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The Oncologist, Vol. 7, No. 5, 458–466, October 2002
© 2002 AlphaMed Press

Combining Radiotherapy with Gene Therapy (From the Bench to the Bedside): A Novel Treatment Strategy for Prostate Cancer

Bin S. Teha,b, Estuardo Aguilar-Cordovaa,d, Maria T. Vlachakic, Laura Aguilard, Wei-Yuan Maia,b, James Caillouetb, Maria Davisb, Brian Milesa, Dov Kadmona, Gustavo Ayalaa, Hsin H. Lua,b, J. Kam Chiua,b, L. Steven Carpentera,b, Shiao Y. Wooa,b, Walter H. Grant, IIIa,b, Thomas Wheelera, Timothy C. Thompsona, E. Brian Butlera,b

a Baylor College of Medicine, b The Methodist Hospital, and c Veterans Affairs Medical Center, Houston, Texas, USA; d Harvard Gene Therapy Initiative, Harvard Medical School, Boston, Massachusetts, USA

Correspondence: Bin S. Teh, M.D., The Methodist Hospital, Radiotherapy Department, 6565 Fannin, MS 121-B, Houston, Texas 77030, USA. Telephone: 713-790-2637; Fax: 713-793-1300; e-mail: bteh{at}bcm.tmc.edu


   ABSTRACT
Top
 Abstract
Introduction
 Combining Radiotherapy with Gene...
 Current Clinical Trials
 Discussion
 References
 
Combined radiotherapy and gene therapy is a novel therapeutic approach for prostate cancer. There are various potential benefits in combining ionizing radiation with gene therapy to achieve enhanced antitumor effects: A) ionizing radiation improves transfection/ transduction efficiency, transgene integration, and possibly, the "bystander effect" of gene therapy; B) gene therapy, on the other hand, may interfere with repair of radiation-induced DNA damage and increase DNA susceptibility to radiation damage in cancer cells, and C) radiotherapy and gene therapy target at different parts of the cell cycle. Preclinical data have demonstrated the enhanced antitumor effects of this combined approach in local tumor control, prolongation of survival, as well as systemic control. This combined radio-gene therapy is under study in an ongoing clinical trial in prostate cancer. Our study adds gene therapy to the standard of care therapy (radiotherapy). These treatment modalities have different toxicity profiles. The goal of this combined approach is to enhance cancer cure without an increase in treatment-related toxicity. This approach also offers a new paradigm in spatial cooperation, whereby two local therapies are combined to elicit both local and systemic effects. Early clinical results showed the safety of this approach.

Key Words. Radiotherapy • Gene therapy • Prostatic neoplasms • Treatment


   INTRODUCTION
Top
 Abstract
 Introduction
Combining Radiotherapy with Gene...
 Current Clinical Trials
 Discussion
 References
 
Radiotherapy and Dose Escalation
Surgery, radiotherapy, and chemotherapy are standard treatments in oncology [1]. Advances in these treatment modalities have improved cancer cure and quality of life in cancer patients. Significant progress in radiophysics and radiobiology has taken place in radiation oncology [1]. Radiation dose is vital in tumor control probability as well as in normal tissue damage. As the radiation dose is escalated, the tumor control probability improves, but normal tissue damage also increases. The advances in radiotherapeutic technology have enabled the improvement of the therapeutic index in the treatment of cancer [2]. More conformal radiation therapy has allowed dose escalation, leading to improvement of local control [3–5]. However, the concern of dose escalation is normal tissue damage. A good example of this is the use of radiation therapy to treat prostate cancer. A radiation dose-response relationship with tumor control has been demonstrated [3–5]. The delivery of high-dose radiation is, however, limited by the proximity of critical normal structures (bladder and rectum). Higher radiation dose is associated with higher incidence of treatment-related toxicity, especially radiation-induced proctitis [6, 7]. Even with highly conformal radiation therapy, high-dose escalation to the prostate is associated with rectal damage [8, 9]. Various methods have been used to overcome this problem, one of which is the use of a rectal shield after reaching radiation tolerance of the rectum [10]. However, this method defeats the purpose of dose escalation, as most (74%) prostate carcinoma foci are in the peripheral zones in very close proximity to the anterior rectal wall [11]. By shielding the rectum, the peripheral zones are shielded, especially in view of daily prostate motion. Without high-dose radiation delivery to peripheral zones, tumor control is limited by spatial restrictions on dose. Secondly, there are radio-resistant cancer cells that will not die despite high-dose radiation. Combining radiotherapy with a biological therapy, such as gene therapy, would appear to be a more logical approach to this problem.

Herpes Simplex Virus Thymidine Kinase (HSV-tk) in Situ "Suicide" Gene Therapy
Gene therapy involves the transfer of genetic material into human cells and the expression of that material in those cells for a therapeutic purpose [12]. In cancer gene therapy, the aim is to treat or prevent malignant disease by using the therapeutic information encoded in DNA sequences. Three different strategies of gene therapy are as follows. Strategy A involves the replacement of a defective or inactivated tumor suppression gene, e.g., p53 [13]. Strategy B requires the transfer or insertion of a gene that results in the activation of a prodrug to produce selective cytotoxicity [14, 15]. Strategy C involves the delivery of a gene to stimulate the immune system [16]. Gene therapy requires a "cargo-ship" (covector) for the delivery or transfer of genetic material into the target cells. We have chosen adenovirus as the covector for the following reasons: A) its ability to enter the cell efficiently; B) its high expression of therapeutic gene, and C) its failure to integrate into the host chromosome.

A feasible gene-therapeutic approach might involve the manipulation of genes that could ultimately bring about the death of a cancer cell. "Suicide" gene therapy, an example of strategy B, could be used to achieve this goal. It involves the transfection of a gene responsible for the production of an enzyme that converts an otherwise benign substance (prodrug) into a toxic agent that kills the cancer cells. Most of the enzymes used in suicide gene therapy are not normally encoded by mammalian cells but originate from viruses, bacteria, or fungi, and thus, are foreign to the transfected malignant mammalian cell. Specifically, we have employed, as our suicide gene therapy, the HSV-tk gene. The vehicle to transfer this gene is a replication-defective adenovirus. This is then followed by administration of antiherpetic agents, such as ganciclovir, acyclovir, or valacyclovir. These prodrugs are poor substrates for mammalian thymidine kinases, but are phosphorylated into effective cytotoxic drugs by HSV-tk [17, 18]. The phosphorylated drugs are nucleotide analogues, which are incorporated into DNA during cell division, leading to termination of DNA replication and cell death [19]. Moreover, the number of cells killed significantly exceeds the number of cells transduced with HSV-tk gene, a phenomenon known as the "bystander effect" [20]. The "bystander effect" may be caused by a number of possible mechanisms: A) passage of toxic metabolites produced in the transduced cells across gap junctions into neighboring cells; B) damaged, suicide-gene-containing cells release of soluble toxic substances into the microenvironment, or C) a local immune response elicited by cytokines released locally by those cells killed by the suicide-gene system. This further attracts immunocytes into the tumor, mediating an antitumor response.

Potential Benefits and Theoretical Advantages of Combining Radiotherapy with Gene Therapy
Our approach at the Baylor College of Medicine has been to combine radiotherapy with in situ gene therapy, two different therapies with different toxicity profiles, with the intention to achieve increased disease control. There are various potential benefits of combining radiation therapy with gene therapy. Gene therapy may cause radiosensitization or additive cell killing [20–23]. Theoretical mechanisms of the enhanced antitumor effects from this combined approach may be:


   COMBINING RADIOTHERAPY WITH GENE THERAPY—FROM LABORATORY TO CLINICS
Top
 Abstract
 Introduction
 Combining Radiotherapy with Gene...
Current Clinical Trials
 Discussion
 References
 
Efficacy of HSV-tk Suicide Gene Therapy as a Single Agent

Preclinical Trials
We have assessed the toxicity and efficacy of adenovirus-mediated HSV-tk + ganciclovir (prodrug) therapy by using both in vitro and in vivo prostate cancer models. The adenoviral transduction efficiency was tested on the mouse prostate cancer cell line, RM-1, using a recombinant vector containing the bacterial ß-galactosidase gene. The efficiency of transduction followed a multiplicity of infection (MOI)-dependent pattern involving the transduction of practically all the cells at MOI values exceeding 100. Also, the HSV-tk enzymatic activity, measured by the ability of extracts of transduced cells to phosphorylate acyclovir, demonstrated viral-dose dependence, with activity being detected at practically all MOI levels [19]. We have also demonstrated that HSV-tk + ganciclovir was highly effective against mouse and human prostate cancer cell lines in vitro [19]. The rationale for using the RM-1 orthotopic model in vivo was that it represented a faithful prostatic environment (the presence of local immunity and growth factors) and a realistic therapeutic testing site for in situ gene therapy. In this model, RM-1 prostate cancer cells were injected into mice subcutaneously. Intratumoral injection of HSV-tk was performed after 6 days. This was then followed by ganciclovir injections intraperitoneally twice daily for 6 days. Using this in vivo model, we set our goals to evaluate the effect of HSV-tk + ganciclovir gene therapy on local control and survival, spontaneous or preexisting metastatic disease, and induced metastatic disease.

HSV-tk + ganciclovir gene therapy demonstrated significant growth suppression of the local tumor and survival advantage when compared with controls [19]. Increased areas of necrosis, increased numbers of apoptotic bodies, and extensive immunocytic infiltration relative to controls were noted to accompany HSV-tk + ganciclovir cytotoxicity [19]. In contrast, transfer of systemically directed gene therapy to the orthotopic prostate was found to be ineffective, due to the clearance of the virus from the circulation by the immune system and to the natural affinity of the virus for respiratory and hepatic tissues [28, 29].

When mice were sacrificed, their lungs were also examined carefully for any metastatic disease. HSV-tk + ganciclovir gene therapy significantly decreased the number of pulmonary metastatic lesions when compared with controls. To further confirm the antimetastatic effects of gene therapy, we created an induced metastatic prostate cancer model by injecting RM-1 cells into the tail veins of the mice in addition to the subcutaneous injection. The intratumoral injection of HSV-tk and intraperitoneal injection of ganciclovir were performed as previously stated. Marked suppression of the induced lung metastatic lesions was achieved with the in situ gene therapy compared with controls [30]. The most likely explanation for the antimetastatic activity was the induction of an antitumor immunity by HSV-tk + ganciclovir gene therapy. Other possible explanations include the release of an antiangiogenic substance, targeting of angiogenesis, and killing of premetastatic cells.

Prostate cancer cells have been well known to be sensitive to androgen ablation. Hall et al. set out to investigate the effects of HSV-tk + ganciclovir gene therapy and androgen ablation on prostate cancer cells [31]. Mice were castrated to achieve androgen ablation. The local tumor control effects of gene therapy were enhanced by concomitant androgen ablation. However, the antimetastatic effects of the combined gene therapy with androgen ablation were similar to and not better than the effects of gene therapy alone [31]. Furthermore, we have reported no systemic spread and minimal local spread of the adenoviral vector within the genitourinary (GU) system in our mouse model [32]. Table 1Go shows a summary of the effects of radiotherapy, gene therapy, hormonal therapy, and combinations thereof on local control and systemic control, as observed in preclinical trials.


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  		Table 1. Effects of various treatment modalities on local and systemic control
 

Clinical Trials
The promising results from our preclinical trials have led to a phase I clinical trial evaluating this type of gene therapy in patients with locally recurrent prostate cancer after initial radiotherapy. This trial consisted of the direct intraprostatic injection of an adenoviral vector containing the HSV-tk gene under transrectal ultrasound guidance followed by intravenous administration of ganciclovir. A total of 18 patients were enrolled in this trial. They were treated at four escalating doses from 1 x 108 to 1 x 1011 infectious units (IU). Treatment-related toxicity was graded according to the Cancer Therapy Evaluation Program (CTEP) Common Toxicity published by the National Cancer Institute. Toxicity was encountered in only 5 of the 18 patients. Four patients experienced mild toxicity of grade 1-2. One patient, at the highest dose level, developed spontaneously reversible grade 4 thrombocytopenia and grade 3 hepatotoxicity. Cultures of nasal mucus, blood, and urine from all patients were consistently negative for adenoviral growth. Three patients achieved an objective response during this phase I study, one each at the three highest dose levels, documented by a fall in serum prostate-specific antigen (PSA) level by 50% or more sustained for 6 weeks to 1 year. The trial demonstrated the safety of HSV-tk + ganciclovir gene therapy in human prostate cancer as well as its anticancer activity [33].

Efficacy of Combined HSV-tk Suicide Gene Therapy and Radiotherapy

Preclinical Trial
The prostate cancer cell line, RM-1, was used for subcutaneous injection into syngeneic C57BL/6 mice [34]. Tumors measuring 50-60 mm3 were established in the hind flank to avoid complications of scatter radiation damage to viscera. HSV-tk was then injected intratumorally. This was followed by ganciclovir given intraperitoneally twice daily for 6 days. Forty-eight to 72 hours after gene vector injection, the tumors were irradiated at 5 Gy using an orthovoltage x-ray generator. To establish lung metastases, RM-1 cells were also injected into the tail vein of the mice in addition to the subcutaneous injection. The end points of these studies were: local tumor control, survival, local immunological response, and systemic effect on lung metastases.

Figure 1Go shows that both monotherapy (either gene therapy or radiotherapy alone) modalities decreased tumor growth compared with the control. The combined gene therapy and radiotherapy group showed the most significant inhibition of tumor growth compared with the control and all other treatment groups.



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  		Figure 1. Effects of therapy on tumor growth. Abbreviations: TK = thymidine kinase; XRT = radiation therapy; PBS = phosphate buffered saline; ß-gal = ß-galactosidase.

 
Similarly, as shown in Figure 2Go, the combined treatment modality group elicited a significant prolongation of survival when compared with the control and monotherapy groups. The improvement in survival may be translated from better local tumor control in the combined gene therapy and radiotherapy groups.



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  		Figure 2. Effects of therapy on survival. Abbreviations: PBS = phosphate buffered saline; ß-gal = ß-galactosidase; XRT = radiation therapy; TK = thymidine kinase.

 
In evaluating local immunological response, lymphocytic infiltrates were noted to be most pronounced in the combined gene therapy and radiotherapy group. Infiltrating lymphocytes were accentuated at the tumor/native tissue interface and percolated throughout the tumor, focally forming lymphocytic clusters. The combined therapy group had a significantly greater frequency of infiltrating CD4 T cells than the control and monotherapy groups.

In the lung metastases model, gene therapy alone resulted in 37% fewer lung nodules than in the control, but the addition of radiotherapy to gene therapy resulted in a further 50% fewer metastatic lesions (Fig. 3Go). Radiation therapy alone had no effect on lung metastases. Figure 4Go illustrates the autopsy specimens showing that the lungs from animals treated with combined gene therapy and radiotherapy had the least number of lung metastatic nodules, followed by the gene therapy alone group. The radiotherapy alone group had the same number of lung metastases as the controls, an expected outcome inasmuch as radiotherapy is a local therapy. We also know from previous experiments that this type of in situ gene therapy had systemic effects, likely through an immunological response [19, 32]. However, it was surprising and encouraging to find that when local therapy, i.e., radiotherapy, was added to in situ HSV-tk + ganciclovir gene therapy, not only local control but also systemic effects were significantly improved. A new form of spatial cooperation is created whereby the interactions of two local therapies enhance both local and systemic control in this model.



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  		Figure 3. Effects of therapy on preexisting lung metastases. Abbreviations: PBS = phosphate buffered saline; TK = thymidine kinase; XRT = radiation therapy.

 


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  		Figure 4. A comparison among the lungs of mice receiving various therapy modalities. Abbreviations: TK = thymidine kinase; XRT = radiation therapy; PBS = phosphate buffered saline.

 

   CURRENT CLINICAL TRIALS
Top
 Abstract
 Introduction
 Combining Radiotherapy with Gene...
 Current Clinical Trials
Discussion
 References
 
Rationale
Preclinical studies, which showed that combined radio-gene therapy caused significant tumor growth control and prolongation of survival as well as suppression of preexisting metastatic disease when compared with the control and either therapy alone, have now been translated into clinical use. This phase I/II trial is the first of its kind, in the field of prostate cancer, that combines a standard of care therapy (radiation therapy with or without hormonal therapy) with a novel therapy (HSV-tk). The hypothesis is that combined radio-gene therapy will lead to a better cure without additional toxicity to patients. This hypothesis is based on: A) preclinical trials showing the added benefits of the combined approach compared with monotherapy; B) a phase I clinical trial demonstrating minimal toxicity of this type of gene therapy, and C) each therapy having a different toxicity profile. Oral valacyclovir was used in this trial to replace the intravenous ganciclovir used in the phase I trial on locally recurrent prostate cancer. Intraprostatic injections of gene vectors can be administered without anesthesia in an outpatient sonography room. This approach has obviated the need to hospitalize enrolled patients, especially in view of our gene vector injection, which was also an outpatient procedure. Thus, the expense of this regimen can be kept lower than inpatient procedures. This trial also demonstrates the feasibility of "marrying" the advances in radiation physics, e.g., intensity-modulated radiation therapy, with advances in molecular biology, namely, gene therapy.

Treatment Schema
There are three arms in this study. Arm A includes patients with a PSA level <10, a Gleason’s score <7, and clinical stage T1-T2a. Arm B patients have one of the following characteristics: a PSA level >=10, a Gleason’s score >=7, or clinical stage T2b-T3. Arm C patients have pathologically proven regional (pelvic) lymph node involvement of prostate cancer. Table 2Go shows the treatment schema in each arm.


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  		Table 2. Treatment schema
 
Gene Vector
The vector used for the in situ gene therapy was an adenovirus of serotype AD5 that contained the HSV-tk gene and a Rous sarcoma virus long terminal repeat promoter in the region of the excised E1/E2 wild-type adenoviral genes. The adenoviral vector was constructed as described previously [35]. Type 5 adenoviruses were chosen because: A) they have demonstrated a high-level efficiency of transduction; B) they are easy to manipulate in vitro; C) they are easy to produce in high titers; D) they infect both dividing and nondividing cells. This is advantageous in prostate cancer, which is known for its low rate of mitotic activity; E) their DNA is not incorporated into the host-cell chromosome, which minimizes concerns about insertional mutagenesis, and F) a replication deficient adenovirus is used. In the event of systemic infection, their symptoms are relatively benign, even following wild-type infection.

The viral vector was produced at the Baylor College of Medicine gene vector laboratory in accordance with good manufacturing practice (21 CFR210 and 211). The vector was characterized for purity and potency for clinical use. Once produced, it was stored at –80° C.

Radiotherapy
A mean dose of 76 Gy (prescribed dose of 70 Gy in 2 Gy/fraction) was delivered to the prostate utilizing a NOMOS Peacock intensity-modulated radiation therapy system (NOMOS Corporation; Sewickley, PA). In addition, arm C patients also received 45 Gy of radiation in 1.8 Gy/fraction to the draining pelvic lymphatics. These techniques have been described in detail previously [36, 37]. Briefly, the patients were treated prone in a customized vacuum bag fitted into a treatment box for the purpose of immobilization. A rectal balloon was placed each day during treatment to prevent prostate motion. Radiotherapy was initiated 48 hours following the first gene vector injection in arm A and 48 hours after the second gene vector injection in arms B and C.

Androgen Deprivation
For arm B (high risk) and arm C (stage D1) patients, androgen deprivation was begun concomitantly with the first gene vector injection on day 0. Hormonal therapy consisted of one intramuscular injection of a 4-month (30 mg) leuprolide acetate (Lupron®) depot, a luteinizing-hormone-releasing hormone agonist, and flutamide (Eulexin®), an antiandrogen given orally in a 125 mg x 2 dose three times a day for fourteen days.

Patient Evaluation
CTEP common toxicity criteria by the National Cancer Institute were used to assess the toxicity related to the gene therapy and hormonal therapy. The Radiation Therapy Oncology Group (RTOG) morbidity score [38] was used to evaluate the toxicity related to radiotherapy, especially of the lower gastrointestinal (GI) and GU systems. PSA was evaluated.

Acute Toxicity
Until September 2001, 45 patients (23 in arm A, 19 in arm B, and three in arm C) had completed the trial. The median follow-up was 10.0 months (from 1.3 to 14.9 months). Fifteen patients (33%) developed CTEP grade 1 flu-like symptoms after gene therapy injection. Nine patients (20%) and two patients (4%) developed grade 1 and 2 fevers, respectively. One patient in arm B developed a grade 3 elevation in liver enzyme level, while 12 and two patients developed grade 1 and 2 abnormal liver function tests, respectively. There was no grade 2 or above toxicity in the complete blood count. Five patients had a grade 1 transient rise in creatinine level. There was no RTOG grade 3 or above lower GI toxicity. There was one patient with RTOG grade 3 GU toxicity. One patient dropped out of the trial due to an allergic reaction to the pill, valacyclovir. No other patient had treatment withheld due to severe toxicity. Posttreatment PSA had declined appropriately in all patients with the exception of one patient in Arm C with pelvic bone metastasis who was then on hormone treatment.


   DISCUSSION
Top
 Abstract
 Introduction
 Combining Radiotherapy with Gene...
 Current Clinical Trials
 Discussion
References
 
This phase I-II trial represents the first clinical trial using combined radio-gene therapy in the treatment of previously untreated prostate cancer. This is also the first trial of its kind in the field of prostate cancer that aims to expand the therapeutic index of radiotherapy by combining it with in situ gene therapy. Early results confirm the safety and feasibility of this approach. Overall, there was no added toxicity in patients receiving combined radio-gene therapy when compared with patients receiving either therapy alone [33, 36, 37]. However, it is still very early in the follow-up (median of 10 months), and this study used a small cohort (45 patients). Longer-term follow-up and a larger cohort are warranted to evaluate long-term toxicity before any conclusion can be made.

It is too early to look at the efficacy of this trial, especially in view of prostate cancer treatment, which needs much longer follow-up. We are currently gathering clinical digital rectal examination (DRE), biochemical (PSA), and pathological (biopsy) data. The end points of efficacy for cancer gene therapy are currently receiving a lot of attention. In the treatment of prostate cancer, the traditional end points include DRE data, biopsy data, PSA level, and evidence of distant metastases [39, 40]. In our previous phase I trial involving salvage gene therapy for patients who failed initial radiotherapy, we noted that gene therapy caused stabilization of PSA rather than true PSA nadir achieved in patients treated with radiotherapy alone. Newer serum markers, such as caveolin-1, may be more representative of response to gene therapy. These markers are currently being evaluated. It is also known that the efficacy of this type of gene therapy depends on "bystander effects" and the host immune system stimulation. Soon, various histological, immunological, and molecular assessments, such as apoptosis, necrosis, p53, p21, inflammatory response, local immunological response, cytokine gene expression, and others, will be performed on the biopsy specimens. Evaluation of the host immune response also will be carried out. This includes the patients’ cytokine profile, such as interleukin-6, transforming growth factor-beta, tumor necrosis factor-alpha, characterization of lymphoid population, proportion of activated T-cells, functional activities of monocytes, and natural killer cells.

Longer-term follow-up in larger cohorts is needed to evaluate efficacy and late toxicity. In view of the potential for enhancing both local tumor control and eliciting antimetastatic properties (a new model of spatial cooperation), this combined radio-gene therapy can be used in the treatment of other tumor types, such as head and neck cancer, pancreatic cancer, lung cancer, etc. This approach is theoretically ideal for cancers which have a high propensity for local recurrence and distant metastases with the currently available treatment modalities. More studies involving this combined radio-gene therapy approach are warranted.

Future directions include the refinement of various issues regarding gene therapy and the best sequencing of radio-gene therapy. This type of gene therapy elicits its antitumor effects via direct cytotoxicity "bystander effects," as well as stimulated immunological response. A more detailed assessment of the mechanisms, especially in humans, is required. Also, the gene vector distribution within the prostate needs to be further elucidated. As prostate cancer can be a multifocal disease, optimal therapy will likely require a uniform distribution of the vector throughout the gland. It may be that we can inject more gene vector into the hypoechoic areas, which have been correlated with a higher incidence of cancer. There is also consideration of the physical size of the prostate gland, which varies a great deal among patients. We are also planning to utilize three-dimensional planning based on reconstructed prostate volume to aid gene vector delivery and distribution. Our initial pathologic volumetric studies (from our neoadjuvant gene therapy followed by prostatectomy trial) showed that only portions of the tumor show morphologic effects as well as an inverse relationship between percentage of the affected tumor and prostate and tumor size [41]. These findings will have a major impact on our future planning for the most optimal gene vector injection and distribution. The best sequencing of radiation therapy and gene therapy needs more investigation in order to achieve the best radiosensitization, maximal cytotoxicity, and optimal new spatial cooperation—a combination of local therapies leading to enhanced local control and systemic effects. We can also explore the combination of radiation therapy with other types of gene therapy based on the safety data from this trial.


   ACKNOWLEDGMENT
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 Abstract
 Introduction
 Combining Radiotherapy with Gene...
 Current Clinical Trials
 Discussion
 References
 
This work was supported by a Specialized Program of Research Excellence (SPORE) grant (CA58204) from the National Cancer Institute, the Methodist Hospital Foundation, the General Clinical Research Center (GCRC), Advantagene, GlaxoSmithKline, and Schering Oncology.


   REFERENCES
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 Introduction
 Combining Radiotherapy with Gene...
 Current Clinical Trials
 Discussion
 References
 

  1. Hellman S, Weichselbaum RR. Radiation oncology. JAMA 1996;275:1852–1853.[Abstract/Free Full Text]
  2. Purdy JA. Intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 1996;35:845–846.[CrossRef][Medline]
  3. Hanks GE, Martz KL, Diamond JJ. The effect of dose on local control of prostate cancer. Int J Radiat Oncol Biol Phys 1988;15:1299–1305.[Medline]
  4. Pollack A, Zagars GK. External beam radiotherapy dose response of prostate cancer. Int J Radiat Oncol Biol Phys 1997;39:1011–1018.[CrossRef][Medline]
  5. Hanks GE, Lee WR, Hanlon AL et al. Conformal technique dose escalation for prostate cancer: biochemical evidence of improved cancer control with higher doses in patients with pretreatment prostate-specific antigen > or = 10 ng/ml. Int J Radiat Oncol Biol Phys 1996;35:861–868.[CrossRef][Medline]
  6. Smit WGJM, Helle PA, van Putten WLJ et al. Late radiation damage in prostate cancer patients treated by high dose external radiotherapy in relation to rectal dose. Int J Radiat Oncol Biol Phys 1990;18:23–29.[Medline]
  7. Lawton CA, Won M, Pilepich MV et al. Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: analysis of RTOG studies 7506 and 7706. Int J Radiat Oncol Biol Phys 1991;21:935–939.[Medline]
  8. Hanlon AL, Schultheiss TE, Hunt MA et al. Chronic rectal bleeding after high-dose conformal treatment of prostate cancer warrants modification of existing morbidity scales. Int J Radiat Oncol Biol Phys 1997;38:59–63.[CrossRef][Medline]
  9. Zelefsky MJ, Cowen D, Fuks Z et al. Long term tolerance of high dose three-dimensional conformal radiotherapy in patients with localized prostate carcinoma. Cancer 1999;85:2460–2468.[CrossRef][Medline]
  10. Lee WR, Hanks GE, Hanlon AL et al. Lateral rectal shielding reduces late rectal morbidity following high dose three-dimensional conformal radiation therapy for clinically localized prostate cancer: further evidence for a significant dose effect. Int J Radiat Oncol Biol Phys 1996;35:251–257.[CrossRef][Medline]
  11. Chen ME, Johnston DA, Tang K et al. Detailed mapping of prostate carcinoma foci: biopsy strategy implications. Cancer 2000;89:1800–1809.[CrossRef][Medline]
  12. Sikora K, Pandha H. Gene therapy for prostate cancer. Br J Urol 1997;79(suppl 2):64–68.
  13. Zhang WW, Fang X, Mazur W et al. High-efficiency gene transfer and high-level expression of wild-type p53 in human lung cancer cells mediated by recombinant adenovirus. Cancer Gene Ther 1994;1:5–13.[Medline]
  14. Moolten FL, Wells JM. Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J Natl Cancer Inst 1990;82:297–300.[Abstract/Free Full Text]
  15. Moolten FL. Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res 1986;46:5276–5281.[Abstract/Free Full Text]
  16. Vieweg J, Rosenthal FM, Bannerji R et al. Immunotherapy of prostate cancer in the Dunning rat model: use of cytokine gene modified tumor vaccines. Cancer Res 1994;54:1760–1765.[Abstract/Free Full Text]
  17. Shalev M, Miles BJ, Thompson TC et al. Suicide gene therapy for prostate cancer using a replication-deficient adenovirus containing the herpesvirus thymidine kinase gene. World J Urol 2000;18:125–129.[CrossRef][Medline]
  18. Fyfe JA, Keller PM, Furman PA et al. Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound, 9-(2-hydroxyethoxymethyl)guanine. J Biol Chem 1978;253:8721–8727.[Free Full Text]
  19. Eastham JA, Chen S-H, Sehgal I et al. Prostate cancer gene therapy: herpes simplex virus thymidine kinase gene transduction followed by ganciclovir in mouse and human prostate cancer models. Hum Gene Ther 1996;7:515–523.[Medline]
  20. Kawashita Y, Ohtsuru A, Kaneda Y et al. Regression of hepatocellular carcinoma in vitro an in vivo by radiosensitizing suicide gene therapy under the inducible and spatial control of radiation. Hum Gene Ther 1999;10:1509–1519.[CrossRef][Medline]
  21. Kim JH, Kim SH, Brown SL et al. Selective enhancement by an antiviral agent of the radiation-induced cell killing of human glioma cells transduced with HSV-tk gene. Cancer Res 1994;54:6053–6056.[Abstract/Free Full Text]
  22. Nishihara E, Nagayama Y, Mawatari F et al. Retrovirus-mediated herpes simplex virus thymidine kinase gene transduction renders human thyroid carcinoma cell lines sensitive to ganciclovir and radiation in vitro and in vivo. Endocrinology 1997;138:4577–4583.[Abstract/Free Full Text]
  23. Atkinson G, Hall SJ. Prodrug activation gene therapy and external beam irradiation in the treatment of prostate cancer. Urology 1999;54:1098–1104.[CrossRef][Medline]
  24. Stevens CW, Zeng M, Cerniglia GJ. Ionizing radiation greatly improves gene transfer efficiency in mammalian cells. Hum Gene Ther 1996;7:1727–1734.[Medline]
  25. Zeng M, Cerniglia GJ, Eck SL et al. High-efficiency stable gene transfer of adenovirus into mammalian cells using ionizing radiation. Hum Gene Ther 1997;8:1025–1032.[Medline]
  26. Jain PT, Gewirtz DA. Sustained enhancement of liposome-mediated gene delivery and gene expression in human breast tumour cells by ionizing radiation. Int J Radiat Oncol Biol Phys 1999;75:217–223.
  27. Simons JW, Marshall FF. The future of gene therapy in the treatment of urologic malignancies. Urol Clin North Am 1998;25:23–38.[CrossRef][Medline]
  28. Prince HM. Gene transfer: a review of methods and applications. Pathology 1998;30:335–347.[CrossRef][Medline]
  29. Van der Eb MM, Cramer SJ, Vergouwe Y et al. Severe hepatic dysfunction after adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene and ganciclovir administration. Gene Ther 1998;5:451–458.[CrossRef][Medline]
  30. Hall SJ, Mutchnik SE, Chen S-H et al. Adenovirus-mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy leads to systemic activity against spontaneous and induced metastasis in an orthotopic mouse model of prostate cancer. Int J Cancer 1997;70:183–187.[CrossRef][Medline]
  31. Hall SJ, Mutchnik SE, Yang G et al. Cooperative therapeutic effects of androgen ablation and adenovirus-mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy in experimental prostate cancer. Cancer Gene Ther 1999;6:54–63.[CrossRef][Medline]
  32. Timme TL, Hall SJ, Barrios R et al. Local inflammatory response and vector spread after direct intraprostatic injection of a recombinant adenovirus containing the herpes simplex virus thymidine kinase gene and ganciclovir therapy in mice. Cancer Gene Ther 1998;5:74–82.[Medline]
  33. Herman JR, Adler HL, Aguilar-Cordova E et al. In situ gene therapy for adenocarcinoma of the prostate: a phase I clinical trial. Hum Gene Ther 1999;10:1239–1249.[CrossRef][Medline]
  34. Chhikara M, Huang H, Vlachaki MT et al. Enhanced therapeutic effect of HSV-tk+GCV gene therapy and ionizing radiation for prostate cancer. Mol Ther 2001;3:536–542.[CrossRef][Medline]
  35. Chen SH, Shine HD, Goodman JC et al. Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc Natl Acad Sci USA 1994;91:3054–3057.[Abstract/Free Full Text]
  36. Teh BS, Mai WY, Uhl BM et al. Intensity-modulated radiation therapy (IMRT) for prostate cancer with the use of a rectal balloon for prostate immobilization: acute toxicity and dose-volume analysis. Int J Radiat Oncol Biol Phys 2001;49:705–712.[CrossRef][Medline]
  37. Teh BS, Woo SY, Butler EB. Intensity modulated radiation therapy (IMRT): a new promising technology in radiation oncology. The Oncologist 1999;4:433–442.[Abstract/Free Full Text]
  38. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–1346.[CrossRef][Medline]
  39. Zagars GK, Pollack A, Kavadi VS et al. Prostate-specific antigen and radiation therapy for clinically localized prostate cancer: an update and review of the MD Anderson experience. Int J Radiat Oncol Biol Phys 1995;32:293–306.[Medline]
  40. Zietman AL, Coen JJ, Shipley WU et al. Radical radiation therapy in the management of prostatic adenocarcinoma: the initial prostate specific antigen value as a predictor of treatment outcome. J Urol 1994;151:640–645.[Medline]
  41. Ayala G, Wheeler TM, Shalev M et al. Cytopathic effect of in situ gene therapy in prostate cancer. Hum Pathol 2000;31:866–870.[CrossRef][Medline]
Received January 31, 2002; accepted for publication June 21, 2002.




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