Chemotherapy for hormone-refractory prostate cancer

Shelley, Mike; Harrison, Craig; Coles, Bernadette; Stafforth, John; Wilt, Timothy J; Mason, Malcolm David

doi:10.1002/14651858.cd005247.pub2

Cited by 77 publications

(69 citation statements)

References 104 publications

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“…The standard management for metastatic prostate cancer is hormone ablation therapy by medical castration with LH-RH agonists with or without antiandrogens [14]. In many cases, at this stage of prostate cancer, it is frequently hormone refractory.…”

Section: Resultsmentioning

confidence: 99%

HPMA Copolymer-Conjugated Pirarubicin in Multimodal Treatment of a Patient with Stage IV Prostate Cancer and Extensive Lung and Bone Metastases

et al. 2015

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Nanomedicine allows achievement of tumor-selective drug delivery because of the enhanced permeability and retention (EPR) effect of solid tumors. We report here the first clinical application of a new agent-HPMA copolymer-conjugated pirarubicin (P-THP)-with a molecular size of about 8 nm, or 38.5 kDa. A patient had advanced prostate cancer with multiple metastases in the lung, pelvis, femur, and perhaps the sacrum. In April 2013, this 60-year-old patient started treatment with leuprorelin and estradiol, which continued until July 2014, but the patient became refractory to this treatment. So the patient underwent proton beam radiotherapy targeted to the primary prostate cancer, and P-THP was administered for numerous metastatic tumor nodules concomitantly with radiotherapy. This combination therapy had remarkable results, with complete remission of multiple metastases in the lung and bone. The prostate-specific antigen (PSA) value was decreased from about 1000 ng/mL on April 30, 2013, to about 100 ng/mL on June 24, 2013, with hormone therapy, but rose again to 964.2 ng/mL and then to 1472 ng/mL in July 2013, during leuprorelin administration. P-THP treatment administered concomitantly with proton beam irradiation was started in August 2013. The PSA value was decreased to 102 ng/mL on August 26, 2013, and then to 0.971 ng/mL on October 8, 2013, and 0.277 ng/mL on January 15, 2015. The P-THP doses ranged from 30 to 75 mg of free THP equivalent/patient every 2-3 weeks without signs of serious toxicity, such as cardiovascular side effects or a reduction in quality of life. No evidence of relapse was found more than 20 months after P-THP administration. This case demonstrates the value of hydrazone-bonded polymeric drugs in multimodal therapy.

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Section: Resultsmentioning

confidence: 99%

HPMA Copolymer-Conjugated Pirarubicin in Multimodal Treatment of a Patient with Stage IV Prostate Cancer and Extensive Lung and Bone Metastases

et al. 2015

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“…According to the current medical guidelines, antimitotic chemotherapy with docetaxel is typically recommended. However, the overall benefit for the patient is typically poor because of the reported side effects and rather short time to progression, with a reported improvement in overall survival of less than 2.5 mo (23).…”

Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer

et al. 2015

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Despite many advances in the past years, the treatment of metastatic prostate cancer still remains challenging. In recent years, prostate-specific membrane antigen (PSMA) inhibitors were intensively studied to develop low-molecular-weight ligands for imaging prostate cancer lesions by PET or SPECT. However, the endoradiotherapeutic use of these compounds requires optimization with regard to the radionuclide-chelating agent and the linker moiety between chelator and pharmacophore, which influence the overall pharmacokinetic properties of the resulting radioligand. In an effort to realize both detection and optimal treatment of prostate cancer, a tailor-made novel naphthyl-containing DOTA-conjugated PSMA inhibitor has been developed. Methods: The peptidomimetic structure was synthesized by solid-phase peptide chemistry and characterized using reversedphase high-performance liquid chromatography and matrix-assisted laser desorption/ionization mass spectrometry. Subsequent 67/68 Ga and 177 Lu labeling resulted in radiochemical yields of greater than 97% or greater than 99%, respectively. Competitive binding and internalization experiments were performed using the PSMA-positive LNCaP cell line. The in vivo biodistribution and dynamic small-animal PET imaging studies were investigated in BALB/c nu/nu mice bearing LNCaP xenografts. Results: The chemically modified PSMA inhibitor PSMA-617 demonstrated high radiolytic stability for at least 72 h. A high inhibition potency (equilibrium dissociation constant [K i ] 5 2.34 ± 2.94 nM on LNCaP; K i 5 0.37 ± 0.21 nM enzymatically determined) and highly efficient internalization into LNCaP cells were demonstrated. The small-animal PET measurements showed high tumor-tobackground contrasts as early as 1 h after injection. Organ distribution revealed specific uptake in LNCaP tumors and in the kidneys 1 h after injection. With regard to therapeutic use, the compound exhibited a rapid clearance from the kidneys from 113.3 ± 24.4 at 1 h to 2.13 ± 1.36 percentage injected dose per gram at 24 h. The favorable pharmacokinetics of the molecule led to tumor-to-background ratios of 1,058 (tumor to blood) and 529 (tumor to muscle), respectively, 24 h after injection. Conclusion: The tailor-made DOTA-conjugated PSMA inhibitor PSMA-617 presented here is sustainably refined and advanced with respect to its tumor-targeting and pharmacokinetic properties by systematic chemical modification of the linker region. Therefore, this radiotracer is suitable for a first-in-human theranostic application and may help to improve the clinical management of prostate cancer in the future.

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“…Cytotoxic agents that act in S-phase are more diverse and include agents that crosslink DNA (cyclophosphamide, cisplatin), antimetabolites [5-flurouracil (5-FU), methotrexate], and topoisomerase I and II inhibitors (camptothecin, doxorubicin, etoposide). 87 Although the influence of AR on S-phase associated cytotoxics has yet to be fully elucidated, pre-clinical studies have provided early insight as to the role of active AR on their efficacy. For example, high levels of androgen induce resistance to etoposide-induced apoptosis in cultured prostate cancer cells.…”

Section: Ar Activity and Other Cell Cycle Based Therapeuticsmentioning

confidence: 99%

The Complex Role of AR Signaling After Cytotoxic Insult: Implications for Cell Cycle Based Chemotherapeutics

Comstock¹,

Knudsen²

2007

Cell Cycle

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Chemotherapy for hormone-refractory prostate cancer

Cited by 77 publications

References 104 publications

HPMA Copolymer-Conjugated Pirarubicin in Multimodal Treatment of a Patient with Stage IV Prostate Cancer and Extensive Lung and Bone Metastases

HPMA Copolymer-Conjugated Pirarubicin in Multimodal Treatment of a Patient with Stage IV Prostate Cancer and Extensive Lung and Bone Metastases

Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer

The Complex Role of AR Signaling After Cytotoxic Insult: Implications for Cell Cycle Based Chemotherapeutics

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