Thomas1

Question 1

Bicalutamide, Nilutamide, Flutamide, Cyproterone

Answer 1

• Bicalutamide, Nilutamide and Flutamide are nonsteroidal AR(androgen receptor) antagonists that inhibit ligand binding to the AR and blocks the translocation of the AR from the cytoplasm to the nucleus.
• Flutamide causes diarrhea, nausea and liver abnormalities.
• Nilutamide has less diarrhea than flutamide. Bicalutamide has few side effects.
• Cyproterone is a steroid that has partial agonist as well as antagonist activity towards AR. It is orally administered as the cyproterone acetate.

Question 2

Mitoxanthrone, Docetaxel

Answer 2

• Progression to hormone-refractory or castration-resistant prostate cancer is the primary mechanism of resistance to hormone therapy, which also includes surgical removal of the testes or orchiectomy.
• To overcome this resistance, mitoxanthrone (doxorubicin analog with less cardiotoxicity) is sometimes used with prednisone.
• Docetaxel (antagonizes microtubule spindle disassembly) has significant activity. Tox- short-lived severe neutropenia.

Question 3

Intravesicular Tx of bladder Cancer: Bacillus Calmette-Guerin, mitomycin, thiotepa, valcrubicin

Answer 3

• Treatment of bladder cancer. Prolonged survival in most patients with superficial-stage, low grade bladder cancers is achieved by transurethral resection (TUR) with intravesical therapy to prevent relapse. For intravesical therapy a Foley catheter into bladder infused with 40-60 ml of one of these agents, clamped for 2 hours.
• Bacillus Calmette-Guerin (BCG) is attenuated, live Bacillus Calmette and Guerin mycobacterium bovis that stimulates the immune system. Bacillus Calmette‐Guerin (BCG) is also a widely used tuberculosis vaccine. Once in the bladder, the live organisms enter macrophages, where they induce the same type of histologic and immunologic reaction as found in patients with tuberculosis. BCG has been shown to have a predilection for entering bladder cancer cells, where the proteins are broken down and fragments are combined with histocompatibility antigens and displayed on the cell surface. This induces a cytokine and direct cell-to-cell cytotoxicity response, which targets these cells for destruction. Intravesical BCG therapy is usually given once per week for 6 weeks.
• Thiotepa is activated by a CYP450 to form an alkylator that forms DNA cross-links. It is absorbed systemically to some extent to cause occasional myelosuppression.
• Mitomycin (alkylator) is not absorbed much, no myelo.
• Valrubicin (not in SG, G&G or Skeel) is a semi-synthetic analog of doxorubicin, used exclusively for intravesicular treatment of BCG-resistant bladder cancer.

Question 4

Advanced bladder cancer Tx-Methotrexate, vinblastine, doxorubicin, cisplatin, carboplatin, paclitaxel, gemcitabine, ipilimumab

Answer 4

The standard treatment of patients with invasive, deep-stage, high grade bladder cancers is radical cystectomy and urinary diversion. Other treatment approaches include TUR and segmental resection with or without radiation therapy or combined chemotherapy-radiation therapy.

• Advanced and metastatic bladder cancer is treated systemically with MVAC (MTX, vinblastine, Doxorubicin, cisplatin). Renal damage by cisplatin prevented by hydration/saline diuresis.
• Carboplatin (less renal tox) in combination with paclitaxel are used for patients with renal dysfunction. Gemcitabine with cisplatin or carboplatin.
• The immune checkpoint inhibitor, ipilimumab, is a recent treatment for advanced BC.

Question 5

Renal Cell Carcinoma Tx-IL-2

Answer 5

• Localized RCC is treated by partial nephrectomy. Metastatic renal cell carcinoma (RCC) can be treated with Interleukin-2.
• IL-2 is a cytokine signaling protein in the immune system. -Human recombinant interleukin-2 (Aldesleukin, Proleukin) differs from native IL-2 in that it is not glycosylated, has no amino terminal alanine, and has a serine substituted for the cysteine at amino acid 125. These modifications greatly increase the plasma half-life.
• This cytokine acts as a cancer chemotherapy agent by enhancement of lymphocyte proliferation and growth of IL-2–dependent cell lines: lymphocyte-mediated cytotoxicity (Cytotoxic T lymphocytes) and lymphokine-activated killer (LAK) cell activity (NK cells).
• The toxicities of IL-2 are likely related to the activation and expansion of cytotoxic lymphocytes in organs and within vessels, resulting in inflammation and capillary leak.
• IL-2 causes hypotension, arrhythmias, peripheral edema, prerenal azotemia, elevated liver transaminases, anemia, thrombocytopenia, nausea, vomiting, diarrhea, confusion, and fever.
• IL-2 is used to treat patients with renal cell carcinoma and melanoma that are refractory to conventional treatment. Historical treatment was by vinblastine, medroxyprogesterone and tamoxifen with a response rate of

Question 6

Newer Tx forRenal Cell Carcinoma-Sunitinib, Sorafenib, Pazopanib

Answer 6

• Sunitinib- oral inhibitor of the binding of ATP to the intrinsic TK domain on VEGFR-2; also inhibitor of multiple receptor tyrosine kinases (RTKs), including Platelet-derived growth factor receptor (PDGF-R), c-KIT (GIST), other TKs. This inhibits growth of tumors with dysregulated RTKs plus inhibits angiogenesis. Resistance: RTK mutations.
• Sorafenib- oral inhibitor of multiple VEGFR-1,2,3 and other tyrosine kinases within tumor cells to reduce proliferation and angiogenesis.
• Pazopanib inhibits the tyrosine kinase activity of VEGFR-2. Tox of all- bleeding, hypertension, proteinuria, thromboembolism, intestinal perforation, myelosuppression (all dose-dependent).

Question 7

Bevacizumab

Answer 7

Bevacizumab (Avastin) is a humanized mAb against VEGF that inhibits its interaction with VEGF receptors. VEGF is angiogenic, so Bevacizumab inhibits angiogenesis in tumors.

• Used to treat NSCLC, colon, renal and breast cancer (FDA just dropped approval for breast cancer).
• Toxicities include hemorrhage, severe hypertension, proteinurea, congestive HF, and gastric perforation (dose-dependent). Infusion reactions uncommon.

Question 8

Temsirolimus and everolimus

Answer 8

Temsirolimus and everolimus - mTOR forms the mTORC1 complex with a member of the FK506-binding protein family, FKBP12.

• Among other actions, mTORC1 phosphorylates S6 kinase and also relieves the inhibitory effect of 4EBP on initiation factor elf-4E, therby promoting protein synthesis and metabolism. The antitumor actions of the rapamycins result from their binding to FKBP12 and inhibition of mTORC1.
• Sirolimus, Temsirolimus (metabolized to sirolimus) or everolimus (oral) (rapamycins) have immunosuppressant effects, inhibit cell-cycle progression and angiogenesis, and promote apoptosis.
• They are used to treat RCC, liver cancer and mantle cell lymphomas as well as for post-transplant immunosuppression.
• Resistance to mTOR inhibitors may arise through the action of a second mTOR complex, mTORC2, which is unaffected by rapamycins.
• Tox- mild maculopapular rash, mucositis, anemia, and fatigue, each occurring in 30-50% of patients. A minority of patients will develop leukopenia or thrombocytopenia. Some drug interactions due Cyt P450 inhibition.