pirarubicin and Prostatic-Neoplasms

The circadian timing of surgery, anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, tumor control, and host survival. Optimally timed cancer chemotherapy with doxorubicin or pirarubicin (06:00h) and cisplatin (18:00h) enhanced the control of advanced ovarian cancer while minimizing side effects, and increased the response rate in metastatic endometrial cancer. Therapy of metastatic bladder cancer with doxorubicin-cisplatin was made more tolerable by this same circadian approach resulting in a 57% objective response rate. This optimally timed therapy is also effective in the adjuvant setting, decreasing the expected frequency of metastasis from locally advanced bladder cancer. Circadian fluorodeoxyuridine (FUDR) continuous infusion (70% of the daily dose given between 15:00h and 21:00h) has been shown effective for metastatic renal cell carcinoma resulting in 29% objective response and stable disease of more than 1 yr duration in the majority of patients. Toxicity is reduced markedly when FUDR infusion is modulated to circadian rhythms. In a multicenter trial in patients with metastatic renal cell cancer, patients were randomized to a flat or a circadian-modified FUDR infusion. This study confirmed a significant difference in toxicity and dose intensity, favoring the circadian-modified group. Hormone refractory metastatic prostate cancer has been treated with circadian-timed FUDR chemotherapy; however, without objective response. Biological agents such as interferon-alpha and IL-2 have shown low but effective disease control in metastatic renal cell cancer, however, with much toxicity. Each of these cytokines shows circadian stage dependent toxicity and efficacy in model systems. In summary, the timing of anthracycline, platinum, and fluoropyrimidine-based drug therapies during the 24h is relevant to the toxic therapeutic ratio of these agents in the treatment of gynecologic and genitourinary cancers.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Cycle; Chronotherapy; Circadian Rhythm; Cisplatin; Doxorubicin; Endometrial Neoplasms; Female; Floxuridine; Genital Neoplasms, Female; Humans; Kidney Neoplasms; Male; Ovarian Neoplasms; Prostatic Neoplasms; Rats; Urinary Bladder Neoplasms; Urogenital Neoplasms

Forty-five patients with muscle-invasive bladder cancer treated with intra-arterial doxorubicin chemotherapy plus low-dose radiotherapy between September 1979 and March 1990 were retrospectively studied. Twenty-eight (62%) patients achieved a complete response (CR) and in all of them, a functional bladder could be preserved. The 10-year cause-specific survival rate of patients with CR was 95.5%, but that of patients not achieving a CR was 39%. These results demonstrate that in patients who achieve a CR with this treatment, we may be able to preserve a functional bladder. In a prospective study, we designed a new intra-arterial chemotherapy regimen in order to achieve a higher degree of effectiveness and to preserve a functional bladder. Twenty-three patients were treated with concurrent pirarubicin/cisplatin intra-arterial chemotherapy and radiotherapy after complete transurethral resection. Twenty-one (91%) patients achieved CR. One of these patients had relapse with lung metastases and was treated surgically. Two patients who did not achieve a CR died of cancer, and 21 patients are alive with preservation of functional bladder. For treatment of prostate cancer, we now administer only adjuvant intra-arterial chemotherapy plus irradiation for patients after radical prostatectomy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Doxorubicin; Drug Administration Schedule; Female; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Retrospective Studies; Urinary Bladder Neoplasms

A total of 20 patients with hormone-refractory prostate carcinoma entered a pilot study of combination chemotherapy based on the EAP (etoposide, Adriamycin and cisplatin) regimen, in which Adriamycin was replaced by pirarubicin, a less cardiotoxic derivative of Adriamycin. The response was assessed by criteria modified from those of the National Prostatic Cancer Project: prostate-specific antigen was employed instead of acid phosphatase. Of 18 evaluable patients, 6 achieved a partial response, 5 had stable disease, and in 7 the disease had progressed during therapy; thus, the overall response rate was 33.3% [95% confidence interval (CI) 11.5-55.1%]. Significant pain alleviation and performance status improvement were obtained in 5 of 12 patients (41.7%; CI 13.8-69.6%) and 3 of 13 patients (23.1%; CI 0.2-46.0%), respectively. Although myelosuppression was moderate to severe, no chemotherapy-related deaths or bacteriologically documented sepsis occurred; nor was there any clinical cardiotoxicity. All the responding patients received maintenance chemotherapy with etoposide thereafter. At present, the median duration of response is 33 weeks (range: 23-91 weeks) and the median survival period for all patients is 42 weeks (range: 27(+)-136 weeks), with 12 deaths. In spite of the small number of patients treated, these results suggest that this chemotherapy regimen is active in advanced hormone-refractory prostate carcinoma.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Doxorubicin; Drug Resistance; Estrogens; Etoposide; Gonadotropin-Releasing Hormone; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Orchiectomy; Prostatic Neoplasms; Treatment Outcome

Twenty one patients with hormone resistant prostate cancer were entered in a phase II study of pirarubicin 70 mg/m2, as a single intravenous injection given at 21 day intervals. All patients had leukopenia (9 severe or life threatening) and 2 died of septicemia. Thrombocytopenia occurred in 5 patients (one life threatening) and anemia in 12 patients. One partial response of 3 months duration was documented. Pirarubicin 70 mg/m2 given intravenously at 21 day intervals causes severe hematological toxicity and has minimal therapeutic activity in patients with hormone resistant prostate cancer.

Topics: Aged; Antibiotics, Antineoplastic; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Drug Resistance; Humans; Injections, Intravenous; Male; Middle Aged; Prostatic Neoplasms; Treatment Outcome

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.

Topics: Antineoplastic Agents; Bone Neoplasms; Combined Modality Therapy; Doxorubicin; Drug Delivery Systems; Humans; Lung Neoplasms; Male; Methacrylates; Middle Aged; Neoplasm Staging; Prognosis; Prostatic Neoplasms

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cells. The anthracycline doxorubicin (DOX) can sensitize several types of cancer cells to TRAIL-mediated apoptosis. Here we report that DOX enhances TRAIL-induced apoptosis and cytotoxicity against prostate cancer cells. Cytotoxicity was determined by a MTT assay. Synergistic effect was assessed by isobolographic analysis. Caspase activity was determined by a quantitative colorimetric assay. The combination treatment with DOX and TRAIL resulted in a synergistic cytotoxic effect on LNCaP, LNCaP-Bcl-2, PC-3, and PC93 human prostate cancer cell lines, but not on normal human prostatic stromal cells. Synergistic cytotoxicity was also obtained even when the exposure time was shortened from 24 to 8 or 2 h. A similar effect was achieved with TRAIL in combination with epirubicin, pirarubicin, or amrubicin. The synergy obtained in cytotoxicity with TRAIL and DOX was also achieved in apoptosis. DOX treatment significantly activated caspase-8, -6, and -3 in LNCaP cells. Furthermore, the synergistic cytotoxicity of TRAIL and DOX was completely inhibited by Z-VAD-FMK, and partly inhibited by Ac-IETD-CHO, Ac-DQTD-CHO, or Ac-DMQD-CHO. These findings indicate that DOX enhances TRAIL-induced apoptosis and cytotoxicity in prostate cancer by activation of caspase cascades, and suggest that TRAIL in combination with DOX have a therapeutic potential in the treatment of prostate cancer.

Topics: Acridine Orange; Anthracyclines; Antibiotics, Antineoplastic; Apoptosis; Apoptosis Regulatory Proteins; Caspase 3; Caspase 6; Caspase 8; Caspase 9; Caspases; Coloring Agents; Dose-Response Relationship, Drug; Doxorubicin; Epirubicin; Humans; Immunohistochemistry; Male; Membrane Glycoproteins; Prostatic Neoplasms; Recombinant Proteins; Tetrazolium Salts; Thiazoles; Time Factors; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Eleven patients with prostate cancer were treated by intra-arterial infusion chemotherapy and radiotherapy combined with hormone therapy. CDDP was given one patient, THP and CDDP to eight patients, and THP and CBDCA to two others. All patients were treated by whole pelvis with prostate boost radiation. Seven patients underwent castration and four were administered LH-RH agonist in hormone therapy. Clinically, CR was observed in two patients and PR in nine. Histologically, G3 was observed in six patients, G2 in four patients and G1 in one. The main side effects were myelosuppression and rectal disturbances, but treatment could be completed in all patients. These results suggest that this treatment is a useful regimen for prostate cancer.

Topics: Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Combined Modality Therapy; Doxorubicin; Drug Administration Schedule; Gonadotropin-Releasing Hormone; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Orchiectomy; Prognosis; Prostatic Neoplasms; Radiotherapy Dosage

Eight patients with bladder cancer and two patients with prostate cancer were given intra-arterial infusion chemotherapy using the reservoir system. The tip of the catheter was inserted through the femoral artery to the common iliac artery and we compressed both femoral arteries during infusion. Five patients with locally advanced bladder cancer and two patients with prostate cancer were evaluated for the clinical and pathological efficacy of the treatment. Clinically, the efficacy of four of the five patients with bladder cancer was CR or PR and pathologically (according to Shimosato's criteria), the efficacy was two in IVb or III, and three in IIb. Clinically, the efficacy in two patients with prostate cancer was CR or PR, and pathologically the efficacy was IVb or IIb. Three patients had complications of the reservoir system. These results suggest that good therapeutic efficacy and an improved quality of life can be obtained by intra-arterial chemotherapy using the reservoir system.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Doxorubicin; Epirubicin; Etoposide; Female; Humans; Infusion Pumps; Infusions, Intra-Arterial; Male; Middle Aged; Prognosis; Prostatic Neoplasms; Urinary Bladder Neoplasms