-Form Deoxycytidine Analogue Monophosphates
Cancer Res., March 1, 2002; 62(6): 1624 - 1631.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
J. S. de Bono, J. Stephenson Jr, S. D. Baker, M. Hidalgo, A. Patnaik, L. A. Hammond, G. Weiss, A. Goetz, L. Siu, C. Simmons, et al.
Troxacitabine, an L-Stereoisomeric Nucleoside Analog, on a Five-Times-Daily Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Malignancies
J. Clin. Oncol., January 1, 2002; 20(1): 96 - 109.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H. Gourdeau, M. L. Clarke, F. Ouellet, D. Mowles, M. Selner, A. Richard, N. Lee, J. R. Mackey, J. D. Young, J. Jolivet, et al.
Mechanisms of Uptake and Resistance to Troxacitabine, a Novel Deoxycytidine Nucleoside Analogue, in Human Leukemic and Solid Tumor Cell Lines
Cancer Res., October 1, 2001; 61(19): 7217 - 7224.
[Abstract] [Full Text] [PDF]

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