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[Cancer Research 59, 1036-1040, March 1, 1999]
© 1999 American Association for Cancer Research

Experimental Therapeutics

A Novel Taxane with Improved Tolerability and Therapeutic Activity in a Panel of Human Tumor Xenografts1

Donatella Polizzi, Graziella Pratesi, Monica Tortoreto, Rosanna Supino, Antonella Riva, Ezio Bombardelli and Franco Zunino2

Division of Experimental Oncology B, Istituto Nazionale Tumori, 20133 Milan [D. P., G. P., M. T., R. S., F. Z.]; and Indena S.p.A., 20139 Milan [A. R., E. B.], Italy


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Clinically available taxanes represent one of the most promising class of antitumor agents, despite several problems with their solubility and toxicity. In an attempt to improve the pharmacological profile of taxanes, a new series of analogues was synthesized from 14ß-hydroxy-10-deacetylbaccatin III and tested in a panel of human tumor cell lines. On the basis of the pattern of cytotoxicity and lack of cross-resistance in tumor cell lines expressing the typical multidrug-resistant phenotype, a compound (IDN5109) was selected for preclinical development. A comparative efficacy study of IDN5109 and paclitaxel was performed using a large panel of human tumor xenografts, characterized by intrinsic (seven tumors) or acquired (four tumors) resistance to cisplatin or doxorubicin, including four ovarian, one breast, one cervical, three lung, one colon, and one prostatic carcinoma. Drugs were delivered i.v. according to the same schedule (four times every 4th day). IDN5109 achieved a very high level of activity (percentage tumor weight inhibition > 70%; log10 cell kill > 1) in all but one of the tested tumors. Compared to paclitaxel, IDN5109 exhibited a significantly superior activity in six tumors (including the four tumors that were resistant to paclitaxel) and a comparable activity against the other five paclitaxel-responsive tumors. Additional advantages of IDN5109 over paclitaxel were also suggested by its toxicity profile. IDN5109 was not only less toxic (maximal tolerated doses were 90 and 54 mg/kg for IDN5109 and paclitaxel, respectively), but it also appeared to be endowed with a reduced neurotoxic potential and an improved profile of tolerability compared to the parent drug. Furthermore, the best antitumor efficacy was often already reached with doses lower than the maximal tolerated dose, suggesting an improved therapeutic index for the new drug. In conclusion, the results support the preclinical interest of IDN5109 in terms of the toxicity profile and of the efficacy with particular reference to the ability to overcome multiple mechanisms of drug resistance.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Taxanes have emerged as one of the most important classes of antitumor agents developed over the last two decades. Evidence of an impressive efficacy of paclitaxel and its analogue, docetaxel, in the treatment of a large number of human tumors has renewed interest in antimicrotubule agents (1) . However, taxanes are characterized by a unique mechanism of action because they promote assembly of microtubules and inhibit tubulin depolymerization (2) . The binding site to tubulin differs from that of Vinca alkaloids and may explain some peculiar features of this novel class of tubulin inhibitors. Relevant drawbacks of the clinically available taxanes are: (a) water insolubility, requiring the use of specific vehicles responsible for major hypersensitivity reactions; (b) dose-limiting toxicities; and (c) the development of resistance mechanisms (1) . Cellular resistance to taxanes has been related to the MDR3 phenotype mediated by the multidrug transporter P-glycoprotein, alterations in tubulins, and changes in expression of apoptotic regulatory proteins (3) .

To identify new active molecules endowed with increased solubility and improved tolerability, a series of taxanes derived from 14ß-hydroxy-10-deacetylbaccatin III has been synthesized (4) . A new compound of the series, IDN5109 (Fig. 1)Citation , was selected for its ability to overcome resistance in cell lines expressing the MDR phenotype. Here, we present the preclinical profile of the antitumor activity of IDN5109 against a large panel of human tumor xenografts chosen for their resistance to the clinically effective drugs doxorubicin and cisplatin. The efficacy of IDN5109 was always compared to that of paclitaxel, the most clinically used taxane (1 , 5) . The results support an improved antitumor activity and potential advantages of the novel analogue, in terms of tolerability at effective dose levels.



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  		Fig. 1. Chemical structure of the taxane analogue, IDN5109.

 

   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Drugs.
Paclitaxel, docetaxel, and a series of five paclitaxel analogues derived from 14ß-hydroxy-10-deacetylbaccatin III were synthesized as reported previously (4 , 6) .

In Vitro Cytotoxicity.
Human tumor cell lines were used throughout the study, i.e., an ovarian carcinoma (A2780), a small cell lung carcinoma (POVD), and their corresponding sublines with acquired resistance to doxorubicin, A2780/DX and POVD/DX, respectively. All cell lines were maintained in RPMI 1640 supplemented with 10% FCS at 37°C in a 5% CO2 atmosphere.

For cytotoxicity assay, drugs were dissolved in ethanol and then diluted in culture medium. Exponentially growing A2780 and A2780/DX cells were seeded in six-well plates; 24 h after seeding, cells were exposed to the drug for 72 h and then trypsinized and counted with a ZBI Coulter counter (Coulter Electronics Ltd., Luton, United Kingdom). Each experimental point represents the mean of three replicates. The small cell lung carcinoma cell lines POVD and POVD/DX, which grow as suspensions, were plated in 96-well plates and treated with drugs 24 h after seeding. After 72 h of exposure to drugs, the MTT assay was carried out. Each experimental point represents the mean of eight replicates. The drug concentration required to inhibit cell growth by 50% (IC50) was determined from the dose-response curves of at least two experiments.

Toxicity Studies.
Healthy athymic Swiss nude mice were used for toxicity study. Drugs were prepared as in antitumor activity studies and given on a schedule of four or six times every fourth day. A single preparation was used for each drug, i.e., 3.6 mg/ml paclitaxel and 6 mg/ml IDN5109. Mice were given different volumes/kg bw, according to the dose to be given. Control mice were injected with the solvent solution (cremophor ELP-ethanol-0.9% NaCl solution, 0.5:0.5:9). Mice were observed for up to 100 days, and the toxicity of the treatment was assessed as follows. (a) Lethal toxicity was defined as any death in treated mice. (b) The difference percentage in mice mean bw after the last treatment (day x) with respect to the beginning of the treatment (day 1) was calculated. Reported maximal BWL values were calculated as: (bw on day x/bw on day 1) x 100. (c) Neurotoxicity was defined as the appearance of neuromotory symptoms (i.e., tremors, ataxia, or paraplegia).

Antitumor Activity Studies.
All experiments were carried out using 10–12-week-old athymic Swiss nude mice (Charles River, Calco, Italy). Mice were maintained in laminar flow rooms with constant temperature and humidity. Experimental protocols were approved by the Ethics Committee for Animal Experimentation of the National Cancer Institute (Milan, Italy) according to the United Kingdom Coordinating Committee on Cancer Research Guidelines (7 , 8) .

The human tumors investigated in the study are reported in Table 1Citation . They were selected to represent different tumor types and different p53 gene status and for their resistance to doxorubicin and/or cisplatin, two clinically active drugs against mammary and ovarian carcinomas.


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  		Table 1 Human tumor models

 
Taxanes were dissolved using the following procedure. Absolute ethanol (5% of the final volume) and Cremophor ELP (5% of the final volume) were added to the drug, in that sequence, on a magnetic stirrer. The solution was stirred until clear and kept at 4°C for 12–24 h. Just before use, it was diluted by slowly adding cold 0.9% NaCl solution (90% of the final volume) while occasionally stirring and cooling the solution on ice. After dilution, drug solutions were always kept on ice. With this procedure, paclitaxel concentration could reach 3.6 mg/ml, whereas IDN5109 was concentrated up to 6 mg/ml, corresponding to 36 and 60 mg/kg, respectively, for a volume of 10 ml/kg of bw. When higher doses were to be given, larger volumes were injected.

For chemotherapy experiments, tumor fragments (~2 x 2 x 2 mm) obtained from tumor lines were used for all tumors except Du145, which was inoculated as a cell suspension from an in vitro cell culture (107 cells/flank). Each control or drug-treated group included five or six mice bearing bilateral s.c. tumors. Tumors were implanted on day 0, and tumor growth was followed by biweekly measurements of tumor diameters with a Vernier caliper. TW was calculated according to the formula: TW (mg) = tumor volume (mm3) = d2 x D/2, where d and D are the shortest and the longest diameters, respectively. Drug treatment started when mean TW was 50–100 mg. All taxanes were administered with a schedule of four times every 3rd or 4th day. Control mice were injected with the solvent solution.

The efficacy of the drug was assessed as follows. (a) TWI% in drug-treated versus control mice was expressed as: TWI% = 100 - (mean TW treated/mean TW control x 100) evaluated usually a week (or a period equal or superior to DT) after the last treatment; values of DT for each tumor line are reported in Table 1Citation . (b) LCK was calculated by the formula: LCK = (T - C)/3.32 x DT, where T and C are the mean times (in days) required for treated and control tumors, respectively, to reach a predetermined weight. A LCK of >1 is indicative of an active compound.

For statistical comparison, TW in paclitaxel- and IDN5109-treated mice was compared on the day of TWI% evaluation. Student’s t test (two-tailed) was used. P <= 0.05 was considered significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
In Vitro Cytotoxicity.
The pattern of cross-resistance of taxane analogues was examined in two pairs of human tumor cell lines, i.e., the ovarian carcinoma A2780 and the small cell lung carcinoma POVD and the corresponding doxorubicin-resistant sublines (A2780/DX and POVD/DX), both positive for P-glycoprotein expression. IDN5109 was the most interesting molecule because it exhibited a cytotoxic potency that was comparable to that of docetaxel and paclitaxel in the parent lines and showed almost no cross-resistance in either MDR cell line. A variable degree of cross-resistance was found for the other tested compounds (Table 2)Citation .


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  		Table 2 Cytotoxicity of taxanesa

 
Toxicity Studies.
Paclitaxel tolerability in experimental animals varies in different reports (9, 10, 11) , and the MTD after i.v. injection seems more dependent on drug solubility than on lethal toxicity (possibly related to myelosuppression). To compare the antitumor effects of the new analogue IDN5109 to that of the parent compound paclitaxel at their optimal doses, a preliminary study in healthy mice was set up to assess the MTD of both drugs according to a every fourth day schedule. In our experience, this schedule was more favorable for paclitaxel activity than the weekly schedule (data not shown). Very marginal BWL occurred with all of the dose levels investigated (Table 3)Citation . Considering the lethal toxicity, the MTDs of IDN5109 and paclitaxel were apparently comparable, i.e., 60 and 54 mg/kg, respectively, with the four times every 4th day schedule. However, paclitaxel at 54 mg/kg caused the immediate death of 2 of 6 mice, possibly related to inadequate solubility. In contrast, no immediate death was observed in animals treated with 60 mg/kg or higher doses of IDN5109, thus suggesting an improved solubility and possible advantages in the formulation. Furthermore, neurotoxicity was observed early in 100% of mice treated with the MTD of paclitaxel. It consisted of neuromotory symptoms (i.e., tremors, ataxia, or paraplegia), which became less severe over time but never completely recovered. In contrast, with IDN5109, neuromotory symptoms were not observed at 60 or at 90 mg/kg. They were only seen at 120 mg/kg and disappeared by day 60. Autonomic neurotoxicity, which instead occurred similarly for both drugs at about 14 days after treatment end, caused impaired intestinal motility and therefore a swollen belly and an increase in bw. Although toxicity-related deaths could be observed with IDN5109 at 90 mg/kg, the significance of the finding is questionable because higher doses are well tolerated. Indeed, the improved tolerability of IDN5109 over paclitaxel was also documented by an increase in the cumulative dose without evidence of toxicity. This feature of IDN5109 is also supported by lack of toxic deaths in tumor-bearing mice (see below). On the basis of these results, for antitumor activity studies, 54 mg/kg paclitaxel and a lower dose (30 or 36 mg/kg) and 60 (or 65) and 90 mg/kg IDN5109 were tested.


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  		Table 3 Toxicity (i.v.) according to every fourth day schedules

 
Antitumor Efficacy Studies.
Table 4Citation shows the comparison of the antitumor effects of IDN5109 and paclitaxel against the panel of human tumor xenografts. The first series is representative of gynecological tumors. Against two human ovarian carcinomas, A2780/DDP and SKOV-3, the optimal antitumor efficacy was high and similar for both taxanes, considering TWI% and LCK values. In contrast, against A2780/DX, IDN5109 was much more active than paclitaxel, as expected from in vitro results (Table 2)Citation . A greater efficacy of IDN5109 was also achieved in an ovarian carcinoma with acquired resistance to cisplatin (IGROV/DDP). A very large range of doses was investigated for IDN5109 in this tumor system, and the activity for all doses was significantly greater than that observed after paclitaxel treatment. The tumor was very resistant to paclitaxel, and response to drug treatment was not affected by dose escalation. In the MX-1 mammary carcinoma and A431 cervical carcinoma, both taxanes achieved complete tumor inhibition. However, paclitaxel cured 100% tumors, whereas in IDN5109-treated groups, only 60% of mice were cured in both tumor systems.


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  		Table 4 Antitumor activity studies

 
Against two non-small cell lung carcinoma lines, CaLu-3 and A549, IDN5109 and paclitaxel were both highly effective. However, against the CaLu-3 tumor, IDN5109 at the doses of 60 and 90 mg/kg showed more efficacy on TWI% (P < 0.005) than paclitaxel at 54 mg/kg. Moreover, in 90 mg/kg-treated mice 40% of tumors were cured and mean TW never reached 500 mg (LCK > 3.7; Fig. 2Citation ). Against the A549 tumor, 90 mg/kg IDN5109 was more effective in maintaining tumor inhibition because it achieved a LCK greater than that of paclitaxel. Some lethal toxicity, which was not dose related, was observed in the experiment. Against the small cell lung carcinoma, POVD/DX, paclitaxel stimulated tumor growth with respect to controls. Nevertheless, IDN5109 exhibited 40% TWI% which, although low, was significantly higher than that of paclitaxel (P < 0.01). A lack of responsiveness of the tumor to paclitaxel was not surprising, considering the high degree of resistance found in the corresponding cell line. The decreased resistance index achieved in vitro by IDN5109 was reflected in a greater antitumor efficacy (Table 2)Citation . A greater antitumor activity of IDN5109 over paclitaxel was also evident in the treatment of the human colon carcinoma LoVo. On this model, the analogue was able to achieve a TWI% of >90% at both doses, whereas paclitaxel did not reach 90% (P < 0.05). A marked difference was seen also in terms of LCK values (3.3 versus 1.5), indicating a slower regrowth of IDN5109-treated tumors (Fig. 2)Citation . The pattern of tumor response is consistent with previous findings that MDR tumors are more responsive to IDN5109. Against the human hormone-independent prostate carcinoma Du145, paclitaxel was active only at the MTD, whereas an excellent efficacy was achieved with IDN5109 at all dose levels.



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  		Fig. 2. Growth curves of human tumor xenografts (CaLu-3 non-small cell carcinoma and LoVo colon carcinoma) after treatment with i.v. taxanes, four times every 3rd or 4th day. x, control; {square}, 60 mg/kg IDN5109; {blacksquare}, 90 mg/kg IDN5109; {circ}, 36 mg/kg paclitaxel; •, 54 mg/kg paclitaxel. Arrows, days of treatment.

 
With regard to the toxicity induced by the two drugs in tumor-bearing mice, from Table 4Citation , it can be seen that they seemed more susceptible than healthy mice to bw reduction (BWL of 0–20% in the different experiments). Despite this effect, all of the doses investigated were well tolerated, without lethal toxicity. IDN5109 (at 90 mg/kg) caused only 1 toxicity-related death of 36 (in the A549 experiment), indicating that this dose level was the MTD for the new drug. This point was particularly relevant, because, from the results achieved on the entire tumor panel (Table 4)Citation , the effects on tumor growth inhibition varied little between different dose levels (Fig. 2)Citation , indicating very flat dose-response curves for both taxanes. Moreover, in all of the tumors in which a clear advantage in antitumor activity was observed for IDN5109 MTD, the difference was maintained even when the two drugs were compared at the same dose level (i.e., 54 mg/kg for paclitaxel and 60 mg/kg for IDN5109).


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of the study support the previous observation that IDN5109 is able to partially overcome resistance mediated by overexpression of P-glycoprotein in cell culture systems (6) . Such an ability was also documented by our in vivo studies using tumor cells growing as tumor xenografts. The results support that, in contrast to paclitaxel, IDN5109 may be a poor substrate for P-glycoprotein. Because tumors that express mdr-1 are likely to be highly resistant to paclitaxel (3 , 12 , 13) , the property of the analogue to overcome the multidrug resistance may have relevant clinical implications.

The pharmacological interest of the selected compound is also supported by the preclinical profile of antitumor activity in a panel of human tumor models representative of a variety of tumor types. Many gynecological tumors were included in the panel, in consideration of the promising activity of paclitaxel in breast and ovarian cancer patients (14, 15, 16, 17) . The tumors were selected for being resistant to doxorubicin (MX-1, A431, and A2780/DX), cisplatin (A2780/DDP and IGROV/DDP), or both drugs (SKOV-3), which are clinically effective for the diseases. The mechanisms implicated in resistance of these tumors remain to be defined, although some biochemical changes may contribute to the resistance status (Table 1)Citation . From the results of the study, IDN5109 was found to be very active (TWI% > 70%, LCK >> 1) against all four ovarian carcinomas tested. An excellent antitumor activity was also evidenced in treatment of the cervical carcinoma A431 and the breast carcinoma MX-1. However, against these two models paclitaxel was even more effective (with 100% cure).

With one exception (POVD/DX, highly resistant to chemotherapy), IDN5109 was found highly efficacious even in all of the other tumors investigated, i.e., two lung (CaLu-3 and A549), one colon (LoVo), and one prostate (Du145) carcinoma. Paclitaxel was less active than IDN5109 in three of them (CaLu-3, LoVo, and Du145) and as active in one (A549). An unexpected finding with paclitaxel treatment was the stimulatory effect of POVD/DX growth, which did not apply to IDN5109-treated tumors, thus confirming differences in the mechanism of cellular response to the two drugs.

In summary, in the panel of 11 human tumor xenografts investigated, the new analogue IDN5109 showed significant improvement in antitumor efficacy over paclitaxel in six of them and a comparable activity in the other five tumor models. These results look very promising for clinical development of IDN5109. In fact, except for docetaxel (Taxotere), which is a very effective semisynthetic taxane now registered for use in breast and ovarian cancer in most countries but which presents important peculiar toxicities such as edema and skin and nail toxicity (18) , a limited number of taxane analogues are under investigation for preclinical antitumor activity profiles (10 , 19) .

An interesting observation of the preclinical evaluation was that, among the tumors significantly more responsive to IDN5109, four (i.e., IGROV/DDP, POVD/DX, CaLu-3 and Du145) are characterized by mutation of the p53 gene. Mutations of p53, which cause cellular resistance to DNA-damaging agents (e.g., cisplatin and doxorubicin) as a consequence of reduced susceptibility to apoptosis (20) , are not associated with resistance to known taxanes (21) . Indeed, tubulin-interacting toxins are able to induce p53-independent apoptosis (22) . Because p53 protein is also involved in regulation of the cell cycle (23) , the role of p53 inactivation in determining sensitivity to taxanes is still under investigation (22 , 24 , 25) . Loss of p53 function may reduce arrest of cells in the G1 phase, thus favoring accumulation of cells in G2-M and sensitization to antimitotic agents (26) . The different responsiveness of the mutant tumors to paclitaxel and IDN5109 again suggests an important role of cellular response to these agents.

A favorable pharmacological profile of IDN5109 is also supported by its improved tolerability in vivo. Despite a comparable or somewhat increased cytotoxic potency of tested taxanes, including IDN5109, the overall toxicity profile of the latter is clearly better than that of paclitaxel. Drug solubility was a limiting factor in dose escalation of IDN5109 because no frankly toxic dose could be administered. At the maximal dose used for antitumor studies (90 mg/kg), IDN5109 produced BWL but very few toxic deaths. Moreover, it was definitely less neurotoxic than paclitaxel MTD (54 mg/kg). Because paclitaxel has been reported to induce cumulative neurotoxicity in clinical studies (27 , 28) , the observation suggests a potential advantage of IDN5109 for clinical use. The molecular mechanisms of Taxol-induced neurotoxicity are still unclear. The lack of significant neurotoxicity of IDN5109 could provide an useful tool for understanding the cellular basis of this toxicity also in relation to the recent finding of drug-mediated specific gene induction (29) . The improved tolerability profile of IDN5109 was likely related to a reduction of its intrinsic toxicity, as documented by marginal manifestations of neurotoxicity. Moreover, because substantially higher doses of IDN5109 were tolerated in comparison to paclitaxel, a reduction of myelosuppressive potential is also expected. Because the solvent used in the study is known to contribute to a clinically toxic effect of paclitaxel (27) , IDN5109 formulation in solvents other than Cremophor and ethanol are currently under investigation. An improved pharmacological profile for IDN5109 compared to paclitaxel may be expected also in view of the lack of a dose dependence of the antitumor effects of IDN5109. In fact, in the responsive tumors, there were no significant differences in response between 60 and 90 mg/kg–treated tumors, except for the case of the A2780/DDP tumor (Table 4)Citation . This does not rule out the possibility that the total cumulative dose may have a relevant impact on the therapeutic outcome. If this is the case, a fractionation of low doses of IDN5109 could have potential advantages in terms of tolerability and efficacy over the use of intensive treatment with high doses.

In conclusion, the preclinical interest in IDN5109 is related to its ability to overcome multidrug resistance mediated by P-glycoprotein, to an improved tolerability and solubility, and to a different spectrum of antitumor activity and enhanced efficacy in paclitaxel-resistant tumors. On the basis of this preclinical pharmacological profile, IDN5109 seems a very promising candidate for clinical evaluation.


   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 This work was partially supported by the Associazione Italiana per la Ricerca sul Cancro (Milan, Italy) and by the Ministero della Sanità (Rome, Italy). Back

2 To whom requests for reprints should be addressed, at Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-2-2390267; Fax: 39-2-2390764; E-mail: zunino{at}istitutotumori.mi.it Back

3 The abbreviations used are: MDR, multidrug-resistant; bw, body weight; BWL, bw loss; TW, tumor weight; TWI%, percentage TW inhibition; DT, doubling time; LCK, log10 cell kill; MTD, maximal tolerated dose. Back

Received 8/14/98. Accepted 1/ 5/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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