Japanese Journal of Clinical Oncology 30:446-449 (2000)
© 2000 Foundation for Promotion of Cancer Research
Treatment with Paclitaxel Alone Rather than Combination with Paclitaxel and Cisplatin May be Selective for Cisplatin-resistant Ovarian Carcinoma
Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama, Japan
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Background: We have previously reported that paclitaxel (taxol) results in cisplatin sensitization to human ovarian cancer cells with cisplatin resistance in vitro. This study was designed to determine effects of taxol and its combination with cisplatin on growth of cisplatin-sensitive cell line (KF28) and the cisplatin-resistant counterpart (KFr13) in nude mice.
Methods: From 14 days after tumor inoculation treatment was initiated. Taxol (3 mg/kg) and cisplatin (2 mg/kg) were administered i.p. once a week for 5 weeks.
Results: In nude mice bearing cisplatin-sensitive cells (KF28), taxol followed by cisplatin and cisplatin plus taxol inhibited significantly (P < 0.05) the tumor growth rate compared with that in nude mice treated with cisplatin alone or taxol alone and cisplatin followed by taxol. On the other hand, in nude mice bearing cisplatin-resistant KFr13 cells, treatment with taxol alone inhibited completely the tumor growth rate, whereas no schedule-dependent interaction of taxol with cisplatin was observed.
Conclusion: These results suggest that treatment with taxol alone may be superior to combination of taxol with cisplatin in patients with cisplatin-resistant ovarian carcinoma.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
In about 15–20% of advanced ovarian cancer patients, the disease progresses during first–line chemotherapy including platinum compounds or relapses a few months after discontinuation of treatment (1,2). This small group of patients is considered platinum refractory or resistant. The introduction in clinical practice of new drugs for ovarian cancer (chiefly paclitaxel) has offered new therapeutic opportunities for the second-line treatment of non-responder patients after platinum-based schedules. However, the optimum treatment of patients who have recurrent disease remains a major management problem in ovarian cancer. Although most patients now achieve a clinically complete response (CR) after completion of cytoreductive surgery followed by paclitaxel (taxol) plus a platinum compound, most of these patients will ultimately experience recurrence of disease. The results of second-line treatment will depend to a great extent on whether the patient has a drug-sensitive or drug-resistant tumor at the time of relapse. The prognosis of patients with drug-resistant tumor is dismal.
We have reported that taxol results in cisplatin sensitization in cisplatin-resistant cell lines in vitro (3). In a preliminary study, we investigated whether taxol can result in similar results in vivo, subsequently being able to overcome cisplatin resistance.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Cell Lines
KF28 is a single-cell clone of the human ovarian carcinoma cell line KF. KFr13 is a cisplatin-resistant subline derived from KF28 cells. KFr13 subline was isolated initially as a single clone after repeated exposure of the parent KF28 cell line to escalating doses of cisplatin (4). These cell lines were grown as monolayer cultures in RPMI 1640 medium supplemented with 10% fetal bovine serum, 2 mM glutamine, 100 units penicillin and 100 µg/ml streptomycin (Grand Island Biological, Grand Island, NY) in a humidified atmosphere of 5% CO2 at 37°C and were usually subcultured once a week with 0.25% trypsin.
Tumor Implantation in Nude Mice
BALB/c nu/nu female mice 4–6 weeks old were used. All mice were kept in a pathogen-free facility with controlled light–dark cycle, temperature and humidity, under NIH guidelines. Cages, bedding, food and water were all autoclaved prior to use. Cells in preconfluent state were harvested and counted using a hematocytometer. The 5 x 105 cells for KF28 and 106 cells for KFr13 were inoculated s.c. into the right flank after an appropriate state of anesthesia. Although the growth rate of KFr13 tumor was slower than that of KF28 tumor, all mice formed palpable tumor about 1–2 mm in diameter within 7 days after tumor inoculation.
Experimental Design
Cisplatin and taxol were kindly supplied by Bristol-Myers Squibb (Tokyo, Japan). Since a combination of taxol and cisplatin has become widely used as the first-line chemotherapy for primary ovarian cancer in Japan, taxol and cisplatin were selected in the present study. Cisplatin was diluted with medium or saline to the desired concentrations prior to use. Taxol was resuspended in 100% DMSO at a concentration of 20 mM, stored at 4°C and diluted in warmed medium before use. From 14 days after tumor inoculation, treatments were performed as follows: untreated group (n = 5), medium alone was administered intraperitoneally (i.p.) once a week for 5 weeks; taxol (3 mg/kg)-treated group (n = 5), 3 mg/kg paclitaxel alone was administered i.p. once a week for 5 weeks; cisplatin (2 mg/kg)-treated group (n = 5), 2 mg/kg cisplatin alone was administered once a week for 5 weeks; cisplatin (2 mg/kg)
taxol (3 mg/kg)-treated group (n = 5), i.p. administration of 3 mg/kg taxol was performed 3 h after i.p. administration of 2 mg/kg cisplatin and this treatment was repeated once a week for 5 weeks; cisplatin (2 mg/kg) plus taxol (3 mg/kg)-treated group (n = 5), cisplatin and taxol were administered simultaneously i.p. once a week for 5 weeks; taxol (3 mg/kg)cisplatin (2 mg/kg)-treated group, i.p. administration of taxol was performed 3 h before i.p. administration of cisplatin and this treatment was repeated once a week for 5 weeks. Each injection was given in a 0.15 ml volume. Tumor growth was determined by the measurement of the diameter of the tumor nodule in two dimensions with a caliper once a week. The tumor growth rate was calculated with the equation growth rate = treated-tumor volume/untreated-tumor volume. Blood from a tail vein was collected in hematocrit tubes every week and the hematocrit and body weight were recorded for monitoring the side-effects of the drugs. The experiment was terminated 14 days after completion of treatment and the mice were killed using CO2 asphyxiation and then fixed in 10% formalin for subsequent autopsy. The results are presented as means ± SD. Statistical analysis of the results was performed using the Mann–Whitney U-test.
Statistical Analysis
The Mann–Whitney U test and the 
2 test were used for comparison of the effects of treatment on the tumor growth rate.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The effects of cisplatin and taxol on the growth of cisplatin-sensitive cell line (KF28) in nude mice are depicted in Fig. 1. Unless treatment was applied, the tumor showed an exponential growth after 21 days of tumor inoculation. In any treatment group, the growth rate was significantly (P < 0.05) inhibited compared with the untreated group, only during the course of treatment. In the treatment group with taxol alone or cisplatin followed by taxol, inhibition of the growth rate was not maintained after completion of treatment, whereas in the treatment groups with cisplatin alone, cisplatin plus taxol and taxol followed by cisplatin the inhibition was maintained. Especially in the treatment groups with cisplatin plus taxol and taxol followed by cisplatin the growth rate was significantly (P < 0.05) slower than that in not only the untreated group but also in treatment group with taxol alone or cisplatin followed by taxol. On the other hand, in nude mice bearing cisplatin-resistant KFr13 cell line the effect of cisplatin and taxol on the KFr13 tumor growth rate was different from that on the KF28 tumor growth rate (Fig. 2). Naturally, treatment with cisplatin alone had no effect on the KFr13 tumor growth. Surprisingly, treatment with taxol alone inhibited the growth rate completely. Subsequently, any other combination with taxol did not have a more marked inhibitory effect on the tumor growth than taxol alone. It is noteworthy that treatment with taxol alone had no adverse effects on the hematocrit and body weight.
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
We have previously reported that cisplatin-resistant cell line (KFr13) was more sensitive to taxol than the parent cisplatin sensitive cell line (KF28) (4). Judson et al. (5) have demonstrated that cisplatin exerts mechanistic dominance over paclitaxel when cisplatin-sensitive human ovarian cancer cells are simultaneously exposed to cisplatin and paclitaxel in vitro, while it can be detrimental to cisplatin-resistant cells in that it blocks paclitaxel-induced apoptosis. Therefore, we examined the effects of cisplatin and taxol on the tumor transplanted into nude mice using cisplatin-resistant (KFr13) and the parental (KF28) cell lines transplantable to nude mice. As shown in Fig. 1, the cisplatin-sensitive (KF28) tumor in nude mice showed a higher sensitivity to treatment with cisplatin alone than treatment with taxol alone. A schedule-dependent effect of cisplatin and taxol was observed, with an optimal effect of taxol followed by cisplatin. On the other hand, cisplatin-resistant tumor (KFr13) transplanted into nude mice was insensitive to treatment with cisplatin alone, whereas it was sensitive to treatment with taxol alone (Fig. 2). Subsequently, cisplatin treatment combined with taxol and also taxol alone completely inhibited the growth rate, regardless of the treatment schedule of cisplatin and taxol. Therefore, in patients with cisplatin-resistant ovarian carcinoma, treatment with taxol alone should be preferred to prevent additional adverse effects of cisplatin. To the best of our knowledge, this is the first report of such results obtained using a nude mouse model.
Whereas 77% of patients responded to cisplatin and taxol chemotherapy, 23% of ovarian cancer patients had tumors that did not respond (6). These women are given various second-line regimens of chemotherapy in an attempt to prolong life and palliate symptoms. Second-line chemotherapeutic agents are rarely curative, with initial response rate ranging from 10 to 33% (7). However, the majority of patients with ovarian cancers experience a recurrence and fail further chemotherapeutic regimens. In the present study, we have demonstrated that not only a taxol-containing regimen but also taxol alone inhibited the cisplatin-resistant tumor completely. Therefore, when we encounter cases with taxol plus platinum resistance, treatment with taxol alone may be used first for obtaining a platinum-free interval and preventing adverse effects of cisplatin. If we have evidence of more resistance to taxol rather than to cisplatin, treatment with cisplatin alone may be considered. There is now clinical evidence that these patients may respond to subsequent single-agent therapy (8,9). Based on these results, we are planning treatment with taxol alone in patients with failure to respond to cisplatin-based chemotherapy.
|
FOOTNOTES |
|---|
+ For reprints and all correspondence: Yoshihiro Kikuchi, Department of Obstetrics and Gynecology, National Defense Medical College, Namiki 3–2, Tokorozawa, Saitama 359-8513, Japan. E-mail: qwl04765@nifty.ne.jp
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1 Cannistra SA. Cancer of the ovary. N Engl J Med 1993;329:1550–9.
2 Bolis G, Favalli G, Danese S, Zanaboni F, Mangili G, Scarabelli C, et al. Weekly cisplatin given for 2 months versus cisplatin plus cyclophosphamide given for 5 months after cytoreductive surgery for advanced ovarian cancer. J Clin Oncol 1997;15:1938–44.
3 Yamamoto K, Kikuchi Y, Kudoh K, Nagata I. Modulation of cisplatin sensitivity by taxol in cisplatin-sensitive and -resistant human ovarian carcinoma cell lines. J Cancer Res Clin Oncol 2000;126:168–72.[Web of Science][Medline]
4 Kikuchi Y, Miyauchi M, Kizawa I, Oomori K, Katoh K. Establishment of a cisplatin-resistant human ovarian cancer cell line. J Natl Cancer Inst 1986;77:1181–5.
5 Judson PL, Watson JM, Gehrig PA, Fowler WC Jr, Haskill JS. Cisplatin inhibits paclitaxel-induced apoptosis in cisplatin-resistant ovarian cancer cell lines: possible explanation for failure of combination therapy. Cancer Res 1999;59:2425–32.
6 McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1–6.
7 Kita T, Kikuchi Y, Hirata J, Nagata I. Prognosis of ovarian cancers today. Cancer J 1998;11:201–7.
8 Mayerhoffer K, Kucera E, Zeisler H, Speiser P, Reinthealler A, Sevelda P. Taxol as second-line treatment in patients with advanced ovarian cancer after platinum-based first-line chemotherapy. Gynecol Oncol 1997;64: 109–13.[Web of Science][Medline]
9 Fennelly D, Aghajanian C, Shapiro F, O’Flaherty C, McKenzie M, O’Connor C, et al. Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 1997;15:187–92.
Received May 22, 2000; accepted July 18, 2000.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. J. Yoon, J. W. Chung, J. H. Park, Y. H. Yoon, J. W. Lee, S. Y. Jeong, and H. Chung Transcatheter Arterial Chemoembolization with Paclitaxel-Lipiodol Solution in Rabbit VX2 Liver Tumor Radiology, October 1, 2003; 229(1): 126 - 131. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||