Antiangiogenesis....is it always an effective strategy in treating cancer?

Antiangiogenic agents probably help control cancer growth by inhibiting blood vessel proliferation....but, are such agents counter-productive in conjunction with chemotherapeutic agents?

  ABSTRACT

Tumor growth depends on angiogenesis---the recruitment of new blood vessels. Antiangiogenic agents inhibit blood vessel growth to cancer cells and thus arrest mitosis (cell growth), or hopefully, cause apoptosis (cell death). Thus, the myriad antiangiogenic agents in development, trial, and practice to inhibit vascular development are desirable to control our cancer. But is this a desirable aspect of prostate cancer (PCa) control once we embark on chemotherapy treatment protocols?

Chemotherapy agents are not cancer-specific and we infuse them into a vein with the objective of using our vascular system to distribute them to our cancer. But, if we are seeking antiangiogenesis with one treatment agent, are we restricting blood flow to the cancer and thus, negating/restricting the ability of the chemo agent to reach/permeate our cancer cells?

Should we attempt to maximized antiangiogenesis during non-chemo treatments, but stop all such efforts once we embark on chemotherapy protocols?

DISCUSSION

Some of our clinical attempts at antiangiogenesis are....

1) COX-2 inhibitors suppress angiogenesis and tumor growth (1) and should be used in the prevention and treatment of a broad range of cancers (2).

2) Thalidomide inhibits angiogenesis (3)--- there were 14 reported thalidomide abstracts in ASCO 2001, and 26 in ASCO 2002; all with marginal results and reporting significant side-effects. An interesting report is ASCO 2002 # 730 wherein daily thalidomide was combined with weekly (3/4) Taxotere vs. weekly single agent Taxotere; the response rate (RR) was 37% with single agent Taxotere and 51% with the combination; conclusion: an antiangiogenesis inhibitor may enhance the activity of cytotoxic agents----but, there were only 75 patients in the combined arms, and weekly single agent Taxotere normally has a RR of 50% (4) without the added toxicity/adverse events of thalidomide. A large trial of this combination is currently being recruited across the United States. For what purpose? does this make any sense?

3) Frequent low-dose chemotherapy produces an antiangiogenic effect and starves the cancer into apoptosis (5, 6, 7). While frequent low-dose chemotherapy seems to possibly be both cytotoxic and antiangiogenic, dosing schedules are certainly not defined to accomplish both tasks. While many reports refer to frequent low-dose chemotherapy as ‘metronomic dosing’, Folkman distinguishes between ‘metronomic dosing’ and ‘antiangiogenic chemotherapy’; the former being simply a schedule of regular intervals of administration of chemotherapeutic agents, while ‘antiangiogenic chemotherapy’ signifies that the target of the chemotherapy is the microvascular endothelium in the tumor bed. (19) Since medical science is still trying to determine the antiangiogenic dosing for each chemotherapeutic agent, all we have in clinical practice is metronomic dosing (we don’t know what we are targeting?).

I elected weekly single agent Taxotere because of its reported antiangiogenic and cytotoxic results; and at the same time I began daily 200 mg Celebrex bid (2 X/day) for its antiangiogenic/anti-inflammatory properties (7). I continued this protocol for 2 years, dropping the Celebrex only last month. Assuming each aspect of my treatment protocol was effective-- combined, did I render each considerably less effective?

We can assume that existing tumors have established a vascular support system and angiogenetic agents/protocols do not affect them...

Many established tumors already have poorly formed blood vascular systems with variable rates of blood flow and much larger intercapillary distances than those found in normal tissue (8); poor blood supply and poorly vascularized regions of established tumors result in problems in delivering cytotoxic drugs to the cancers (9); drug delivery to established tumors depends on distribution through vascular space, transport across microvessel walls, diffusion through interstitial space (spaces within a tissue), and tumor density (10); anticancer drugs have limited ability to penetrate tumor tissue and achieve a lethal concentration in all of the cells, especially those that are distant from blood vessels (11). Therefore, there are significant barriers to delivering cytotoxic agents to established cancers and the inherent vascular problems therein force the tumor to constantly strive for additional blood vascular systems. By utilizing antiangiogenic agents with chemotherapy, are we compromising the ability to deliver cytotoxic drugs to established tumors?

Even if we can transport chemo agents to the cancer, as stated above there are significant barriers to overcome to effect mitotic arrest and apoptosis....and, once the chemo agent (Taxol) is present in the cell, it is unclear whether mitotic arrest correlates with apoptotic cell death or growth delay (12) and Taxotere, even when present in the tumor/cell, is a potent inducer of mitotic arrest, but a weak inducer of apoptosis (13). My point is that we must deliver a maximum dose of chemo agents to existing tumors and cells that are dividing. Can we accomplish this if we inhibit (with antiangiogenic agents) the very vascular system we require to transport the chemo agent to the cancer? I am told by a respected medical oncologist that the two TXs (antiangiogenesis and chemo) are complementary; attack the cancer from two aspects-- but, I have difficulty reconciling inhibiting the vascular system which is used to transport cytotoxic drugs to our cancer.

Moreover, it is to our advantage to assure maximum transport of chemo agents to the cancer...high tumor cell density is a barrier to Taxol penetration and the apoptotic effect enhances its penetration in solid tumors (14); limited penetration of Taxol into solid tumors may limit its therapeutic efficacy, but Taxol enhances its own delivery to tumors by inducing apoptosis and the resultant tumor density; proper TX scheduling allows Taxol to tunnel its own way into tumors as it is confined to the periphery until apoptosis at that location, followed by penetration of the next layer (15); the increase in vessel induced by the taxanes suggests that they improve tumor response by increasing the vascular surface area for delivery of therapeutic agents (16). My question: in view of the above evidence that delivery of optimum chemo agents to the cancer via our vascular system is required for mitotic arrest and apoptosis, does it make sense to inhibit the transport system by antiangiogenesis?

If we treat our cancer with both antiangiogenic and chemotherapeutic agents concurrently...are we exacerbating the side-effects of both? Prolonged use of any chemotherepeutic agent(s) will certainly induce peripheral neuropathy; and prolonged use of the available antiangiogenic agents will likewise induce peripheral neuropathy, and possibly deep vein thromboses. (See http://www.prostate-help.org/caperneu.htm by clicking on BA - Peripheral Neuropathy and Chemotherapy for a discussion of peripheral neuropathy induced by chemotherapy.) If we combine antiagiogenic and chemotherapeutic agents, we logically multiply the side-effects arithmetically, and perhaps exponentially.

What are we attacking with common cytotoxic agents?...

1) the taxanes (Taxotere and Taxol) are cell-cycle-specific agents that stabilize and inhibit cell growth and division by binding to tubulin, stabilize microtubules and suppress cellular division (17, 18); the taxanes (and other vinca alkaloids; Navelbine and Velban) must be present on mitosis and cell division and they must be delivered to the cell by our vascular system---if we have inhibited the cell’s ability to develop a blood supply, have we not also denied the chemotherapy delivery system to the cell and to the established tumor that spawned the dividing cell? Assume that antiangiogenic agents will block development of a vascular system to the cell that is dividing, it will also inhibit the required chemotherapy transport to the established tumor as well as the dividing cell.

2) Adriamycin and VP-16 affect cells by effecting single- and double-strand DNA breaks during cell division; again, if we have inhibited the blood system development to the cell with antiangiogenic agents, we have also denied chemotherapy transport to the established cancer as well as the dividing cell.

SUMMARY

Most of us agree with the premise that antiangiogenesis is a viable TX to treat our disease and delay progression. But, once we enter chemotherapy protocols, does it make sense to continue to inhibit blood vessel growth and thus, restrict the delivery system required to transport the cytotoxic agents to the cancer?

ASCO 2002 abstract # 730 reported that single agent thalidomide @ 200 mg/day had a RR of 18%; and daily thalidomide @ 200 mg + weekly (3/4) Taxotere @ 30 mg/m2 = RR of 51% and concludes that the addition of antiangiogenesis inhibitors may enhance the activity of cytotoxic agents; and, a major study is recruiting for the next phase of this protocol.

But, weekly single agent Taxotere has a RR of 47% (4). Is the trial or TX worth the significant additive side-effects of thalidomide (peripheral neuropathy, blood clots, etc.)? And, again, does it make sense to inhibit the vascular delivery system of cytotoxic agents when it is obvious that we require maximum chemo agent presence in existing tumors and dividing cells?

This issue was obliquely approached in a recent Folkman J et al. complicated paper addressing future trends and clinical needs for experimental antiangiogenic agents. Folkman states that chemotherapy is angiogenesis dependent (blood flow is required as a transport system); in vitro experimental antiangiogenetic agents actually increase tumor blood flow and oxygen delivery and thus, increase delivery of the cytotoxic agent; but, continued antiangiogenic agent use resulted in first, a steady blood flow, followed by a rapidly decreasing blood flow. (19) But the Folkman discussion is based on experimental antiangiogenic agents and does not address the few antiangiogenic agents available to us in current clinical practice.

For those of us in late-stage disease and searching for salvage therapy, I question whether active attempts at antiangiogenesis with available agents/protocols and concurrently attacking our cancer with cytotoxic chemotherapy are contraindicated?

Bill Aishman October 2002 blaishman@worldnet.att.net

NOTE---I am not a doctor; nor am I a medical researcher. I am an Oklahoma Redneck unemployed prostate cancer patient in late-stage disease and I can not offer medical advice. I performed this analysis for my own edification and treatment decision process. I make no claim that this analysis is complete or definitive. Every cancer patient must participate with their medical team to determine their disease status and treatments therefor. I invite any and all constructive critique of this analysis that might render it more thought-provoking for our fellow PCa patients.

REFERENCES

(1) Sawaoka H, et al.; Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo; Lab Invest 1999 Dec;79(12):1469-77---and, see www.cooleyville.com/cancer/cansaid1.htm

(2) Kalgutkar AS & Zhao Z; Discovery and design of selective cyclooxygenase-2 inhibitors as non-ulcerogenic, anti-inflamatory drugs with potential utility as anti-cancer agents; Curr Drug Targets 2001 Mar;2(1):79-106.

(3) Li Z, et al.; Phase II Study of Thalidomide for Patients with Metastatic Renal Cell Carcinoma (MRCC) Progressing After Interleukin-2 (Il-2)-Based Therapy (RX); ASCO 2001 # 717.

(4) Beer TM, et al.;Phase II Study of Weekly Docetaxel (Taxotere) in Hormone Reafctory Prostate Cancer; ASCO 2000, # 1368.

(5) Hortobagyi G; Recent progress in the Clinical Development of Docetaxel (Taxotere); Semin Oncol, Vol. 26,No. 3, Suppl 9(Jun), 1999:32-36.

(6) Belotti, et al.; The microtubule-affecting drug pacitaxel has antiangiogenic activity; Clin Cancer Res, 1996 Nov.;2(11):1843-9.

(7) See Part 1, Chemotherapy for Hormone refactory Prostate Cancer; www.cooleyville.com/cancer/cachrpc.htm

(8) Tungaal JK, et al.; Penetration of anticancer drugs through solid tissue: a factor that limits the effectiveness of chemotherapy for solid tumors; Clin Cancer Res 1999 Jun;5(6):1583-6.

(9) Phillips RM, et al.; Evaluation of a novel in vitro assay for assessing drug penetration into avascular regions of tumors; Br J Cancer 1998 Jun;77(12):2112-9.

(10) Au JL, et al.; Determinants of drug delivery and transport to solid tumors; J control Release 2001 Jul 6;74(1-3):31-46.

(11) Tannock IF, et al.; Limited penetration of anticancer drugs through tumor tissue: a potential cause of resistance of solid tumors to chemotherapy; Clin Cancer Res 2002 Mar;8(3):878-84.

(12) Milross CG, et al.; Relarionship of mititic arrest and apoptosis to antitumor effect of paclitaxel; J Natl Cancer Inst 1996 Sep 18;88(18):1308-14.

(13) Schimming R, et al.; Lack of correlation between mititic arrest or apoptosis and antitumor effect of docetaxel; Cancer chemother Pharmacol 1999;43(2):165-72.

(14) Kuh HJ, et al.; Determinants of paclitaxel penetration and accumulation in human solid tumor; J Pharmacol Exp Ther 1999 Aug;290(2):871-80.

(15) Jang SH, et al.; Ehanncement of paclitaxel delivery to solid tumors by apoptosis-inducing pretreatment: effect of treatment schedule; J Pharmacol Exp Ther 2001 Mar;296(3):1035-42.

(16) Griffon-Etienne G, et al.; Taxane-induced apoptosis decompresses blood vessels and lowers interstitial pressure in solid tumors: clinical implications; Cancer Res 1999 Aug 1;59(15):3776-82.

(17) Chan OT & Yang LX; The immunological effects of taxanes; Cancer Immunol Immunother 2000 Jul;49(4-5):181-5.

(18) Stein CA; Mechanisms of taxanes in prostate Cancer; Semin Oncol 1999 Oct;26(5 Suppl 17):3-7.

(19) Kerbel R & Folkman J; Clinical Translation of Antiangiogenesis Inhibitors; Nature Reviews/Cancer; Vol. 2, October 2002; pp. 727-739.