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Annals of Surgical Oncology 10:463-468 (2003)
© 2003 Society of Surgical Oncology

ORIGINAL ARTICLES

Thermal Enhancement of New Chemotherapeutic Agents at Moderate Hyperthermia

Faheez Mohamed, MBChB, MRCS, Pierre Marchettini, MD, O. Anthony Stuart, BS, M. Urano, MD and Paul H. Sugarbaker, MD, FACS, FRCS

From The Washington Cancer Institute (FM, PM, OAS, PHS), Washington, DC; and Memorial Sloan-Kettering Cancer Center (MU), New York, New York.

Correspondence: Address correspondence and reprint requests to: Paul H. Sugarbaker, MD, FACS, FRCS, The Washington Cancer Institute, Washington Hospital Center, 110 Irving St., NW, Washington, DC 20010; Fax: 202-877-8602; E-mail: paul.sugarbaker{at}medstar.net


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Hyperthermia enhances the cytotoxicity of some chemotherapeutic agents. We have studied the effect of moderate hyperthermia (41.5°C) on the cytotoxicity of five new chemotherapeutic agents (docetaxel, paclitaxel, irinotecan, oxaliplatin, and gemcitabine) and melphalan against a spontaneous murine fibrosarcoma.

Methods: The tumor was an early-generation isotransplant of a spontaneous C3Hf/Sed mouse fibrosarcoma, FSa-II. Hyperthermia was administered by immersing the tumor-bearing foot into a constant temperature water bath set at 41.5°C for 30 minutes when the tumor reached 34 mm3. Chemotherapy was administered intraperitoneally immediately before hyperthermia. Tumor response was studied by the mean tumor growth time and the mean tumor growth delay time.

Results: Hyperthermia significantly increased the tumor growth times of the animals treated with docetaxel, irinotecan, and gemcitabine at low dose and these drugs plus oxaliplatin at high dose. Docetaxel at high dose showed the greatest control of tumor growth by hyperthermia, with a 26% reduction. Concerning the taxanes, paclitaxel cytotoxicity was not enhanced by hyperthermia, but docetaxel was enhanced by hyperthermia at both doses of drug.

Conclusions: Moderate hyperthermia increases the cytotoxicity of docetaxel, irinotecan, and gemcitabine on mouse fibrosarcoma. Paclitaxel did not show heat enhancement. Oxaliplatin and docetaxel showed greater heat enhancement when the drug dose was high.

Key Words: Hyperthermia • Intraperitoneal chemotherapy • Thermal enhancement • Animal tumors


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Many studies have shown the potential for a response to chemotherapy by the simultaneous use of hyperthermia and drug.1–3 Clinical efforts to combine these two treatment modalities have been less fruitful than might be expected from laboratory data. As new chemotherapeutic agents are developed, experimental in vivo data regarding augmentation by heat are necessary before its use in clinical trials.

The purpose of this work was to quantitatively evaluate the enhancement of cytotoxicity and other physiological processes that may delay tumor growth when heat is used with new chemotherapeutic agents. It is possible that events inducing the delay of tumor growth are cytostatic rather than cytotoxic. The agents studied included docetaxel, paclitaxel, irinotecan, oxaliplatin, and gemcitabine. These are new chemotherapeutic agents being considered for heated intraoperative intraperitoneal chemotherapy protocols for patients with carcinomatosis, sarcomatosis, and peritoneal mesothelioma. These drugs seem promising when used at physiological temperatures, but their activity at increased temperatures is not clear.

The taxanes docetaxel and paclitaxel are mitotic spindle poisons that stabilize microtubules and inhibit their depolymerization to free tubulin.4 Paclitaxel is currently the most commonly used taxane, although docetaxel seems to be at least equally effective in systemic chemotherapy for primary or recurrent advanced epithelial ovarian cancer.5–7 Antitubulin agents are particularly interesting agents to examine in combination with therapeutic hyperthermia, because their intracellular target, the soluble tubulin/microtubule complex, is highly temperature dependent, at least in vitro.8 There are conflicting reports as to the interaction of hyperthermia and the taxanes in vitro with experiments performed with different end points, treatments, and protocols.9 The activity of the taxanes when used with hyperthermia has not been studied extensively in vivo.

Irinotecan, a semisynthetic derivative of camptothecin, is a selective inhibitor of the DNA enzyme topoisomerase I. Its novel mechanism of action makes it a promising new agent for the treatment of advanced colorectal cancer.10 In vitro studies using hyperthermia and irinotecan in a mouse mammary carcinoma cell line have shown enhanced formation of single-strand breaks of DNA at low concentrations of drug.11

Oxaliplatin is a third-generation platinum complex that acts through the formation of DNA adducts in malignant cells throughout the cell-cycle phase. Oxaliplatin activity is potentiated by hyperthermia in vitro,12 and heated intraperitoneal oxaliplatin gives high intraperitoneal and tumor drug concentrations with limited systemic absorption.13

Gemcitabine (2'-2' difluorodeoxycytidine) is a broad-spectrum oncolytic compound with activity against murine leukemias, murine solid tumors, and human tumor xenografts in animal models.14,15 It has also shown efficacy in cancers of the pancreas, lung, and breast.16,17 The products of gemcitabine phosphorylation inhibit ribonucleotide reductase, which regulates the production of deoxynucleotides necessary for DNA synthesis and repair.18 The interaction between gemcitabine and hyperthermia has been studied in vitro and in vivo.19 The addition of hyperthermia 48 hours after intravenous administration in a rat model was found to enhance the effectiveness of gemcitabine.

Studies previously performed with these drugs used a variety of in vivo and in vitro experimental models. The in vivo experiments described here were therefore conducted to determine the effects of intraperitoneal administration of these chemotherapy agents with simultaneous hyperthermia by using a validated animal model.20 The validity of these data was documented by using the model to demonstrate the known thermal enhancement of melphalan. These laboratory data may provide the scientific basis for more completely assessing hyperthermic modification of the agents used.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Mice and Tumor
Three hundred C3Hf/Sed mice weighing 17 to 23 g were obtained from a single breeding colony (Charles River Laboratories, Inc., Wilmington, MA). At least 12 mice were used in each group. Animals were kept two per cage in our animal facility and were allowed free access to food and water. These experiments were conducted after approval by the Animal Care and Use Committee.

Tumors were early-generation isotransplants of a fibrosarcoma, FSa-II, that arose spontaneously in a C3Hf/Sed mouse. The single-cell suspensions were prepared by trypsinization with .25% trypsin (Gibco, Grand Island, NY), and the number of cells was counted on a hemocytometer. Tumor cells were harvested, and a uniform tumor inoculum was aliquoted and frozen at -80°C. The same uniform tumor inoculum was used for all experiments. Ten microliters of the single-cell suspensions (approximately 106 cells) were inoculated subcutaneously through a 22S-gauge Hamilton microliter syringe (Hamilton Co., Reno, Nevada) into the dorsum of the mouse right hind foot. Thermochemotherapy was administered when tumors reached 34 mm3.20

Thermochemotherapy
Heat treatment of tumors was for 30 minutes at 41.5°C. A uniform heat treatment was achieved by immersing the tumor-bearing leg in a constant-temperature water bath as described by Urano et al.21 Room temperature was 22°C to 24°C.

The drugs investigated were paclitaxel (Bristol-Myers Squibb, Princeton, NJ), docetaxel (Rhone-Poulenc Rore, Anthony, France), oxaliplatin (Sanofi Pharmaceuticals, Malvern, PA), irinotecan (Pharmacia & Upjohn, Kalamazoo, MI), gemcitabine (Eli Lilly Laboratories, Indianapolis, IN), and melphalan (Glaxo Wellcome Inc., Research Triangle Park, NC). For paclitaxel, docetaxel, oxaliplatin, irinotecan, and gemcitabine, two doses were used. A dose approximately 5% below the intraperitoneal 10% lethal dose was used as the high-dose chemotherapy treatment. The low dose consisted of half of the high dose. The high and low doses were, respectively, 150 and 75 mg/m2 for paclitaxel, 350 and 175 mg/m2 for docetaxel, 17 and 8.5 mg/kg for oxaliplatin, and 40 and 20 mg/kg for irinotecan. For gemcitabine, the high dose (120 mg/kg) and low dose (60 mg/kg) was determined from prior experiments in a rat model.22 These doses were extrapolated from human phase I studies. The 10% lethal dose for gemcitabine in a mouse model was not available. Melphalan was used in this study at a single high dose of 16 mg/kg, as used by Urano et al.23 This dose was used to validate the experimental model. The drugs were given intraperitoneally immediately before hyperthermia at a constant volume of .02 mL/g of body weight. Each drug was studied independently and in a uniform fashion.

Evaluation of Results
Tumor response was studied by the tumor growth time assay. Three diameters of each tumor—a, b, and c—were measured at least three times a week, and the formula {pi}abc/6 was used to determine the tumor volume. The growth curve was drawn for each tumor, and the mean tumor growth time was determined. This was defined as the mean time required from the treatment day for the tumors to reach 700 mm3. The mean tumor growth delay time was the difference between the mean tumor growth time of treated tumors and the mean tumor growth time of control tumors. A tumor growth delay by chemotherapy alone and by chemotherapy plus hyperthermia was determined for each drug.

Statistical Analysis
For each drug, the tumor growth time at 41.5°C was compared with that of the drug alone to derive the tumor growth delay time by hyperthermia. Statistical analysis was performed by using the tumor growth delay time. Data were analyzed by using the Wilcoxon signed rank test with Prism for Windows, version 3.0 (GraphPad Software Inc., San Diego, CA). For all statistical procedures, values for P < .05 were taken as significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Technical Validation of the Thermochemotherapy Model
The tumor growth time (mean ± SD) in the control group at physiological temperature was 8.04 ± 1.65 days, whereas it was 8.4 ± .84 days in the control group treated with heat alone (P = .6523; Fig. 1). To test the validity of our use of the assay system, a drug with known heat synergy, melphalan, was used. The mean tumor growth time in the group treated with melphalan alone was 13.1 ± 2.03 days, whereas it was 38.9 ± 9.91 days in the group treated with melphalan plus heat (41.5°C; P = .0156). The tumor growth delay time by hyperthermia was 26.1 days (Fig. 1).



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  		FIG. 1. Tumor growth time with and without hyperthermia for melphalan. Tumor growth delay can be determined by subtracting the tumor growth time at room temperature from the tumor growth time with hyperthermia.

 
Thermochemotherapy of New Drugs at Low Dose
Hyperthermia at 41.5°C significantly increased the mean tumor growth delay time in the groups treated with docetaxel, irinotecan, and gemcitabine (Fig. 2). When treated at room temperature or at 41.5°C, the groups that received docetaxel had a mean tumor growth delay of 3.68 ± .87 days and 4.66 ± .84 days (P = .0342). The groups treated with irinotecan showed a mean tumor growth delay with chemotherapy of 4.03 ± .58 days and with thermochemotherapy of 6.69 ± 1.12 days (P = .001). The groups treated with gemcitabine had a mean tumor growth delay of 6.14 ± 1.23 days and 8.46 ± 1.08 days (P = .0005).



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  		FIG. 2. Tumor growth time with chemotherapy alone and by thermochemotherapy. A low dose and high dose of chemotherapy were used. Tumor growth delay can be determined by subtracting the tumor growth time at room temperature from the tumor growth time with hyperthermia. DXL, docetaxel; PXL, paclitaxel; CPT, irinotecan; OXA, oxaliplatin; GEM, gemcitabine. *Statistically significant.

 
The treatment at 41.5°C increased the mean tumor growth delay time in the group treated with oxaliplatin, but this augmentation was not statistically significant. The mean tumor growth delay time was 4.21 ± .65 days in the group treated at room temperature and was 5.17 ± 1.26 days at 41.5°C (P = .123).

When treated at room temperature or at 41.5°C, the animals treated with paclitaxel had mean tumor growth delay times of, respectively, 4.3 ± 1.4 days and 3.3 ± 1.3 days (P = .042). Moderate hyperthermia significantly decreased the mean tumor growth delay.

Thermochemotherapy of New Drugs at High Dose
High-dose chemotherapy with hyperthermia significantly increased the mean tumor growth delay time in the groups treated with docetaxel, irinotecan, oxaliplatin, and gemcitabine (Fig. 2). When treated at room temperature or at 41.5°C, the groups treated with docetaxel had a mean tumor growth delay of 7.01 ± 1.64 days and 10.95 ± .89 days (P = .002); the groups that received irinotecan showed a mean tumor growth delay of 4.59 ± .58 days and 7.07 ± 1.3 days (P = .0005); the groups treated with oxaliplatin had a mean tumor growth delay of 4.31 ± 1.08 days and 7.35 ± .6 days (P = .001); and the groups treated with gemcitabine had a mean tumor growth delay of 7.6 ± .6 days and 9.05 ± .8 days (P = .002).

The treatment at 41.5°C decreased the mean tumor growth delay time in the group treated with paclitaxel, but this inhibition was not statistically significant. The mean tumor growth delay time was 3.5 ± 2.3 days in the group treated at room temperature and was 3.2 ± 1.58 days at 41.5°C (P = .123).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
A number of possible interactions have been suggested for the enhancement of cytotoxicity of chemotherapeutic agents by hyperthermia. Hyperthermia is thought to increase drug-induced DNA damage, to inhibit the repair of drug-induced DNA damage, to induce primary protein damage, and to beneficially influence the pharmacokinetics of drugs.24

In vivo and in vitro results often differ, with factors such as tumor physiology, microcirculation, pH, and hypoxia playing a role in the interaction between hyperthermia and different drugs. In addition, the use of different cell lines and hyperthermia protocols further confuses the interpretation of these studies. This is illustrated in the conflicting results of experiments performed over the last decade (Table 1).


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  		TABLE 1. Summary of prior studies of new chemotherapeutic agents with hyperthermia
 
The experimental model that produced our data used a fibrosarcoma implanted in the hind foot of a mouse. Hyperthermia was induced simultaneously with chemotherapy injected into the peritoneal cavity. A high and low dose of chemotherapy was used so that hyperthermia effects would not be missed by an improper amount of drug. Three of the five drugs tested (docetaxel, irinotecan, and gemcitabine) delayed the number of days required for the tumor to reach a size of 700 mm3 at a low and high dose; oxaliplatin was significantly augmented by heat only at a high dose of drug (Table 2).


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  		TABLE 2. Reduction in tumor size induced by hyperthermia with new drugs at high and low dosesa
 
It seems from our data that the combination of hyperthermia and melphalan used to validate our experimental model was highly effective in delaying tumor growth. Melphalan is a well-known antineoplastic alkylating agent that has been in use to treat cancer patients for over 50 years.33 It has markedly increased pharmacological activity with heat, both in vitro and in vivo.23,34 Clinically, it remains the most effective single drug used in heated limb perfusion to treat in-transit metastases from melanomas and advanced primary or recurrent extremity soft tissue sarcomas.35,36 Melphalan exerts its antineoplastic effect through the formation of interstrand DNA cross-links. It is thought that the formation of these DNA cross-links is facilitated at increased temperatures, leading to enhanced cell killing.34 Our data suggest that further investigation of heated melphalan for intraoperative intraperitoneal chemotherapy is warranted.

The rationale for the use of hyperthermia with the taxanes is based on the fact that mild hyperthermia results in a disorganization of the microtubule system,37 and the taxanes are considered microtubule stabilizing agents. Thus, a common target of cytotoxic damage is involved. However, paclitaxel has been shown to protect against the effects of hyperthermia in vitro.30 Our results with paclitaxel in vivo showed that when it was combined with hyperthermia, there was a statistically significant decrease in tumor growth control at a low dose when compared with paclitaxel alone. This is similar to results from in vitro studies.9,26 It is not clear how hyperthermia interacts with paclitaxel. The synthesis of heat-shock proteins, such as hsp74, may be inhibited by paclitaxel,38 so it is conceivable that structural modifications of the mitotic spindle occur under hyperthermic conditions, altering the sensitivity of spindle microtubules to antitubulin agents. This suggests that the cytotoxicity of paclitaxel is inhibited at increased temperatures. However, our results with docetaxel in vivo show hyperthermia-enhanced cytotoxicity. This differs from results of in vitro experiments,25,26 but the factors mentioned previously may play a role in the interaction of hyperthermia and drug in vivo.

Our results with irinotecan, oxaliplatin, and gemcitabine are similar to those published previously. It seems that for gemcitabine, the timing of hyperthermia administration is important. It has been shown both in vivo and in vitro that simultaneous application of heat results in decreased cytotoxicity of gemcitabine.19,32 In our study, the intraperitoneal route of drug administration may have resulted in enhanced cytotoxicity with hyperthermia. Further studies are required regarding the optimal scheduling of gemcitabine and hyperthermia.

Hyperthermia alone was not effective in delaying the growth of the mouse fibrosarcoma. Mice treated with hyperthermia alone were tested in the validation experiments performed with melphalan. However, to prevent the needless death of laboratory animals, this control was not used in any of the subsequent experiments with the new chemotherapy agents.

From these data many other experiments can be planned. Changes in the timing of chemotherapy delivery related to the application of hyperthermia should be explored with schedules for chemotherapy delivery before hyperthermia. The timing for thermochemotherapy effects on different-sized tumor nodules needs investigation. We used a very small tumor, approximately 3 mm in diameter, in these initial experiments. Application of thermochemotherapy at an earlier and later time with larger tumor nodules warrants study. The small tumor nodules studied in the mouse model may be appropriate for clinical researchers interested in the treatment of small peritoneal implants with thermochemotherapy. It is clear that these experiments are the beginning rather than the end of this important work. Further studies with melphalan and docetaxel, as a result of these early investigations, are under way.


   Acknowledgments
 
Supported by a grant from the MedStar Research Institute.

The acknowledgments are available online at www.annalssurgicaloncology.org.


   Footnotes
 
Hyperthermia enhances the cytotoxicity of some chemotherapeutic agents. We studied the effect of moderate hyperthermia (41.5°C) on the cytotoxicity of five new chemotherapeutic agents (docetaxel, paclitaxel, irinotecan, oxaliplatin, and gemcitabine) against a spontaneous murine fibrosarcoma. Moderate hyperthermia increases the cytotoxicity of all these drugs except paclitaxel.

Received for publication August 7, 2002. Accepted for publication December 12, 2002.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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